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Kadziauskienė, Aistė, Ernesta Strelkauskaitė, Eglė Mockevičiūtė, Rimvydas Ašoklis, Eugenijus Lesinskas, and Leopold Schmetterer. "Changes in macular thickness after trabeculectomy with or without adjunctive 5-fluorouracil." Acta medica Lituanica 24, no. 2 (July 17, 2017): 93–100. http://dx.doi.org/10.6001/actamedica.v24i2.3489.
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Conflict of interest. None of the authors have any conflict of interest to declare, financial or otherwise. No financial or other support was received for the study. Background. The aim of the study was to assess changes in macular thickness after trabeculectomy in respect to the use of 5-fluorouracil (5-FU) as well as to analyse possible associations between the postoperative changes in macular thickness and intraocular pressure (IOP). Materials and methods. The prospective observational study included 106 eyes (100 patients) with glaucoma who underwent trabeculectomy with or without 5-FU. Subsequently 5-FU needling was performed if failure of the filtrating bleb occurred. Macular thickness and the IOP were evaluated before, one week, and six months after the surgery. The mean and sectoral macular thickness was assessed using spectral domain optical coherence tomography. Results. The mean (±SD) IOP reduced from 27.71 (±6.88) mmHg at baseline to 18.3 (±8.1) mmHg one week (p
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Engelman, Dan, Michel Moreau, Antonia Lepida, Yasmine Zaouak, Marianne Paesmans, and Ahmad Awada. "Metastatic breast cancer and pseudocirrhosis: an unknown clinical entity." ESMO Open 5, no. 3 (June 2020): e000695. http://dx.doi.org/10.1136/esmoopen-2020-000695.
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PurposePseudocirrhosis is a radiological term used to describe rapid changes in the contour of liver invaded by metastases and treated with chemotherapy. Our primary objectives were to analyse the clinical and biological characteristics of those patients with breast cancer and to assess the prevalence of complications generally associated with decompensated cirrhosis. We have also assessed associated treatments and response.MethodsThis retrospective study included all women with metastatic breast cancer to the liver who had imaging protocols describing diffuse liver contour abnormalities during systemic treatment between 2003 and 2018 in our centre. The following were identified: neoplastic characteristics, complications presented, treatments administered and response.Results48 patients were included. There was a trend towards an increased proportion of luminal cancers (88.2%, n=30, p=0052) when compared with our hospital cancer registry. Most patients (97.9%, n=47) had a widespread liver invasion, 58.3% (n=28) had ascites on physical examination; 90% (n=18) of ascites were classified as transudate. Nearly 23% (n=11) of patients had oesophageal varices and 6.5% (n=3) had an episode of variceal rupture. At the time of the appearance of liver contour abnormalities, the most frequently used molecules were: 5-fluorouracil (22.9%; n=11) and cisplatin (18.8%; n=9). A partial response was observed in 52.1% (n=25) of patients.ConclusionThis is the largest reported series of patients with pseudocirrhosis. Many patients developed complications related to portal hypertension and liver failure, similar to those observed in decompensated cirrhosis. Luminal subtypes could be over-represented. In our series, pseudocirrhosis appears to develop at the expense of extensive liver disease burden and most often under 5-fluorouracil, or its derivatives, with or without cisplatin, possibly following a response to treatment.
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Thomas, Ritty Ann, and Vasim Ismail Patel. "A comparative analysis between intralesional 5-fluorouracil versus surgical excision with intralesional triamcinalone acetonide in keloid excision." International Journal of Otorhinolaryngology and Head and Neck Surgery 6, no. 5 (April 21, 2020): 904. http://dx.doi.org/10.18203/issn.2454-5929.ijohns20201684.
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<p class="abstract"><strong>Background:</strong> Keloids are characterized by an uncontrolled proliferation of fibrous tissue after injury of the skin and has been treated by various modalities. Recently, newer therapeutic modalities have been studied including intralesional 5-FU, verapamil, laser therapy, cryotherapy, silicone sheet dressings, irradiation, retinoids, tacrolimus, imiquimod and combination therapy. The aim of this study is to analyse the response of intralesional 5-FU alone with that of intralesional triamcinolone acetonide with surgical excision thus to provide the best possible treatment modality to patients.</p><p class="abstract"><strong>Methods:</strong> Sixteen patients having keloid in head and neck region were taken into the study and divided into two groups after a routine blood check-up. Group A intralesional 5-FU once in three weeks for six sessions. Group B surgical excision followed by intralesional triamcinalone acetonide once weekly for six sessions. Patients were followed up for one year. </p><p class="abstract"><strong>Results:</strong> In group A, 7 patients came for review regularly. Aesthetic improvement was excellent for 6 but was considerably painful for all. In group B, 8 patients came for regular review, 6 had minimal scarring and all patients complained of mild pain post operatively.</p><p><strong>Conclusions:</strong> Intralesional 5-FU can be a very effective treatment modality for keloids, with no recurrence noted, except for its poor tolerability owing to side effects such as pain, nausea and vomiting. Classical method of surgical excision followed by intralesional steroids is better tolerated but has higher recurrence rates. </p>
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Zhang, Cong, Hongpeng Liu, Bin Ma, Yongxi Song, Peng Gao, Yingying Xu, Dehao Yu, and Zhenning Wang. "The Impact of the Expression Level of Intratumoral Dihydropyrimidine Dehydrogenase on Chemotherapy Sensitivity and Survival of Patients in Gastric Cancer: A Meta-Analysis." Disease Markers 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/9202676.
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The potential impact that the intratumoral expression level of dihydropyrimidine dehydrogenase (DPD) has on chemotherapy sensitivity and long-term survival for gastric cancer (GC) patients remains controversial; therefore, this study seeks to clarify this issue. Our meta-analysis was performed using Review Manager (RevMan) 5.3 software. In vitro drug sensitivity tests, correlation coefficients between sensitivity to 5-fluorouracil (5-FU), and expression levels of intratumoral DPD were used as effective indexes to analyse. Overall survival (OS) and progression-free survival (PFS) were used as endpoints for patient outcome, and hazard ratios (HRs) and 95% confidence intervals (CIs) were noted as measures of effect. There were 15 eligible studies including 1805 patients for the final analysis. The analysis revealed a statistically significant difference between the expression level of intratumoral DPD activity, DPD mRNA levels, and sensitivity to 5-FU in GC patients, with high expression levels of intratumoral DPD resulting in low sensitivity to 5-FU. However, no matter what therapeutic regimens were used, there was no significant difference for patient outcomes between high and low DPD expression groups, either in OS or in PFS. In conclusion, high levels of intratumoral DPD expression have a negative impact on sensitivity to 5-FU in GC patients, but no prognostic value for long-term survival was uncovered.
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Izyumov, Mikhail Sergeevich, Viktor Viktorovich Bulynin, Andrey Mikhailovich Bobrovskih, and Olga Gennadevna Deryaeva. "Comparative Assessment of Morphological Changes in the Pleura and Lung Tissue after Pleurodesis with Various Solutions in the Experiment." Journal of Experimental and Clinical Surgery 15, no. 2 (June 24, 2022): 147–53. http://dx.doi.org/10.18499/2070-478x-2022-15-2-147-153.
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Introduction. Currently, spontaneous pneumothorax occurs in 6,2-7,1% of patients with nonspecific lung diseases. There has been a steady increase in prevalence of this disease. The relevance of preventing recurrence of spontaneous pneumothorax is still beyond doubt. Most authors recommend performing chemical pleurodesis when nonspecific spontaneous pneumothorax occurs, especially if it is recurrent. At the present time, the issue of choosing the optimal chemical agent for performing pleurodesis remains important.The aim of the study was to analyse the nature and severity of the inflammatory reaction from the lungs, pleura and adjacent subpleural tissues of the chest wall in experimental animals during chemical pleurodesis with 4% sodium bicarbonate, 6% hydrogen peroxide and 5-fluorouracil solutions.Materials and methods. The experiment was conducted at the experimental laboratory of Voronezh Regional Clinical Hospital № 1. The study involved 200 experimental rats (WISTAR type) with simulated spontaneous pneumothorax; after a fixed time, one of the preparations was sprayed into the pleural cavity. All animals were divided into 3 groups depending on the method of pleurodesis (5-fluorouracil solution, 4% sodium bicarbonate solution and 6% hydrogen peroxide solution) and control (0,9% sodium chloride solution). Groups of animals were withdrawn from the experiment in accordance with the rules of humane treatment of animals in 3, 5, 7, 10, 30 days with sampling of organs and tissues of the chest for histological examination to compare severity of inflammatory reactions in the pleura and adjacent areas of the lungs depending on the drug used for pleurodesis. The main criterion for assessing the comparative effectiveness of chemical agents was the morphological picture of inflammation presented by counting free cell populations (lymphocytes, macrophages, neutrophils, histiocytes) in the pleura and adjacent areas of the lung tissue of the studied animals.Quantitative results were statistically processed using parametric and nonparametric methods with STATISTICA 10. The main statistical parameters of the studied data were estimated by the methods of descriptive statistics. Comparison of the studied samples was conducted with the Kruskal-Wallis test. Differences between the compared samples were considered significant at p0,05.Results. The morphology of the inflammatory reaction in the pleura and adjacent lung tissue in all the studied groups of animals was characterized by the predominance of neutrophils over other cells in the first days of the experiment; the fact supporting acute aseptic inflammation in response to drug administration. Further, the content of lymphocytes, macrophages and their inactive forms (histiocytes) increased, and the content of neutrophils decreased, which was typical for the transition of acute inflammation to chronic. Compared dynamics in the number of analyzed immunocompetent cells evidenced that the number of lymphocytes, macrophages and histiocytes increased faster. After pleurodesis with a 6% hydrogen peroxide solution, the lowest content of immunocompetent cells in the studied tissue samples was noted if compared with the samples obtained from other groups in the same period. In all cases, pleurodesis with 6% hydrogen peroxide resulted in the minimal number of neutrophils, and the dynamics of their decrease was the most pronounced. In the control group, the number of studied cells fluctuated within the average value for this group.Conclusion. The dynamics in the number of studied cell populations in all comparison groups was assessed as common. The method of pleurodesis significantly affects the number of cellular elements involved in the inflammatory response. Clinical outcomes of pleurodesis performed with a 6% hydrogen peroxide solution are characterized by a shorter duration and severity of the inflammatory response from the pleura and adjacent parts of the chest wall, compared with 5-fluorouracil and 4% sodium bicarbonate solutions.
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Mohan, Ambikavathy, and Chandan Kumar. "Clinical profile and management of breast cancer in women in a rural based tertiary care hospital our experience." International Surgery Journal 4, no. 2 (January 25, 2017): 697. http://dx.doi.org/10.18203/2349-2902.isj20170216.
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Background: Breast cancer is the second most common cancer among women in India and accounts for 7% of global burden of breast cancer and one-fifth of all cancers among women in India. The risk factors are related to lifestyle, early menarche, nulli parity, prolonged use of oral contraceptive pills, hormone replacement therapy, not breast‑feeding, alcohol, obesity, lack of exercise, and induced abortion. A woman who attains menopause after fifty five years of age has an increased risk of ovarian, breast, and uterine cancers. The risk is greater if a woman also began menstruating before twelve years of age. A longer exposure to estrogen increases a woman’s risk of breast cancers.Methods: This is a prospective observational study, conducted in the department of surgery, between December 2013 and June 2015(2 years). Patients diagnosed as breast carcinoma and admitted in surgical wards were included, Data pertaining to demography, clinical and pathological tumor profile, and treatment details were collected prospectively for each patient based on patient interviews and medical records. To analyse the Prevalence of breast cancer, clinical presentation, risk factors, diagnostic methods, treatment protocols, difference between pre and post‑menopausal breast cancer women regarding risk factors, assess the impact of treatment given and women’s knowledge about breast cancer.Results: A total number of 25 cases of breast carcinoma based on detailed history, clinical examination, Trucut biopsy, ultrasonography breast and axilla, ultrasound abdomen, mammogram and chest x-ray were analysed. All of them received three cycles of anterior chemotherapy consisting of 5- Fluorouracil 500 mg/m2,Adriamycin 50 mg/m2 Cyclophosphamide 80 mg/m2 (FAC regimen) administered intravenously followed by modified radical mastectomy. There were no recurrences seen on follow up till date.Conclusions: Late stage at presentation of breast cancer is a challenge to the health care providers. Cancer awareness programmes, multidisciplinary approach and evidence‑based strategies for early detection and effective management of the disease can go a long way in prevention.
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Simon, Ole, Georg Beyer, Ujjwal Mahajan, and Julia Mayerle. "Pankreaskarzinom 2018 – reif für personalisierte Therapiekonzepte?" TumorDiagnostik & Therapie 40, no. 03 (April 2019): 180–83. http://dx.doi.org/10.1055/a-0870-8867.
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Zusammenfassung Epidemiologie Die 5-Jahres-Überlebensrate (5-JÜR) aller Pankreaskarzinompatienten liegt mit rund 6 % sehr niedrig und die potenziell kurative Operation ist nur bei 15 – 20 % der Erkrankten möglich. Durch häufigeren Einsatz und Kombination systemischer Chemotherapeutika konnte in den letzten Jahren eine verbesserte Lebenserwartung erreicht werden. Resektables Stadium Nach vollständiger operativer Resektion eines Pankreaskarzinoms trägt eine adjuvante Chemotherapie zur Verlängerung des Gesamtüberlebens bei. Mittel der Wahl sind Gemcitabin oder 5-Fluorouracil (5-FU) und Folinsäure (FS). Kürzlich konnte für die Kombination aus Gemcitabin und Capecitabin (Gem-Cap) eine signifikante Verlängerung des Gesamtüberlebens im Vergleich zur Gemcitabin-Monotherapie gezeigt werden. Für den Einsatz einer adjuvanten Radiochemotherapie gibt es derzeit keine Empfehlung. Borderline-resektables Stadium Eine neoadjuvante Therapie hat bei Pankreaskarzinomen außerhalb klinischer Studien keinen Stellenwert. Eine Ausnahme stellen borderline-resektable Pankreaskarzinome dar. Fortgeschrittenes Stadium (M1) Patienten mit fortgeschrittenem oder metastasiertem Pankreaskarzinom profitieren von einer Chemotherapie. Für Patienten mit gutem ECOG-Status konnte kürzlich in 2 Phase-III-Studien eine signifikante Lebenszeitverlängerung durch die Kombination aus Gemcitabin plus nab-Paclitaxel (Gem-Nab) sowie durch das Kombinationsschema aus Folinsäure, 5-FU, Irinotecan und Oxaliplatin (FOLFIRINOX) gezeigt werden. In der Zweitlinie steht nanoliposomales Irinotecan oder Oxaliplatin kombiniert mit 5FU/FS (OFF) zur Verfügung. Personalisierte Therapien Die molekulare Charakterisierung des Pankreaskarzinoms hat Fortschritte gemacht und bietet schon heute Ansätze zur personalisierten Medizin. Bei gutem ECOG-Status sollte vor Zweitlinientherapie eine MSI-H/dMMR-Analyse erfolgen, um den möglichen Einsatz einer Checkpoint-Inhibitor-Therapie zu evaluieren. Bei BRCA-Mutationen kann die Gabe von PARP-Inhibitoren vielversprechend sein.
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Chen, Xiaorong, Weibing Leng, YuWen Zhou, Yongyang Yu, Wenjian Meng, Peng Cao, Ziqiang Wang, and Meng Qiu. "Pathological response and safety of FOLFOXIRI for neoadjuvant treatment of high-risk relapsed locally advanced colon cancer: study protocol for a single-arm, open-label phase II trial." BMJ Open 13, no. 1 (January 2023): e062659. http://dx.doi.org/10.1136/bmjopen-2022-062659.
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IntroductionNeoadjuvant chemotherapy (NAC) has been demonstrated effective in several tumours, but its benefit has not yet been elucidated in colorectal cancer, especially locally advanced colorectal cancer (LACRC).Methods and analysisThis is a single-arm, open-label, prospective phase II exploratory clinical trial. Patients with LACRC will receive four cycles of NAC with 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI), followed by operation and then adjuvant chemotherapy with capecitabine and oxaliplatin for two to five cycles or single-agent capecitabine for five cycles, or observation. The primary endpoint is the rate of tumour regression grade (TRG) 0–2 in the resected tumour tissue, which is evaluated by experienced pathologists according to the Ryan R TRG grading system. Secondary endpoints include objective response rate, pathologic complete response, microscopically complete resection rate, progression-free survival, distant metastasis-free survival, overall survival, toxicity and compliance to study treatment, molecular markers, quality of life to study treatment and the number of patients with 30-day postoperative mortality. The objective of this study is to analyse the efficacy and safety of FOLFOXIRI as the NAC regimen in patients with LACRC and to identify a promising treatment strategy in this setting.Ethics and disseminationWritten informed consent will be required from and provided by all patients enrolled. The study protocol has been approved by the independent ethics committee of West China Hospital, Sichuan University (approval number: 2021403). This study will demonstrate the potential benefit of NAC with the FOLFOXIRI regimen. Results will be shared with policymakers and the academic community to promote the clinical management of colon cancer.Trial registration numberNCT05018182.
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Raj, Ben, and Madhan Shankar S. R. "Analysis Of Anticancer Activity And Its Molecular Interaction Mechanism Of Withanone, An Active Ingredient Of Withania Somnifera Using Molecular Docking." International Journal of pharma and Bio Sciences 11, no. 6 (November 30, 2021): 35–41. http://dx.doi.org/10.22376/ijpbs/lpr.2021.11.6.l35-41.
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Withania somnifera is an annual evergreen shrub from the Solanaceae family, commonly known as Indian ginseng or Ashwagandha. The plant is mainly found in Asia and Africa regions. In the traditional Indian medicinal system ayurveda, Withania somnifera is used as a rejuvenator and sold in many countries as a dietary supplement. Withanolides are the major phytochemical constituent group found in the Withania somnifera, among which withaferin A and withanone, are considered to be major withanolides, which believed to be involved in majority of biological activity of Withania somnifera. Various studies including both in vitro and in vivo have reported regarding the anticancer potential of Withania somnifera. Along with the anticancer activity of W.somnifera, the anticancer efficacy of one of its major ingredients Withaferin A is also studied previously. This study aimed to analyse the anticancer potential of another major Withanolide present in W. Somnifera, Withanone. The study used Molecular Docking method to find the molecular binding affinity of Withanone towards various cancer proteins. The four major cancer proteins were B-cell lymphoma- extra large (Bcl-xL), Cellular FLICE (c-FLIP), Glutathione Reductase (GR) and Glutathione S- Transferases (GST). The protein structure obtained from the protein data bank and the structure of the molecule obtained from pubchem were modified and prepared for Docking studies with the help of MGL Tools. The protein ligand interaction study was conducted using the software, Autodock vina. The already known anticancer standard, 5-FluoroUracil is used as standard for comparison. Output obtained from the study is visualised using molecular visualiser tool, Pymol. Like the Withaferin A, Withanone also exhibited promising anticancer activity while studied using molecular docking methods.
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Ortega-García, María Belén, Alberto Mesa, Elisa L. J. Moya, Beatriz Rueda, Gabriel Lopez-Ordoño, Javier Ángel García, Verónica Conde, et al. "Uncovering Tumour Heterogeneity through PKR and nc886 Analysis in Metastatic Colon Cancer Patients Treated with 5-FU-Based Chemotherapy." Cancers 12, no. 2 (February 7, 2020): 379. http://dx.doi.org/10.3390/cancers12020379.
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Colorectal cancer treatment has advanced over the past decade. The drug 5-fluorouracil is still used with a wide percentage of patients who do not respond. Therefore, a challenge is the identification of predictive biomarkers. The protein kinase R (PKR also called EIF2AK2) and its regulator, the non-coding pre-mir-nc886, have multiple effects on cells in response to numerous types of stress, including chemotherapy. In this work, we performed an ambispective study with 197 metastatic colon cancer patients with unresectable metastases to determine the relative expression levels of both nc886 and PKR by qPCR, as well as the location of PKR by immunohistochemistry in tumour samples and healthy tissues (plasma and colon epithelium). As primary end point, the expression levels were related to the objective response to first-line chemotherapy following the response evaluation criteria in solid tumours (RECIST) and, as the second end point, with survival at 18 and 36 months. Hierarchical agglomerative clustering was performed to accommodate the heterogeneity and complexity of oncological patients’ data. High expression levels of nc886 were related to the response to treatment and allowed to identify clusters of patients. Although the PKR mRNA expression was not associated with chemotherapy response, the absence of PKR location in the nucleolus was correlated with first-line chemotherapy response. Moreover, a relationship between survival and the expression of both PKR and nc886 in healthy tissues was found. Therefore, this work evaluated the best way to analyse the potential biomarkers PKR and nc886 in order to establish clusters of patients depending on the cancer outcomes using algorithms for complex and heterogeneous data.
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Simon, Ole, Georg Beyer, Ujjwal Mahajan, and Julia Mayerle. "Pankreaskarzinom 2018 – reif für personalisierte Therapiekonzepte?" DMW - Deutsche Medizinische Wochenschrift 143, no. 15 (July 30, 2018): 1109–12. http://dx.doi.org/10.1055/a-0542-4310.
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Was ist neu? Epidemiologie In Deutschland werden im Jahr 2018 schätzungsweise 19 000 Menschen an einem Pankreaskarzinom erkranken. Die 5-Jahres-Überlebensrate (5-JÜR) aller Pankreaskarzinompatienten liegt mit rund 6 % sehr niedrig und die potenziell kurative Operation ist nur bei 15 – 20 % der Erkrankten möglich. Durch häufigeren Einsatz und Kombination systemischer Chemotherapeutika konnte in den letzten Jahren eine verbesserte Lebenserwartung erreicht werden. Resektables Stadium Nach vollständiger operativer Resektion eines Pankreaskarzinoms trägt eine adjuvante Chemotherapie zur Verlängerung des Gesamtüberlebens bei. Mittel der Wahl sind Gemcitabin oder 5-Fluorouracil (5-FU) und Folinsäure (FS). Kürzlich konnte für die Kombination aus Gemcitabin und Capecitabin (Gem-Cap) eine signifikante Verlängerung des Gesamtüberlebens im Vergleich zur Gemcitabin-Monotherapie gezeigt werden. Für den Einsatz einer adjuvanten Radiochemotherapie gibt es derzeit keine Empfehlung. Borderline-resektables Stadium Eine neoadjuvante Therapie hat bei Pankreaskarzinomen außerhalb klinischer Studien keinen Stellenwert. Eine Ausnahme stellen borderline-resektable Pankreaskarzinome dar. Fortgeschrittenes Stadium (M1) Patienten mit fortgeschrittenem oder metastasiertem Pankreaskarzinom profitieren von einer Chemotherapie. Für Patienten mit gutem ECOG-Status konnte kürzlich in 2 Phase-III-Studien eine signifikante Lebenszeitverlängerung durch die Kombination aus Gemcitabin plus nab-Paclitaxel (Gem-Nab) sowie durch das Kombinationsschema aus Folinsäure, 5-FU, Irinotecan und Oxaliplatin (FOLFIRINOX) gezeigt werden. In der Zweitlinie steht nanoliposomales Irinotecan oder Oxaliplatin kombiniert mit 5FU/FS (OFF) zur Verfügung. Personalisierte Therapien Die molekulare Charakterisierung des Pankreaskarzinoms hat Fortschritte gemacht und bietet schon heute Ansätze zur personalisierten Medizin. Bei gutem ECOG-Status sollte vor Zweitlinientherapie eine MSI-H/dMMR-Analyse erfolgen, um den möglichen Einsatz einer Checkpoint-Inhibitor-Therapie zu evaluieren. Bei BRCA-Mutationen kann die Gabe von PARP-Inhibitoren vielversprechend sein.
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Blaschke, Martina, Silke Cameron, Jutta Blumberg, Ulrike Wegner, and Giuliano Ramadori. "Measurements of 5-FU levels in plasma of patients with gastrointestinal cancer." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 437. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.437.
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437 Background: 5-fluorouracil (5-FU) 50 years after its first introduction into therapy of gastrointestinal tumors is still one of the most effective anticancer drugs. Due to large interindividual metabolism optimal dosing has not yet been established. As 5-FU is mostly used in combination with other drugs elevated serum levels could be responsible for severe side effects. The aim of this study was to analyse intra- and interindividual variability of 5-FU levels in patients with 5-FU infusional therapy. Methods: 230 blood samples were obtained from 31 gastrointestinal cancer patients (esophagus (8), stomach (10), ileum (1), colorectum (12)) treated with 5-FU-infusional regimens, based on a 24 or 48 hour AIO treatment schedule. 5-FU was delivered using a Baxter pump. Intra- and interindividual differences in 5-FU plasma concentrations were analysed before (0h; n=115), at 2-3 hours after start of infusional 5-FU treatment (n=19) (early sampling) and towards the end of the infusion (n=96) (late sampling). 5-FU plasma concentrations were measured using an immunolinked Elisa assay (Saladax 5-FU PCM). Results: Early blood sampling resulted in lower 5-FU plasma concentrations (541±126,9 ng/ml) due to NaCl prefilling (4,5 ml) of the 5-FU tubing, as the Baxter pump delivers 4ml/h. Blood sampling at the later time-point resulted in reliable values (971±81,1 ng/ml). 5-FU concentrations did increase with elevated 5-FU doses. Measurements of 5-FU plasma concentrations lead to reproducible results. 5-FU concentrations were dose-dependent with low intra- and interindividual variability. However, care has to be taken, as the results can be influenced by inaccurate blood sampling (e.g at the port), early blood sampling (steady state-levels not reached), too late sampling (folfusor-pump already empty, i.e. in summer with elevated temperature), delayed centrifugation or hemolysis. Critical analysis of the measurements and correct performance of the sampling is therefore necessary. Conclusions: Measurement of 5-FU plasma concentrations may in the future allow to optimize the 5-FU dosing and to identify the cause of toxicity. Changes of 5-FU clearance in long-term therapy have to be studied.
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Roth, Susanne, Christoph Springfeld, Markus K. Diener, Christine Tjaden, Phillip Knebel, Ulla Klaiber, Christoph W. Michalski, et al. "Protocol of a prospective, monocentric phase I/II feasibility study investigating the safety of multimodality treatment with a combination of intraoperative chemotherapy and surgical resection in locally confined or borderline resectable pancreatic cancer: the combiCaRe study." BMJ Open 9, no. 8 (August 2019): e028696. http://dx.doi.org/10.1136/bmjopen-2018-028696.
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IntroductionPancreatic cancer is a devastating disease with an exceptionally poor prognosis. Complete resection of the primary tumour followed by adjuvant chemotherapy is the current standard treatment for patients with resectable disease and the only curative treatment option. However, long-term survival remains rare. Tumour cell dissemination due to manipulation during surgery may increase the rate of future metastases and local recurrence, and perioperative chemotherapy might diminish local, distant and circulating minimal residual disease. Yet, safety and feasibility of systemic chemotherapeutic treatments during pancreatic cancer resection have to be evaluated in a first instance.Methods and analysisThis is a prospective, single-centre phase I/II feasibility study to investigate the safety and tolerability of a combination of intraoperative chemotherapy and surgical resection in pancreatic cancer. Forty patients with locally confined or borderline resectable pancreatic cancer, meeting all proposed criteria will be included. Participants will receive 400 mg/m2 calcium folinate over 2 hours and 2000 mg/m2 5-fluorouracil over 48 hours, started on the day before pancreatic surgery and thus continuing during surgery. Participants will be followed until 60 days after surgery. The primary endpoint is the 30-day overall complication rate according to the Clavien-Dindo classification. Secondary endpoints comprise toxicity and treatment associated complications. Patients receiving perioperative chemotherapy will be compared with a propensity score matched contemporary control group of 70 patients with pancreatic cancer receiving the standard treatment. This trial also contains an ancillary translational study to analyse disseminated tumour cells and effects of pharmacological interventions in pancreatic cancer.Ethics and disseminationCombiCaRe has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4042787) and the Medical Ethics Committee of Heidelberg University (reference number AFmo-269/2018). The results of this trial will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberGerman Clinical Trials Register (DRKS00015766).
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Mathews, Sunil, Asha T. Jose, Varun Gangwar, Arumugam S. Vadivu, and Raghu Nandhan. "Judicious management of pinna keloids: our experience with combination therapy." International Journal of Otorhinolaryngology and Head and Neck Surgery 8, no. 9 (August 25, 2022): 729. http://dx.doi.org/10.18203/issn.2454-5929.ijohns20222164.
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<p class="abstract"><strong>Background:</strong> Keloids occur as a result of overgrowth of fibrous tissue following healing of a cutaneous injury and they cause aesthetic issues when they appear on the exposed parts of the body, especially the face. Keloids are difficult to treat, with a high recurrence rate. There are several treatment modalities for management of keloids, though no single modality is completely effective. Most commonly used treatment modalities are intra-lesional steroids, surgical excision, pressure application, silicone gel sheets, 5-fluorouracil (5-FU), cryotherapy, radiation therapy, laser therapy or a combination of these modalities. The aim of the study was to analyse the causes of development of keloids on the pinna and evaluated the outcomes of various treatment modalities applied. It focused on assessing the clinical efficacy of combined surgical excision of pinna keloids with serial steroid injections to prevent recurrence, in comparison to monotherapy with intra-lesional steroid injections alone.</p><p class="abstract"><strong>Methods:</strong> A retrospective review based on medical records was done for 18 patients with keloid of pinna, who were treated with either monotherapy or combination therapy. </p><p class="abstract"><strong>Results:</strong> Satisfactory low recurrence rates were observed with meticulous surgical excision followed by serial steroid injections (18.2%), as compared to monotherapy with serial steroid injections alone (71.4%), and these comparative results were statistically significant at p<0.05 in the cohort.</p><p class="abstract"><strong>Conclusions:</strong> A judicious plan for management for pinna keloids is necessary in order to achieve the best functional and cosmetic outcomes, while reducing the recurrence rates to a minimum. Following a combination of interventions has proved safe and effective for managing this challenging entity.</p>
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Ibrahim, T., P. Serra, B. Vertogen, M. Marangolo, and D. Amadori. "Doxorubicin (Dox), cyclophosphamide (Cyc) and weekly docetaxel (Doc) as first-line treatment of advanced breast cancer (ABC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 11516. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.11516.
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11516 Background: The breast is one of the leading cancer sites in women. ABC is essentially incurable with standard therapy and have a median survival of approximately 2 years. Dox, Cyc and Doc showed better efficacy results but also an increased rate of neutropenia and febrile neutropenia with respect to FAC (which is considered one of the most used standard option). The substitution of 5- fluorouracil with docetaxel resulted in an increase in the efficacy parameters but showed a higher hematological toxicity. One possible approach to reduce the rate of neutropenia is the administration of weekly docetaxel wich demostrated efficacy in ABC. Methods: ABC patients (pts) were enrolled in an open, single arm, non-randomized phase I escalation trial in 3 to 6 pts/cohorts. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity.*The treatment schedule was: Doc 20 mg/m2 (or 25, depending on dose level assignment) on day 1, 8, 15; Dox 40 mg/m2 (or 50, depending on dose level assignment) and Cyc 500 mg/m2 on day 1, every four weeks. Results: Eleven pts, median age 56 yrs, were enrolled. Five pts were allocated to dose level 20/50 (Doc/Dox) and six pts to dose level 20/40. At the dose level 20/50 febrile neutropenia (DLT) occurred in 2 pts. Other 3 pts experienced neutropenia WHO grade 4 (not DLT). Six patients were allocated at previous dose level and MTD was defined at Doc 20 mg/m2 in combination with Dox 40 mg/m2 and Cyc 500 mg/m2 Conclusions: We didn’t observe toxic deaths and all the toxicity was limited and resolved. The accrual was stopped and we are waiting for one patient to end the treatment in order to analyse the final data and to design the phase II study a the dose Doc 20 mg/m2 (days 1, 8 and 15) in combination with Dox 40 mg/m2 and Cyc 500 mg/m2 (day 1) every 4 weeks. No significant financial relationships to disclose.
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Stanford, William L., Nicole M. Anderson, Mark D. Minden, and Dwayne L. Barber. "Induction of Transient Cytopenia To Analyze Hematopoiesis in Mutant Mice." Blood 106, no. 11 (November 16, 2005): 3158. http://dx.doi.org/10.1182/blood.v106.11.3158.3158.
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Abstract The mouse plays an indispensable role in developing our current understanding of mammalian hematopoiesis. Most hematopoietic phenotyping assays in the mouse are non-viable techniques designed to evaluate homeostatic populations, enumerate progenitor populations, and perform functional analysis. The worldwide effort to generate mouse models of human disease and functionally annotate the mammalian genome using mouse mutagenesis (including dominant ENU screens) requires the development of robust standardized viable phenotyping tools. We have developed a phenotyping assay that induces transient cytopenias using various pharmacological agents (5-fluorouracil, phenylhydrazine, and hydroxyurea), the responses to which are monitored by tracing changes in peripheral blood levels of red blood cells, white blood cells and platelets. We have performed detailed analysis of lineage recovery kinetics, developing lineage recovery curves for various strains of mice for both males and females, which allowed us to identify appropriate testing days to identify phenodeviants. We have compared the recovery data with conventional progenitor assays and analyzed a cohort of well-studied naturally occurring and targeted hematopoietic mutants using the transient anemia assays that has yielded novel phenotypes of hemizygous mutant animals. For example, erythropoietin receptor null embryos die of severe anemia at mid-gestation; however, no defect in erythropoiesis has been reported in EpoR +/− mice. We have found that 5-fluorouracil and phenylhydrazine elicit delayed RBC recovery in EpoR +/− mice, demonstrating a critical dose-dependent role for the erythropoietin receptor in stress erythropoiesis. In addition, Stat5 has been shown to play an important role in erythropoiesis and in the regulation of steady state hematopoiesis. We have found that Stat5a/b+/− mice treated with 5-fluorouracil show altered recovery kinetics in RBC, WBC and platelets. Finally, we have adapted the transient cytopenia assay to develop a sensitized dominant ENU screen, enabling us to identify hematopoietic mutants that do not present abnormal blood cell counts in a homeostatic state. Thus, these standardized cytopenia response assays function as surrogate viable assays to analyze progenitor populations.
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Yan, Xiaowei, Maolin Hu, Qian Miao, Shun Wang, and Kejian Zhao. "The Synthesis and Anticancer Activities of Peptide 5-fluorouracil Derivatives." Journal of Chemical Research 2009, no. 4 (April 2009): 261–64. http://dx.doi.org/10.3184/030823409x431364.
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A new series of peptide 5-fluorouracil derivatives was designed and synthesised in order to test in vitro anticancer activities. The results indicated that peptide 5-fluorouracil derivatives possessed anticancer activities against human HL-60 and Bel-7402 cell lines. The structures of the compounds were determined by means of 1H NMR, 13C NMR, IR, mass spectra and elemental analyses.
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Goncharova, A. S., A. V. Galina, D. V. Khodakova, G. Yu Egorov, A. Yu Maksimov, E. N. Kolesnikov, E. F. Komarova, et al. "Inhibition of growth of colorectal cancer patient-derived subcutaneous xenografts using combined Wnt signaling pathway inhibitor and 5‑fluorouracil." Research and Practical Medicine Journal 9, no. 1 (February 18, 2022): 33–42. http://dx.doi.org/10.17709/2410-1893-2022-9-1-3.
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Purpose of the study. Was to analyze antitumor efficacy of the XAV 939 Wnt signaling pathway inhibitor and its combination with 5 fluorouracil in subcutaneous xenografts derived from patients with colorectal cancer.Materials and methods. Antitumor efficacy of the agents and their combination was studied in xenografts derived from patients with colorectal cancer and subcutaneously implanted in immunodeficient Balb/c Nude mice. All animals with tumors were divided into 4 groups (n = 5): group 1 received 5 fluorouracil 25 mg/kg, group 2 – XAV 939 25 mg/kg, group 3–5 fluorouracil and XAV 939 combination at the same dosages, group 4 was control. Criteria for the efficacy of the tested agents and their combination included tumor growth rate and tumor growth inhibition rate (TGI %).Results. The mean volumes of xenografts and tumor growth rate in the group receiving a combination of 5 fluorouracil and XAV 939 were 335.2 ± 40.7 mm3 , being lower than the averages of xenografts in controls – 609.3 ± 69.5 mm3 (p < 0.05). The mean volumes of xenografts in the group receiving 5 fluorouracil monotherapy were 601.9 ± 45.5 mm3 , in the group with the XAV 939 monotherapy – 527.9 ± 258.6 mm3 . The highest TGI (44.99 %) was registered in the group receiving a combination of 5 fluorouracil and XAV 939.Conclusion. The study revealed the ability of combined XAV 939 Wnt signaling pathway inhibitor and 5 fluorouracil to inhibit the growth of subcutaneous xenografts derived from patients with colorectal cancer.
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Minchev, Velko T. "Toxic and Adverse Effects of Chemotherapy with 5-Fluoropyrimidine Drugs. Could Dihydropyrimidine Dehydrogenase Enzyme Screening Serve as a Prerequisite to Successful Chemotherapy?" Journal of Biomedical and Clinical Research 13, no. 2 (December 1, 2020): 87–99. http://dx.doi.org/10.2478/jbcr-2020-0013.
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Summary The article presents a detailed survey of recent publications in the literature concerning clinical expertise, existing guidelines, and differing opinions on Fluoropyrimidine chemotherapy-related toxicity and the implication of Dihydropyrimidine dehydrogenase (DPD) screening aiming to prevent severe 5-Fluorouracil-induced adverse drug reactions. The first section provides information on the mechanism of action, clinical application, pharmacokinetics and pharmacodynamics, and toxicity and adverse reactions of 5-Fluorouracil, Capecitabine, Floxuridine, and Flucytosine. The second section summarizes DPD phenol- and genotype data and provides reasons for determining a DPD life-threatening complete or partial enzyme deficiency. The pros and cons of the methodological approaches for DPD screening are analysed, and recommendations are made to introduce them into clinical practice. The third section includes a brief economic analysis of expenses for DPD screening of patients scheduled for 5-Fluorouracil chemotherapy. The costs are compared to those related to the treatment of patients suffering from 5-Fluorouracil-induced toxicity and unwanted adverse effects.
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Grabenbauer, Alexander, Thomas Aigner, Holger Göbel, Bernhard J. Leibl, Christof Lamberti, Gerhard G. Grabenbauer, and Luitpold V. Distel. "Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under “Real World“ Conditions?" Cells 12, no. 3 (January 22, 2023): 399. http://dx.doi.org/10.3390/cells12030399.
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This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients’ characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471–0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245–4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.
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Zhu, Ping, Jingping Zhang, Jianfei Zhu, Jun Shi, Qiuwei Zhu, and Yuanyuan Gao. "MiR-429 Induces Gastric Carcinoma Cell Apoptosis Through Bcl-2." Cellular Physiology and Biochemistry 37, no. 4 (2015): 1572–80. http://dx.doi.org/10.1159/000438524.
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Background/Aims: MicroRNAs (miRNAs) play an essential role in the tumorigenesis of gastric carcinoma (GC). MiR-429 has been recently reported to inhibit GC growth, but the underlying mechanisms are not clear. Methods: Here, we studied the levels of miR-429 and anti-apoptotic protein Bcl-2 in GC specimens. We performed bioinformatics analyses and used luciferase-reporter assay to analyze the relationship between miR-429 and Bcl-2 in GC cells. Cell survival upon Fluorouracil treatment was analyzed in a CCK assay. Cell apoptosis was measured by flow cytometry based FITC Annexin V apoptosis detection assay. Results: MiR-429 levels were significantly decreased and Bcl-2 levels were significantly increased in GC specimens, compared to the paired adjacent non-tumor gastric tissue. Moreover, the levels of miR-429 and Bcl-2 inversely correlated in GC specimens. MiR-429-low subjects had an overall inferior survival, compared to miR-429-high subjects. Bioinformatics analyses showed that miR-429 targeted the 3'-UTR of Bcl-2 mRNA to inhibit its translation, which was confirmed by luciferase-reporter assay. Overexpression of miR-429 inhibited Bcl-2-mediated cell survival against apoptosis induced by Fluorouracil, while depletion of miR-429 augmented it. Conclusion: Our data suggest that miR-429 suppression in GC promotes Bcl-2-mediated cancer cell survival against chemotherapy-induced cell death. Re-expression of miR-429 levels in GC cells may enhance cancer apoptosis during chemotherapy.
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Fekete, János Tibor, and Balázs Győrffy. "New Transcriptomic Biomarkers of 5-Fluorouracil Resistance." International Journal of Molecular Sciences 24, no. 2 (January 12, 2023): 1508. http://dx.doi.org/10.3390/ijms24021508.
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The overall response rate to fluoropyrimidine monotherapy in colorectal cancer (CRC) is limited. Transcriptomic datasets of CRC patients treated with 5-fluorouracil (5FU) could assist in the identification of clinically useful biomarkers. In this research, we aimed to analyze transcriptomic cohorts of 5FU-treated cell lines to uncover new predictive biomarker candidates and to validate the strongest hits in 5FU-treated human colorectal cancer samples with available clinical response data. We utilized an in vitro dataset of cancer cell lines treated with 5FU and used the reported area under the dose–response curve values to determine the therapeutic response to 5FU treatment. Mann–Whitney and ROC analyses were performed to identify significant genes. The strongest genes were combined into a single signature using a random forest classifier. The compound 5-fluorouracil was tested in 592 cell lines (294 nonresponders and 298 responders). The validation cohort consisted of 157 patient samples with 5FU monotherapy from three datasets. The three strongest associations with treatment outcome were observed in SHISA4 (AUC = 0.745, p-value = 5.5 × 10−25), SLC38A6 (AUC = 0.725, p-value = 3.1 × 10−21), and LAPTM4A (AUC = 0.723, p-value = 6.4 × 10−21). A random forest model utilizing the top genes reached an AUC value of 0.74 for predicting therapeutic sensitivity. The model correctly identified 83% of the nonresponder and 73% of the responder patients. The cell line cohort is available and the entire human colorectal cohort have been added to the ROCPlot analysis platform. Here, by using in vitro and in vivo data, we present a framework enabling the ranking of future biomarker candidates of 5FU resistance. A future option is to conduct an independent validation of the established predictors of resistance.
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Ross, Philippa. "Retraction: Facile synthesis of quantum dots/mesoporous silica/quantum dots core/shell/shell hybrid microspheres for ratiometric fluorescence detection of 5-fluorouracil in human serum." Analyst 145, no. 23 (2020): 7766. http://dx.doi.org/10.1039/d0an90114h.
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Retraction of ‘Facile synthesis of quantum dots/mesoporous silica/quantum dots core/shell/shell hybrid microspheres for ratiometric fluorescence detection of 5-fluorouracil in human serum’ by Rijun Gui et al., Analyst, 2013, 138, 5956–5964, DOI: 10.1039/C3AN01089A
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Goldstein, Daniel A., Qiushi Chen, Turgay Ayer, David H. Howard, Joseph Lipscomb, Bassel F. El-Rayes, and Christopher R. Flowers. "First- and Second-Line Bevacizumab in Addition to Chemotherapy for Metastatic Colorectal Cancer: A United States–Based Cost-Effectiveness Analysis." Journal of Clinical Oncology 33, no. 10 (April 1, 2015): 1112–18. http://dx.doi.org/10.1200/jco.2014.58.4904.
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Purpose The addition of bevacizumab to fluorouracil-based chemotherapy is a standard of care for previously untreated metastatic colorectal cancer. Continuation of bevacizumab beyond progression is an accepted standard of care based on a 1.4-month increase in median overall survival observed in a randomized trial. No United States–based cost-effectiveness modeling analyses are currently available addressing the use of bevacizumab in metastatic colorectal cancer. Our objective was to determine the cost effectiveness of bevacizumab in the first-line setting and when continued beyond progression from the perspective of US payers. Methods We developed two Markov models to compare the cost and effectiveness of fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab in the first-line treatment and subsequent fluorouracil, leucovorin, and irinotecan with or without bevacizumab in the second-line treatment of metastatic colorectal cancer. Model robustness was addressed by univariable and probabilistic sensitivity analyses. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Results Using bevacizumab in first-line therapy provided an additional 0.10 QALYs (0.14 life-years) at a cost of $59,361. The incremental cost-effectiveness ratio was $571,240 per QALY. Continuing bevacizumab beyond progression provided an additional 0.11 QALYs (0.16 life-years) at a cost of $39,209. The incremental cost-effectiveness ratio was $364,083 per QALY. In univariable sensitivity analyses, the variables with the greatest influence on the incremental cost-effectiveness ratio were bevacizumab cost, overall survival, and utility. Conclusion Bevacizumab provides minimal incremental benefit at high incremental cost per QALY in both the first- and second-line settings of metastatic colorectal cancer treatment.
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Medinger, Steinbild, and Mross. "Die systemische Therapie des Kolonkarzinoms 2004." Praxis 93, no. 40 (September 1, 2004): 1633–44. http://dx.doi.org/10.1024/0369-8394.93.40.1633.
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Bei Patienten mit Stadium III-Kolonkarzinom hat sich die adjuvante Chemotherapie etabliert. Fluorouracil und Folinsäure über sechs Monate ist zurzeit (noch) der Standard und sollte als Kontrollarm für randomisierte Studien neuer Substanzen verwendet werden. Da im Stadium II die Wahrscheinlichkeit eines Rezidivs geringer ist, ist auch der absolute Nutzen einer Chemotherapie geringer als im Stadium III. Die bisher vorliegenden Daten sind nicht ausreichend, um eine statistisch eindeutige Aussage über den Nutzen bezüglich des Gesamtüberlebens nach adjuvanter Therapie im Stadium II treffen zu können. Durch den Einsatz neuer Medikamente wie Irinotecan und Oxaliplatin könnte die Effektivität einer adjuvanten Therapie weiter verbessert werden. Bei dem metastasierten kolorektalen Karzinom sind heute Kombinationen aus 5-FU/FS plus CPT-11 oder OXA Therapie der Wahl für die First-line-Therapie. Welcher der letztgenannten Substanzen der Vorrang gegeben werden soll, ist bis jetzt noch nicht definiert. FOLFOX ist in der Lage, im Vergleich zu IFL, die mittlere progressionsfreie Zeit von 6,9 auf 8,8 Monate zu verlängern. Des Weiteren zeigt sich im Vergleich eine statistisch signifikante Verlängerung des Gesamtüberlebens um 4,5 Monate (Ergebnisse der N9741- Intergroup-Study). Für FOLFOX spricht weiterhin die bessere Verträglichkeit. Abgesehen von Grad 3/4-Parästhesien sind schwere Nebenwirkungen wie febrile Neutropenien, Diarrhoe, Übelkeit und Erbrechen wesentlich seltener als unter Therapie mit Irinotecan. Für eine sequentielle Therapie spricht, dass das mittlere Gesamtüberleben bis auf etwa 20 Monate gesteigert werden konnte. Ergebnisse einer Phase II-Studie lassen erwarten, dass Capecitabine die 5-FU/FS-Komponente moderner Kombinationsprotokolle mit Irinotecan bzw. Oxaliplatin möglicherweise ersetzen kann. Für ältere, komorbide Patienten oder Patienten mit langsamem Tumorwachstum kann für die First-line-Therapie Capecitabine eingesetzt werden oder das Ardalan (bzw. AIO-) Protokoll [49]. Grundsätzlich profitieren ältere Patienten > 65 Jahren von der Kombinationstherapie genauso wie jüngere Patienten, wie in einer Metaanalyse von zwei Phase III-Studien [50] sowie in einer retrospektiven Analyse von Rougier et al. belegt werden konnte [51]. Der neue VEGF-Rezeptor-Inhibitor Bevacizumab ist ein weiterer Meilenstein in der first-line palliativen Behandlung kolorektaler Karzinome. Mittlere Überlebenszeiten von 24 Monaten und möglicherweise mehr könnten demnächst durch optimierte Behandlungssequenzen der zur Verfügung stehenden Medikamente erzielt werden. Für die second-line-Therapie steht mit Cetuximab ein weiterer Antikörper zur Verfügung, der seinen festen Platz in der Therapie kolorektaler Karzinome finden dürfte. Inzwischen ist Cetuximab zugelassen worden. Bemerkenswert ist, dass die Antikörper mit den Zytostatika kombiniert werden können, ohne die Toxizität deutlich zu erhöhen. Allerdings sind auch diese neuen Target-spezifischen Antikörper nicht ohne Nebenwirkungen, das NW-Spektrum der Therapien wird sich durch Hinzufügen dieser Medikamente verändern.
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Takeuchi, Jaffer A, Fang, Pfeiffer, Takeuchi, and van Laarhoven. "Meta-Enrichment Analyses to Identify Advanced Gastric Cancer Patients Who Achieve a Higher Response to S-1/Cisplatin." Cancers 11, no. 6 (June 21, 2019): 871. http://dx.doi.org/10.3390/cancers11060871.
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The Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study (FLAGS) and the Diffuse Gastric and Esophagogastric Junction Cancer S-1 Trial (DIGEST) have shown that patients with advanced gastric cancer treated with S-1/Cisplatin (CS) have similar overall survival (OS) compared to 5-fluorouracil/cisplatin (CF). The purpose of this analysis was to identify patients who may specifically benefit from CS using meta-enrichment analysis of the combined two datasets. Eleven clinico-pathological factors were selected and a high response enrichable population was determined. The efficacy of CS in the combined data set of 1365 patients (n = 1019 from FLAGS and n = 346 from DIGEST) was analyzed. We identified 683 patients (n = 374 from CS, n = 309 from CF) as the high response enrichable population who were classified as those with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1, more than two metastatic sites and low neutrophil-lymphocyte ratio (log(NL ratio)). In the high response enrichable population, the median OS in the CS group was 241 days compared to 210 days in the CF group (hazard ratio 0.776; 95% confidence interval 0.658 to 0.915; p-value 0.004). Through meta-enrichment analysis, the high response enrichable population to CS was identified. Our findings show the clinical importance of selecting the appropriate treatment based on specific patient characteristics.
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Goekkurt, Eray, Salah-Eddin Al-Batran, Jörg T. Hartmann, Ulrike Mogck, Gunter Schuch, Michael Kramer, Elke Jaeger, Carsten Bokemeyer, Gerhard Ehninger, and Jan Stoehlmacher. "Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie." Journal of Clinical Oncology 27, no. 17 (June 10, 2009): 2863–73. http://dx.doi.org/10.1200/jco.2008.19.1718.
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PurposeTo evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).Patients and MethodsBlood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction–based techniques.ResultsMedian overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).ConclusionThese findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.
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Ma, Yuxiang, Yuehao Lin, Benyan Zou, Wanli Liu, Yang Zhang, Liping Zhao, Yan Huang, et al. "Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma." Clinical Pharmacokinetics 55, no. 10 (April 30, 2016): 1205–16. http://dx.doi.org/10.1007/s40262-016-0395-2.
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Pavithran, Keechilat, Prasanth Ariyannur, Hridya Jayamohanan, Arun Philip, Wesley Mannirathil Jose, and Sumi Soman. "Dihydropyrimidine dehydrogenase deficiency in patients treated with 5FU or capecitabine based regimens: A single center experience from South India." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15517-e15517. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15517.
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e15517 Background: DPYD deficiency is present in 3-5% of patients. The risk of treatment-related death in DPYD mutation carriers who receive fluoropyrimidine chemotherapy has been estimated at 3-10%. There is growing data in support of widespread screening for DPYD deficiency prior to fluoropyrimidine chemotherapy. The purpose of our study was to identify the prevalence of DPYD deficiency among patients receiving 5-fluorouracil (5FU) or capecitabine based combination chemotherapy, and to analyse the toxicity profile among the DPYD deficient group. Methods: The study involved patients who have received 5FU and capecitabine based chemotherapy for the treatment for gastrointestinal, breast and head and neck cancers between 2019-2020. Four DPYD variants were checked using real-time PCR based Genotyping assay. Three common DPYD variants recommended by the CPIC guidelines (IVS14+1 G>A (*2A), c.1679T>G (*13), c.2846A>T) and a common variant in Asian population (c.496A>G), based on previous studies, was included in our analysis. These variants were assessed prior to the initiation of the chemotherapy and dose was modified based on the activity score and the toxicity profile was assessed. Descriptive statistics was performed using SPSS version 20. Results: 375 patients were included in this analysis. The median age of the cohort was 61years (21-84 years). 51.3% were males and 49.7% females. Among the 375 patients, 47 patients had DPYD mutation (12.5%). The median age of the DPYD mutated patients were 68 years; 29 (61.7%) males and 18 (38.2%) females. 32 (68.8%) had deleterious mutation in DPYD variant c.496A>G (rs2297595) and 15 (31.9%) showed mutation IVS14+1 G>A (rs3918290). 35 out 47 patients had grade II-III toxicity even after dose reduction during the first cycle of chemotherapy. The commonly seen adverse events were hand and foot syndrome in 18 (38.3%), mucositis in 7 (14.9%), diarrrhoea in 15 (31.9%) and neutropenia in 25 (31.9%) patients. Four patients had febrile neutropenia. One patient experience myocardial infarction. There was no mortality. Chi square analysis showed DPYD mutation had significant association with presence of severe adverse reaction (74.5%, p-value. 0.002). Conclusions: Prevalence of DPYD mutation in our patients was 12.5%. They experienced more toxicities while receiving 5-FU/Capecitabine even after dose modification. c.496A>G (rs2297595) was the most common variant seen in our patients. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using pharmacogenetic methods may help identify those patients who are at risk for adverse effects, allowing a more individualized approach to their chemotherapy management. c.496A>G (rs2297595) variant should also be in included routinely in DPYD screening among South Asian population.
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Marable, Carmen A., Christopher L. Frank, Roland F. Seim, Susan Hester, W. Matthew Henderson, Brian Chorley, and Timothy J. Shafer. "Integrated Omic Analyses Identify Pathways and Transcriptomic Regulators Associated With Chemical Alterations of In Vitro Neural Network Formation." Toxicological Sciences 186, no. 1 (December 20, 2021): 118–33. http://dx.doi.org/10.1093/toxsci/kfab151.
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Abstract Development of in vitro new approach methodologies has been driven by the need for developmental neurotoxicity (DNT) hazard data on thousands of chemicals. The network formation assay characterizes DNT hazard based on changes in network formation but provides no mechanistic information. This study investigated nervous system signaling pathways and upstream physiological regulators underlying chemically induced neural network dysfunction. Rat primary cortical neural networks grown on microelectrode arrays were exposed for 12 days in vitro to cytosine arabinoside, 5-fluorouracil, domoic acid, cypermethrin, deltamethrin, or haloperidol as these exposures altered network formation in previous studies. RNA-seq from cells and gas chromatography/mass spectrometry analysis of media extracts collected on days in vitro 12 provided gene expression and metabolomic identification, respectively. The integration of differentially expressed genes and metabolites for each neurotoxicant was analyzed using ingenuity pathway analysis. All 6 compounds altered gene expression that linked to developmental disorders and neurological diseases. Other enriched canonical pathways overlapped among compounds of the same class; eg, genes and metabolites altered by both cytosine arabinoside and 5-fluorouracil exposures are enriched in axonal guidance pathways. Integrated analysis of upstream regulators was heterogeneous across compounds, but identified several transcriptomic regulators including CREB1, SOX2, NOTCH1, and PRODH. These results demonstrate that changes in network formation are accompanied by transcriptomic and metabolomic changes and that different classes of compounds produce differing responses. This approach can enhance information obtained from new approach methodologies and contribute to the identification and development of adverse outcome pathways associated with DNT.
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Norman, G., M. Soares, P. Peura, S. Rice, D. Suh, K. Wright, M. Sculpher, and A. Eastwood. "Capecitabine for the treatment of advanced gastric cancer." Health Technology Assessment 14, Suppl 2 (October 2010): 11–17. http://dx.doi.org/10.3310/hta14suppl2-02.
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This paper presents a summary of the evidence review group (ERG) report into capecitabine for advanced gastric cancer (aGC). Capecitabine is an oral prodrug of 5-fluorouracil (5-FU). The decision problem addressed was the use of capecitabine (X) compared to 5-FU (F), in combination regimens with platinum agents [cisplatin (C) or oxaliplatin (O)] with or without epirubicin (E), in patients with inoperable aGC. Approximately 7000 new cases of gastric cancer are diagnosed in England and Wales every year. Of these, 80% are candidates for palliative chemotherapy and around 2900 receive such treatment. The standard UK practice for patients with aGC who are considered fit enough has consisted of a triplet regimen comprising intravenous 5-FU in combination with a platinum agent (capecitabine or oxaliplatin) and epirubicin. The manufacturer’s submission (MS) focused on direct evidence from two phase III non-inferiority randomised controlled trials (RCTs), REAL-2 (Randomized ECF for Advanced and Locally advanced oesophagogastric cancer-2; n = 1002) and ML17032 (n = 316). REAL-2 randomised patients to four regimens (ECF, ECX, EOF and EOX) to compare 5-FU with capecitabine and cisplatin with oxaliplatin, whereas ML17032 compared CX with CF. Efficacy outcomes from these trials were pooled in an individual patient data (IPD) meta-analysis. Both RCTs demonstrated statistically significant non-inferiority of capecitabine on the outcome of overall survival (OS) assessed in the per-protocol population; equivalent results were also demonstrated for progression-free survival (PFS). The IPD meta-analysis found a statistically significant benefit in OS for capecitabine compared with 5-FU [unadjusted hazard ratio (HR): 0.87; 95% confidence interval (CI) 0.77 to 0.98, p = 0.027]. There was no evidence of a poorer safety profile for capecitabine overall, nor of any difference in quality of life (QoL) between the two fluoropyrimidines. The MS included a de novo economic evaluation based on a cost-minimisation analysis (CMA), where the costs of capecitabine-based regimens were compared with their equivalent 5-FU-based regimens in aGC. A time horizon of 5.5 cycles (each lasting for 21 days) was used in the base-case analysis, representing the duration of treatment. The results of the manufacturer’s base-case analysis showed that capecitabine regimens are associated with mean net cost savings of £1620 (ECX vs ECF), £1572 (EOX vs EOF) and £4210 (CX vs CF). The manufacturer failed to comment explicitly on the uncertainty around the estimates of efficacy and on the fact that the IPD meta-analysis suggests that capecitabine may actually be more effective on average. Further analyses exploring additional costs incurred by the UK NHS from extending survival duration showed that these are unlikely to have a material effect on conclusions. A full probabilistic analysis was not performed; however, the evidence explored by the MS and ERG is consistent in suggesting that capecitabine has a lower mean cost than 5-FU-based regimens. The submission was considered to contain convincing evidence of the non-inferiority of capecitabine to 5-FU on survival; this evidence was considered to be applicable to UK practice. Although some uncertainty remains, the ERG deemed CMA to be an appropriate framework with which to analyse this decision problem. Overall cost estimates for the CMA were generated appropriately and were robust to uncertainties regarding assumptions and sources. At the time of writing, the guidance document issued by NICE on 28 July 2010 states that capecitabine in combination with a platinum-based regimen is recommended for the first-line treatment of inoperable advanced gastric cancer.
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Yang, Yu, Yuxuan Li, and Xiaohui Du. "Does Intraperitoneal Chemotherapy Increase the Incidence of Anastomotic Leakage after Colorectal Cancer Surgery: A Systematic Review and Meta-Analysis." Gastroenterology Research and Practice 2021 (January 25, 2021): 1–5. http://dx.doi.org/10.1155/2021/9204373.
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Purpose. To identify and evaluate the influence of intraperitoneal chemotherapy without hyperthermia (ICwh) to the incidence of anastomotic leakage (AL) after colorectal cancer surgery. Methods. A systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses in order to review all studies investigating the relationship between ICwh and AL in patients undergoing colorectal surgery. The primary outcome was overall incidence rate of anastomotic leakage. Results. Four studies were included in the final review. ICwh was associated with an overall increased risk of anastomotic leakage [OR 2.05 (1.06, 3.98), P = 0.03 ]. But there was no significant increased incidence rate when fluorouracil was implanted into the abdominal cavity for ICwh [OR 2.48 (0.55, 11.10), P = 0.24 ]. Conclusions. This meta-analysis provides some evidence to suggest ICwh may increase the incidence of postoperative AL in colorectal cancer. However, fluorouracil implantation for ICwh does not increase the risk of AL, which seems to be a relatively safe method of ICwh.
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Raskin, Grigoriy Aleksandrovich, Rashida Vakhidovna Orlova, Anna Eduardovna Protasova, Sergey Aleksandrovich Koshkin, and Ruslan Ivanovich Glushakov. "Predictive markers of the efficacy of colon adenocarcinoma treatment by 5-fluoropyrimidines determined by means of immunohistochemistry method." Reviews on Clinical Pharmacology and Drug Therapy 12, no. 4 (December 15, 2014): 50–53. http://dx.doi.org/10.17816/rcf12450-53.
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5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colon cancer (CC).The purpose of this study was to evaluate the expression of the thymidine phosphorylase (TP), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPYD)in CC patients treated with 5-fluorouracil (5-FU) to determine their predictive and prognostic significance. Immunohistochemistry (IHC) analysis of the expression of proteins was performed on tumour tissue of 104 patients with stage IV colon cancer. All patient was treated withfluoropyrimidine/antifolate-based therapy (FOLFOX, De Gramont, FOLFIRI). Usedmultivariate logistic regression analyses we found the level of expression of proteins thymidine phosphorylase (TP), thymidylate synthase (TS) as predictors efficiency 5 - fluoropyrimidine with adenocarcinoma of the colon. The value of expression of TP and TS has a statistically significant effect (p = 0,006 and p = 0.0036) on time to disease progression, respectively.Our data demonstrated the efficacy of the 5-fluoropyrimidine chemotherapy colon adenocarcinoma may be utilized evaluation of expression of TS and TP.
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Heppt, Markus V., Igor Dykukha, Sara Graziadio, Rafael Salido-Vallejo, Matt Chapman-Rounds, and Mary Edwards. "Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials." Journal of Clinical Medicine 11, no. 6 (March 16, 2022): 1654. http://dx.doi.org/10.3390/jcm11061654.
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Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle. The network meta-analysis revealed the following odds ratios and 95% credible intervals: cryosurgery 13.4 (6.2–30.3); diclofenac 3% 2.9 (1.9–4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6–13.5); fluorouracil 4% 30.3 (9.1–144.7); fluorouracil 5% 35.0 (10.2–164.4); imiquimod 3.75% 8.5 (3.5–22.4); imiquimod 5% 17.9 (9.1–36.6); ingenol mebutate 0.015% 12.5 (8.1–19.9); photodynamic therapy with aminolevulinic acid 24.1 (10.9–52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0–21.9); tirbanibulin 1% 11.1 (6.2–20.9). Four sensitivity analyses, from studies assessing efficacy after one treatment cycle only, for ≤25 cm2 treatment area, after 8 weeks post-treatment, and with single placebo/vehicle node confirmed the findings from the base case. Safety outcomes were assessed qualitatively. These results suggest that tirbanibulin 1% offers a novel treatment for AK, with a single short treatment period, favourable safety profile and efficacy, in line with existing topical treatments available in Europe.
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Brasiūnienė, Birutė, and Elona Juozaitytė. "The effect of combined treatment methods on survival and toxicity in patients with pancreatic cancer." Medicina 43, no. 9 (September 27, 2007): 716. http://dx.doi.org/10.3390/medicina43090093.
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In Lithuania, there were 476 new pancreatic cancer cases in 2005. Based on international scientific literature and the results of our retrospective studies, a prospective study has been designed. The aim of study was a prospective evaluation of the impact of two concomitant chemoradiation methods on the survival and the time to disease progression in patients diagnosed with resectable and unresectable pancreatic cancer and prospective evaluation of the safety of two concomitant chemoradiation methods for the treatment of resectable and unresectable pancreatic cancer. Material and methods. During the period of 2000–2005 at the Clinic of Oncology, Kaunas University of Medicine Hospital, we performed a prospective randomized study to analyze two concomitant chemoradiation treatment methods. The patients were stratified according to the resectability of the tumor: with resectable tumor (stage I–IVA) and with unresectable tumor (stage III–IVA). Treatment for each group of patients was selected randomly choosing concomitant chemoradiation treatment: radiation therapy and 5-fluorouracil or radiation therapy and gemcitabine. Criteria of the efficacy of the treatment methods were median survival, time to disease progression, and treatment safety (qualitative and quantitative analysis). Results and conclusions. The treatment methods – radiotherapy and 5-fluorouracil or radiotherapy and gemcitabine – were equally effective when assessing the survival and time to disease progression in patients diagnosed with pancreatic cancer. Treatment of patients diagnosed with pancreatic cancer with radiotherapy and 5-fluorouracil was a safer approach than treatment with radiotherapy and gemcitabine, which induced more severe toxic adverse effects.
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Berardi, Rossana, Tiziana Saladino, Davide Mari, Rosa Rita Silva, Mario Scartozzi, Lorena Verdecchia, Azzurra Onofri, and Stefano Cascini. "Elderly Patients with Advanced Colorectal Cancer: Tolerability and Activity of Chemotherapy." Tumori Journal 91, no. 6 (November 2005): 463–66. http://dx.doi.org/10.1177/030089160509100603.
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Aims and Background Colorectal cancer is the most common gastrointestinal tumor in Western countries and is increasing in elderly patients. In recent years, new treatments based on the use of 5-fluorouracil associated with oxaliplatin or CPT-11 have shown promising activity. The aim of the present study was to analyze the tolerability and activity of chemotherapy with 5-fluorouracil plus oxaliplatin or CPT-11 in elderly patients with advanced colorectal cancer. Methods Patients aged 70 years or older with advanced colorectal cancer were treated with 5-fluorouracil (400 mg/m2 in bolus and 600 mg/m2 in a 22-hr continuous infusion on days 1-2) plus folinic acid (100 mg/m2) associated to oxaliplatin (85 mg/m2 on day 1, FOLFOX regimen) or CPT-11 (180 mg/m2 on day 1, FOLFIRI regimen), every 14 days. Results Twenty-nine patients with a median age of 76 years (range, 70-82) were treated with FOLFOX or FOLFIRI as first-line chemotherapy for metastatic disease. We observed a partial response in 8/29 (27.6%), stable disease in 11/29 (37.9%) and progressive disease in 10/29 (34.5%). Median survival was 21 months; 1-year survival probability was 89.8%. Grade III leukopenia was observed in 2/29 (7%) patients and grade III diarrhea in 1/29 patients. No other grade III-IV toxicity was observed. Conclusions FOLFOX and FOLFIRI appear to be active and well tolerated regimens for elderly patients with advanced colorectal cancer.
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Biambo, A. A., U. M. Aliyu, M. O. Adibe, A. Samaila, N. Usman, K. K. Abubakar, and C. V. Ukwe. "Toxicity Profile of Chemotherapeutic Agents among Cancer Patients Receiving Care in a Nigerian Tertiary Health Care Facility." Journal of Basic and Social Pharmacy Research 1, no. 5 (2020): 53–64. http://dx.doi.org/10.52968/27451327.
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Background: Chemotherapeutic agents are among the mainstay of managing cancer patients. However, they are associated with various degrees of toxicity. Objectives: To evaluate the toxicity profile of chemotherapeutic agents among cancer patients receiving care in Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria. Method: Retrospective cross-sectional design and systematic random sampling were used in selecting the records of patients that met the eligibility criteria for the study. Five-year records (2014–2018) of Full Blood Count (FBC), Serum Electrolyte Urea and Creatinine (SrEUCr) and Liver Function Test (LFT) were evaluated for changes from baseline to the end of chemotherapy. The data were compared with standards and analysed using descriptive, t-test and correlation analyses at p<0.05. Results: The mean age of the 260 patients evaluated was 47.1±16.3 years. T-test analysis showed that the percentage changes in the patients’ parameters under FBC and SrEUCr tests were normal while the ones under LFT were abnormal. Patients on platinum-based combinations especially Cisplatin+Fluorouracil+Paclitaxel (87.5±87.4%) and Carboplatin+Paclitaxel (68.4±114.5%) had the highest percentage increase in their overall LFT results while those on Doxorubicin+Cyclophosphamide+Vincristine (4.8±18.7%) and Doxorubicin+ Cyclophosphamide+ Paclitaxel (12.3±27.9%) had the least. The number of chemotherapy cycles was weakly correlated with Hepatotoxicity (r=0.165, p=0.046). Conclusion: The patients had essentially normal FBC and SrEUCr results, however, LFT was abnormal due to the elevation of liver enzymes. Platinum-based combinations especially Cisplatin + Fluorouracil + Paclitaxel and Carboplatin + Paclitaxel had the highest elevation in liver enzymes while Doxorubicin+Cyclophosphamide+Vincristine and Doxorubicin+Cyclophosphamide+Paclitaxel had the least. These findings should be considered by clinicians in managing cancer patients to minimise their medication-related toxicities.
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Akushevich, Igor, Arseniy Yashkin, Julia Kravchenko, and Miklos Kertai. "Chemotherapy and Anesthesia in Colorectal Cancer Survivors and the Risk of Alzheimer’s Disease." Innovation in Aging 4, Supplement_1 (December 1, 2020): 263–64. http://dx.doi.org/10.1093/geroni/igaa057.845.
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Abstract Exposures common in cancer patients––chemotherapy, surgical injury and/or anesthesia, alone or in combination with predisposing factors––have been suggested as potential risk factors for Alzheimer’s disease (AD). We explored the relationship between chemotherapy and cumulative anesthesia exposure, and development of AD in colorectal cancer survivors. We conducted a retrospective cohort study of individuals age 65 and older diagnosed with colorectal cancer between 1998 and 2013, drawing on SEER-Medicare data and employing a proportional hazards model. We found that exposure to chemotherapy in colorectal cancer survivors demonstrated a protective effect for AD HR=0.821 (0.784-0.860). The beneficial effect held in race-, sex-, cancer-stage-specific subgroups, across chemotherapy agents (e.g., Fluorouracil, Oxaliplatin, or Fluorouracil+Leucovorin), in multivariable analyses, and in propensity score-based pseudorandomization based on 70 demographic, socioeconomic, cancer-diagnosis-related, and comorbidity variables. The effect was diminished or absent when non-AD dementias were analyzed. Findings further demonstrated that the association between chemotherapy exposure and AD was not affected by competing risk of long-term mortality or possible correlation between choosing chemotherapy and higher cognitive score or use of alternative health insurance. The effect of anesthesia on AD was not significant (0.998 per hour, 0.992-1.005) and this effect held in all subgroups, multivariable analyses, and for pseudorandomized subpopulations. Harmful effect was detected for cerebral degeneration, excluding AD, cognitive deficits following cerebral hemorrhage, cognitive disorder due to injury, hepatic encephalopathy, and hepatolenticular degeneration. Sensitivity analyses focused on SEER-Registry-specific effects and possible misspecifications in anesthesia records with alternative models demonstrated stability of estimates.
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Naito, Masahito, Tomoya Yamamoto, Chikao Shimamoto, and Yoshihiro Miwa. "Retrospective Analysis of the Risk Factors for Grade IV Neutropenia in Oesophageal Cancer Patients Treated with a Docetaxel, Cisplatin, and 5-Fluorouracil Regimen." Chemotherapy 62, no. 4 (2017): 215–24. http://dx.doi.org/10.1159/000464273.
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Background: Previous Japanese trials of the docetaxel, cisplatin, and 5-fluorouracil regimen for oesophageal cancer have demonstrated that a large proportion of patients also develop grade IV neutropenia. Our aim was to examine the risk factors for neutropenia in patients treated with this regimen. Methods: We retrospectively analysed the risk factors for developing grade IV neutropenia in 66 patients with oesophageal cancer using a multivariate analysis. Results: After administering the docetaxel, cisplatin, and 5-fluorouracil regimen, 49 patients (74.2%) developed grade IV neutropenia. Grade IV neutropenia was significantly associated with platelet count (p < 0.01), alanine transaminase level (p = 0.05), and proton-pump inhibitor administration (p < 0.05). Receiver operating characteristic curve analysis confirmed a platelet count of 290 × 103/μL as the optimal diagnostic cut-off value for grade IV neutropenia. The receiver operating characteristic area for grade IV neutropenia was increased by including patients that were administered a proton-pump inhibitor and alanine transaminase level (updated model; sensitivity and specificity, 75.5 and 88.2%, respectively). Conclusions: Our findings suggest that a platelet count is the most significant predictor of grade IV neutropenia.
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Jia, Yiduo, Yinmeng Zhang, and Hong Zhu. "Clindamycin Derivatives: Unveiling New Prospects as Potential Antitumor Agents." Pharmaceuticals 17, no. 3 (February 22, 2024): 276. http://dx.doi.org/10.3390/ph17030276.
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This study delves into the exploration of Clindamycin derivatives, specifically compounds 3 and 3e, to unveil their antitumor potential by employing a multidisciplinary approach. Screening a repertoire of 200 Clindamycin-associated targets pinpointed the Family A G-protein-coupled receptor as a prominent antitumor candidate. Subsequent analyses unearthed 16 pertinent antitumor proteins, with compound 3 exhibiting robust affinity towards a specific protein via stable hydrogen bonding. Molecular dynamics simulations underscored the adrenergic receptor β as a pivotal target, primarily situated in the plasma membrane and endoplasmic reticulum. These revelations hint towards compound 3’s potential to bolster natural defense mechanisms against tumors by modulating immune responses within the tumor microenvironment, thus paving the way for novel avenues in antitumor drug development. Furthermore, employing the MTT assay, we evaluated the anti-HepG2 cell activity of compounds 3 and 3e, with 5-fluorouracil serving as the control drug. Results revealed that compound 3 exhibited significant differences (p < 0.01) across all concentrations (2.5, 5, 10 μg/mL) compared to the control group, paralleled by the pronounced differences (p < 0.01) observed with 5-fluorouracil.
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Starenkiy, Viktor, Sergii Artiukh, Mykhaylo Ugryumov, Viktoriia Strilets, Serhii Chernysh, and Dmytro Chumachenko. "A Method for Assessing the Risks of Complications in Chemoradiation Treatment of Squamous Cell Carcinoma of the Head and Neck." Open Bioinformatics Journal 14, no. 1 (November 19, 2021): 138–43. http://dx.doi.org/10.2174/18750362021140100138.
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Background: More than 500,000 new cases of squamous cell carcinoma of the head and neck (SCCHN) are registered annually in the world. 7,036 new cases of the disease were registered in Ukraine during 2018, about 35% of patients did not live even a year from the date of diagnosis as a modern standard for the treatment of patients with inoperable locally advanced SCCHN, chemoradiation treatment in the classical dose fractionation mode with chemo modification with cisplatin is used by specialists. Objective: The objective of this study is to analyze the effectiveness of chemoradiation treatment with cisplatin and 5-fluorouracil in the treatment of patients with SCCHN using modern mathematical models. Methods: During the investigation we assessed the effectiveness of treatment in 108 patients with locally advanced SCCHN (stages III, IVa, IVb). The results of calculating the probabilities of complications were obtained using the method of multivariate classification based on the radial basis ANN. Results: Analyzing the groups with different methods of chemo modification, we can conclude that the method of chrono-modulated radiochemotherapy with 5-fluorouracil and the chemoradiation therapy with cisplatin were almost equal in efficiency, namely 77% and 73.5%, respectively (p=0.35). Conclusion: Using the chemoradiation therapy with 5-fluorouracil in the treatment of patients with low somatic status and elderly patients is more expedient in contrast to the methods using cisplatin. The advantage of selection of mentioned treatment method is also confirmed by the results of calculating the average complication risks using the method of multivariate classification based on a radial-basis neural network.
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Ma, Yuxiang, Yuehao Lin, Benyan Zou, Wanli Liu, Yang Zhang, Liping Zhao, Yan Huang, et al. "Correction to: Pharmacokinetic and Pharmacodynamic Analyses of 5-Fluorouracil in East-Asian Patients with Nasopharyngeal Carcinoma." Clinical Pharmacokinetics 57, no. 1 (December 26, 2017): 103–4. http://dx.doi.org/10.1007/s40262-017-0615-4.
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Ozaki, Yoshinao, Hirotaka Imamaki, Aki Ikeda, Mitsuaki Oura, Shunsaku Nakagawa, Taro Funakoshi, Shigeki Kataoka, et al. "Successful management of hyperammonemia with hemodialysis on day 2 during 5-fluorouracil treatment in a patient with gastric cancer: a case report with 5-fluorouracil metabolite analyses." Cancer Chemotherapy and Pharmacology 86, no. 5 (October 3, 2020): 693–99. http://dx.doi.org/10.1007/s00280-020-04158-1.
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Abstract Purpose Hyperammonemia is an important adverse event associated with 5-fluorouracil (5FU) from 5FU metabolite accumulation. We present a case of an advanced gastric cancer patient with chronic renal failure, who was treated with 5FU/leucovorin (LV) infusion chemotherapy (2-h infusion of LV and 5FU bolus followed by 46-h 5FU continuous infusion on day 1; repeated every 2 weeks) and developed hyperammonemia, with the aim of exploring an appropriate hemodialysis (HD) schedule to resolve its symptoms. Methods The blood concentrations of 5FU and its metabolites, α-fluoro-β-alanine (FBAL), and monofluoroacetate (FA) of a patient who had hyperammonemia from seven courses of palliative 5FU/LV therapy for gastric cancer were measured by liquid chromatography–mass spectrometry. Results On the third day of the first cycle, the patient presented with symptomatic hyperammonemia relieved by emergency HD. Thereafter, the 5FU dose was reduced; however, in cycles 2–4, the patient developed symptomatic hyperammonemia and underwent HD on day 3 for hyperammonemia management. In cycles 5–7, the timing of scheduled HD administration was changed from day 3 to day 2, preventing symptomatic hyperammonemia. The maximum ammonia and 5FU metabolite levels were significantly lower in cycles 5–7 than in cycles 2–4 (NH3 75 ± 38 vs 303 ± 119 μg/dL, FBAL 13.7 ± 2.5 vs 19.7 ± 2.0 μg/mL, FA 204.0 ± 91.6 vs 395.9 ± 12.6 ng/mL, mean ± standard deviation, all p < 0.05). After seven cycles, partial response was confirmed. Conclusion HD on day 2 instead of 3 may prevent hyperammonemia in 5FU/LV therapy.
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Gorneva, Galina, Rada Mateva, Roumyana Gugova, and Evgeny Golovinsky. "The study of the apoptogenic effect of pyrimidine derivatives on murine leukemia cells." Archive of Oncology 13, no. 2 (2005): 62–64. http://dx.doi.org/10.2298/aoo0502062g.
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BACKGROUND: In the light of the recent findings concerning the role of apoptosis and of tumor cell enzymes in cancer chemotherapy, the interest in pyrimidine derivatives has greatly increased. Thio- and hydrazine- pyrimidines were synthesized as potential antimetabolites inhibiting the biosynthesis of nucleic acids. Some of them demonstrated biological activity, including antibacterial and antitumor action. The aim of this study was to analyze the cytotoxic activity and the ability of some derivatives to induce apoptosis in murine leukemia cells. METHODS: Exponentially growing cells were incubated with compounds and after 24, 48, and 72 hours were stained with trypan blue and counted hemocytometrically. For detection of the cell fraction undergoing apoptosis, a morphological analysis was made using fluorescent dye propidium iodide. RESULTS: Eight thio- and hydrazine- pyrimidine derivatives were investigated. 2-Thiouracil and 6- hydrazinouracil did not influence the cell growth. 2,4-dithiouracil, 2-thio-4-hydrazinouracil, 2-hydrazinouracil, and 2-thio-5-fluorouracil decreased cell proliferation, but even at the highest studied concentration (1000 ?M) had no cytostatic action. Only high concentrations of 2,4-dihydrazinouracil and 2- chloro-4-hydrazinouracil showed a strong cytotoxic activity. The treatment with 2,4-dihydrazinouracil as well as with 5-fluorouracil caused the appearance of apoptotic cells with typical fragmented condensed nuclei, ghosts and apoptotic bodies. In contrast, dead cells treated with 2-chloro-4-hydrazinouracil did not show apoptotic morphology. CONCLUSION: Among studied eight thio- and hydrazine- pyrimidine derivatives only 2,4-dihydrazinouracil demonstrated strong apoptogenic activity. Its active concentrations were about 100 times higher than apoptogenic concentrations of 5-fluorouracil which points to different mechanisms of cytotoxic action.
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Manuyakorn, Ananya, Rebecca Paulus, James Farrell, Nicole A. Dawson, Sheila Tze, Gardenia Cheung-Lau, Oscar Joe Hines, et al. "Cellular Histone Modification Patterns Predict Prognosis and Treatment Response in Resectable Pancreatic Adenocarcinoma: Results From RTOG 9704." Journal of Clinical Oncology 28, no. 8 (March 10, 2010): 1358–65. http://dx.doi.org/10.1200/jco.2009.24.5639.
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Purpose Differences in cellular levels of histone modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three histone modifications in pancreatic adenocarcinoma. Methods Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for histone H3 lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. Conclusion Cellular levels of histone modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
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Sultana, Asma, Catrin Tudur Smith, David Cunningham, Naureen Starling, John P. Neoptolemos, and Paula Ghaneh. "Meta-Analyses of Chemotherapy for Locally Advanced and Metastatic Pancreatic Cancer." Journal of Clinical Oncology 25, no. 18 (June 20, 2007): 2607–15. http://dx.doi.org/10.1200/jco.2006.09.2551.
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PurposeThere are a large number of randomized controlled trials involving chemotherapy in the management of advanced pancreatic cancer. Several chemotherapeutic agents, either alone or in combination with other chemotherapy or novel agents, have been used. The aim of these meta-analyses was to examine the different therapeutic approaches, and the comparisons examined were as follows: chemotherapy versus best supportive care; fluorouracil (FU) versus FU combination chemotherapy; gemcitabine versus FU; and gemcitabine versus gemcitabine combination chemotherapy.MethodsRelevant trials were identified by searching databases, trial registers, and conference proceedings. The primary end point was overall survival.ResultsOne hundred thirteen randomized controlled trials were identified, of which 51 trials involving 9,970 patients met the inclusion criteria. Chemotherapy improved survival compared with best supportive care (hazard ratio [HR] = 0.64; 95% CI, 0.42 to 0.98). FU-based combination chemotherapy did not result in better overall survival compared with FU alone (HR = 0.94; 95% CI, 0.82 to 1.08). There was insufficient evidence of a survival difference between gemcitabine and FU, but the wide CI includes clinically important differences in both directions, making a clear conclusion difficult (HR = 0.75; 95% CI, 0.42 to 1.31). Survival was improved after gemcitabine combination chemotherapy compared with gemcitabine alone (HR = 0.91; 95% CI, 0.85 to 0.97).ConclusionThere was a significant survival benefit for chemotherapy over best supportive care and gemcitabine combinations over gemcitabine alone. This supports the use of gemcitabine-based combination chemotherapy in the treatment of advanced pancreatic cancer.
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Yang, Junjun, Yang Xiang, Xirun Wan, Fengzhi Feng, and Tong Ren. "Analysis of the Prognosis and Related Factors for Patients With Stage IV Gestational Trophoblastic Neoplasia." International Journal of Gynecologic Cancer 24, no. 3 (March 2014): 594–99. http://dx.doi.org/10.1097/igc.0000000000000070.
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ObjectiveThis study aimed to investigate and analyze the treatments and prognoses of patients with stage IV gestational trophoblastic neoplasia (GTN).MethodsBetween January 1990 and January 2010, 105 patients with stage IV GTN were treated in our hospital (Peking Union Medical College Hospital). A retrospective study is presented herein to report the prognoses of these patients and to statistically analyze the risk factors that affected the prognoses of patients with stage IV GTN.ResultsAfter the treatments, of the 105 patients, 71 (67.6%) patients achieved complete remission, 15 (14.3%) patients exhibited partial remission, and 19 (18.1%) patients exhibited progression of the disease. In total, of the 105 patients, 30 (28.6%) patients died. Our statistical analyses have revealed that a previously failed multidrug chemotherapy history, multiorgan metastasis concomitant with renal metastasis, and surgical intervention all affected the prognoses of patients with stage IV GTN. In addition, patients with stage IV GTN with International Federation of Gynecology and Obstetrics scores below 12 were relatively more likely to obtain complete remission.ConclusionsMultidrug, multiroute chemotherapy, assisted by surgery when necessary, is the predominant strategy for patients with stage IV GTN. Fluorouracil-based multidrug chemotherapy can produce good outcomes for patients with stage IV GTN who were treated primarily. Adequate attention should be given to patients who have previously failed multidrug chemotherapy, have experienced multiorgan metastasis concomitant with renal metastasis, or have International Federation of Gynecology and Obstetrics scores of more than 12.
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Kubo, Katsumaro, Yuji Murakami, Masahiro Kenjo, Nobuki Imano, Yuki Takeuchi, Ikuno Nishibuchi, Tomoki Kimura, et al. "Long-term outcomes of induction chemotherapy followed by chemoradiotherapy using volumetric-modulated arc therapy as an organ preservation approach in patients with stage IVA-B oropharyngeal or hypopharyngeal cancers." Journal of Radiation Research 61, no. 4 (June 17, 2020): 554–62. http://dx.doi.org/10.1093/jrr/rraa033.
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Abstract The present study aimed to analyze treatment outcomes after induction chemotherapy followed by chemoradiotherapy (CRT) using volumetric-modulated arc therapy (VMAT) in patients with stage IVA-B oropharyngeal cancer (OPC) or hypopharyngeal cancer (HPC), with long-term observation, including examination of larynx preservation. A total of 60 patients with stage IVA-B OPC or HPC, who underwent induction TPF chemotherapy (a combination regimen consisting of docetaxel, cisplatin, and 5-fluorouracil) followed by CRT using VMAT were analyzed. Overall survival (OS), progression-free survival (PFS), laryngoesophageal dysfunction-free survival (LEDFS), and locoregional control (LRC) were calculated and compared. Univariate and multivariate analyses were performed to determine statistical differences in OS and LEDFS. The median follow-up period at the time of evaluation was 61 months. Twenty-six (43%) patients had OPC and 34 (57%) had HPC. The 5-year OS, PFS, LEDFS, and LRC rates were 57%, 52%, 52%, and 68%, respectively. Response to TPF therapy was the only significant predictive factor of OS and LEDFS in multivariate analyses. Regarding long-term toxicities, grade ≥ 2 late toxicities accounted for 15%. No patients experienced grade ≥ 3 xerostomia, and 5% of all patients developed grade 3 dysphagia. With long-term observation, the OS, PFS, and LEDFS rates were relatively good, and the incidence of late toxicities was low. TPF followed by CRT using VMAT was feasible and more effective in those who responded to induction chemotherapy.
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Lonardi, S., M. Stefani, A. Jirillo, C. Ghiotto, L. M. Pasetto, C. Falci, E. Lamberti, and S. Monfardini. "Benefit of fluorouracil and folinic acid adjuvant in colon cancer elderly patients." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13564. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13564.
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13564 Background: Retrospective analyses on elderly people enrolled in clinical trials of adjuvant chemotherapy for colon cancer indicated the maintenance of the efficacy in that subset of patients (pts). However, data on the benefit of the routinely used adjuvant treatment in an unselected population of pts aged more than 65 years are few. Methods: All the charts of pts radically operated for colon cancer from 1996–2001 at Medical Oncology, Padua Hospital, were retrospectively analysed. 147 out of 330 pts consecutively treated with fluorouracil (FU)-based chemotherapy was aged 65 years or more at the time of diagnosis. Kaplan-Meyer progression-free-survival (PFS) and overall survival (OS) of stage II and III pts were calculated. Results: Pts characteristics were: males/females: 87/60, median age 71 (range 65–87), ECOG PS 0/1: 124/23, right/left colon primary tumor: 62/85, TNM stage: 24/63/60. 86 out of 147 pts were treated with the following regimen of adjuvant chemotherapy: FU 370 mg/mq + leucovorin (LV) 20 mg/mq day 1–5 q 28 for 6 cycles (Machover regimen, n=69), or FU 500 mg/mq + LV 250 mg/mq weekly × 6 q 56 for 4 cycles (Roswell Park regimen, n=17). Treated pts were staged as follows: TNM stage I/II/III: 1/38/47. No toxic death were observed and only nine of 86 pts (10.4%) stopped the treatment due to acute grade III gastrointestinal toxicity. At a median follow-up of 73.2 months, 19 out of 86 pts (22%) developed cancer recurrence (3-y PFS: 82.2%, 5-y PFS: 80.3%). Seventeen pts (19.7%) died, 13 (15.1%) due to tumor progression, 3 (3.4%) due to acute heart failure, and 1 (1.1%) due to chronic pulmonary disease (3-y OS: 88.8%, 5-y OS: 82.4%). No statistically significant difference in survival was observed comparing pts aged 65–70 (n=41) with pts more than 70 years old (n=45): 5-y OS 84.1% vs 77.8%, respectively (p=2.23, log rank test). A separate survival analysis on stage II pts was performed (n=63). 5 of 38 (13.1) treated pts dead, compared to 9 of 25 (36%) non treated pts; 5-y survival in the two groups were 86.6% and 60.8%, respectively (p= 0.03, log-rank test). Conclusions: The efficacy of adjuvant chemotherapy appears maintained in an unselected population of elderly pts. Surprisingly, our retrospective analysis suggest that even stage II pts may benefit of a fluorouracil-based well tolerated chemotherapy. No significant financial relationships to disclose.
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Odin, Elisabeth, Arvid Sondén, Göran Carlsson, Bengt Gustavsson, and Yvonne Wettergren. "Folate pathway genes linked to mitochondrial biogenesis and respiration are associated with outcome of patients with stage III colorectal cancer." Tumor Biology 41, no. 6 (June 2019): 101042831984623. http://dx.doi.org/10.1177/1010428319846231.
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5-fluorouracil in combination with the folate leucovorin is the cornerstone in treatment of colorectal cancer. Transport of leucovorin into cells, and subsequent metabolic action, require expression of several genes. The aim was to analyze if tumoral expression of genes putatively involved in leucovorin transport, polyglutamation, or metabolism was associated with outcome of patients with stage III colorectal cancer treated with adjuvant chemotherapy. A total of 363 stage III colorectal cancer patients who received adjuvant bolus 5-fluorouracil + leucovorin alone, or in combination with oxaliplatin according to Nordic bolus regimes were included. Expression of 11 folate pathway genes was determined in tumors using quantitative real-time polymerase chain reaction and related to disease-free survival. The median follow-up time was 5 years. During follow-up, 114 (31%) patients suffered from recurrent disease. A high tumoral expression of the genes SLC46A1/PCFT, SLC19A1/RFC-1, ABCC3/MRP3, GGH, and MTHFD1L, which are involved in folate transport, polyglutamation, or metabolism, was associated with longer disease-free survival of the patients. Each of these genes either encodes mitochondrial enzymes or is being regulated by mitochondrial transcription factors. Expression of the SLC46A1/PCFT gene was most strongly associated with disease-free survival, regardless of treatment regimen. In conclusion, the results show that expression of folate pathway genes are associated with outcome of colorectal cancer patients treated with adjuvant 5-fluorouracil in combination with leucovorin. A prospective study needs to be conducted to determine if expression of these genes can be used to predict response to leucovorin and other folates that are now being tested in clinical studies. Moreover, there seems to be a link between folate metabolism and mitochondrial biogenesis and respiration that deserves further exploration.