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1.
Hypertriglyceridemia induced by S-1: A novel case report and review of the literature.
Saito, Y, Takekuma, Y, Komatsu, Y, Sugawara, M
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2021;(4):1020-1025
Abstract
INTRODUCTION S-1, a compounding agent of tegafur, gimeracil, and oteracil potassium, is one of the most effective chemotherapeutic agents for colorectal cancer. In this case, following S-1 administration, we observed predominant elevation of serum triglyceride. CASE REPORT A 49-year-old man with stage IV transverse colon adenocarcinoma received S-1 + irinotecan + bevacizumab. At the end of the S-1 administration period in every course, his serum triglyceride level was found to be elevated. Finally, it reached grade 4, without any symptoms of acute pancreatitis in the fifth course, and fenofibrate 80 mg once a day was administered.Management & outcome: Interestingly, the elevation spontaneously normalized without any pharmacotherapy 14 days after S-1 withdrawal, and this elevation did not occur when S-1 was not administered. Further, fenofibrate administration attenuated the hypertriglyceridemia to grades 1-3, with no complications. DISCUSSION S-1 administration induced hypertriglyceridemia owing to the elevated serum triglyceride; however, a contrasting result was observed in the S-1 withdrawal period and during the S-1-cessation cycle. Since dietary intake was poorer during the S-1 administration period, it is considered that S-1 might have disturbed lipid metabolism. Further, we know that capecitabine, which is a prodrug of fluorouracil, also induces hypertriglyceridemia. As the end product of these medicines is fluorouracil, the presence of fluorouracil or its metabolizing enzymes, the genetic background of the patient might have affected the results. We have to be aware of the risk of asymptomatic and temporal occurrence of hypertriglyceridemia by S-1 administration for the early detection with appropriate pre-emptive treatment.
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2.
Advances in adjuvant therapy of biliary tract cancer: an overview of current clinical evidence based on phase II and III trials.
Belkouz, A, Wilmink, JW, Haj Mohammad, N, Hagendoorn, J, de Vos-Geelen, J, Dejong, CHC, Homs, MYV, Groot Koerkamp, B, van Gulik, TM, van Oijen, MGH, et al
Critical reviews in oncology/hematology. 2020;:102975
Abstract
Patients with biliary tract cancer (BTC) have a high recurrence rate after complete surgical resection. To reduce the risk of recurrence and to improve survival, several chemotherapeutic agents that have shown to be active in locally advanced and metastatic BTC have been investigated in the adjuvant setting in prospective clinical trials. Based on the results of the BILCAP phase III trial, capecitabine was adapted as the standard of care by the ASCO clinical practice guideline. Ongoing randomized controlled trials mainly compare capecitabine with gemcitabine-based chemotherapy or chemoradiotherapy. This review provides an update of adjuvant therapy in BTC based on published data of phase II and III trials and ongoing randomized controlled trials (RCTs).
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How to rescue high-dose methotrexate induced nephrotoxicity and literature review about hemodiafiltration?
Yang, YY, Gao, L, Ding, N, Wang, XB, Zhang, LP, Gao, LH, Wang, Z
Pakistan journal of pharmaceutical sciences. 2020;(3):1163-1167
Abstract
Methotrexate (MTX) is a highly renal and liver toxicity drug used in hematological malignancy treatment in children and adults. High-dose methotrexate (HD-MTX) therapy may cause impairment of kidney and decrease the elimination of MTX, at the same time, the serum concentration of MTX increased. Today the treatment for preventing MTX toxicity after renal shutdown is Carboxypeptidase. We report a patient who experienced nephrotoxicity after the HD-MTX infusions during the treatment for non-Hodgkin lymphoma (NHL) and received hemodiafiltration (HDF) with large dose of leucovorin (LV) to treat MTX intoxication. LV is very potent in the prevention of neurotoxicity and administration of LV could protect the normal cells, but the dosage and duration of LV should be according to the MTX concentration. Although a large dose of LV was applied, the patient's condition did not improve. It was found that the HDF with large dose of LV to save the patient and steadily improved the patient's clinical condition.
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4.
Actinic keratosis - review for clinical practice.
de Oliveira, ECV, da Motta, VRV, Pantoja, PC, Ilha, CSO, Magalhães, RF, Galadari, H, Leonardi, GR
International journal of dermatology. 2019;(4):400-407
Abstract
Actinic keratosis (AK) is a lesion that arises as a result of excessive exposure to solar radiation and appearing predominantly on Fitzpatrick phototype I and II skin. Given that some AKs evolve into squamous cell carcinoma, these lesions are considered premalignant in nature, occurring mostly in elderly men and immunosuppressed individuals chronically exposed to ultraviolet (UV) radiation. There are several mechanisms for the formation of AKs; among them are oxidative stress, immunosuppression, inflammation, altered proliferation and dysregulation of cell growth, impaired apoptosis, mutagenesis, and human papillomavirus (HPV). Through the understanding of these mechanisms, several treatments have emerged. Among the options for AK treatment, the most commonly used include 5-fluorouracil (5-FU), cryotherapy, diclofenac, photodynamic therapy (PDT), imiquimod (IQ), retinoids, and ingenol mebutate (IM). There have been recent advances in the treatment options that have seen the emergent use of newer agents such as resiquimod, betulinic acid, piroxicam, and dobesilate. The combination between therapies has presented relevant results with intention to reduce duration of therapy and side effects. All AK cases must be treated because of their propensity to transform into malignancy and further complicate treatment. In addition to medical or surgical care, education about sun exposure prevention remains the best and most cost-effective method for AK prevention. The objective of this article is to conduct a literature review of the clinical presentation of AK including advances in treatment options available.
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5.
Advanced Adrenocortical Carcinoma - What to do when First-Line Therapy Fails?
Megerle, F, Kroiss, M, Hahner, S, Fassnacht, M
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2019;(2-03):109-116
Abstract
Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.
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6.
Pharmacogenomics of Methotrexate: Current Status and Future Outlook.
Cao, M, Guo, M, Wu, DQ, Meng, L
Current drug metabolism. 2018;(14):1182-1187
Abstract
BACKGROUND Methotrexate (MTX) is a folate analogue with high therapeutic efficiency in the treatment of cancers and autoimmune diseases. The efficacy and toxicity of MTX may be altered by genetic polymorphisms in genes involved in MTX metabolic pathway. Personalized pharmacotherapy based on gene polymorphisms enables a more efficient, compatible and cost-effective treatment of patients. OBJECTIVE The present article aims to review genetic polymorphisms associated with MTX pharmacokinetics, toxicity, and outcome, and points out future development directions of individualized MTX therapy. METHODS Details regarding the pharmacogenetics and pharmacogenomics of MTX are obtained from PubMed literatures. CONCLUSION The influences of single nucleotide polymorphisms (SNPs) in genes involved in MTX pathway are controversial. Many pharmacogenetic associations are disease specific and race specific. Present studies have almost limited to some certain ethnic groups and diseases. The data from these studies are not convincing enough to draw far-reaching conclusions about the applicability of MTX pharmacogenetics in clinical practice. Studies with large scale and multiple centers are needed in the future. MTX-PG inhibits folic metabolism through three mechanisms. TS, MTHFR and ATIC are the rate-limiting enzymes separately. The function of SNPs in these genes is often onesided. Works focusing on the analysis of polymorphism in MTX transporters should be more efficient and meaningful.
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7.
Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives.
Ribeiro, RA, Wanderley, CW, Wong, DV, Mota, JM, Leite, CA, Souza, MH, Cunha, FQ, Lima-Júnior, RC
Cancer chemotherapy and pharmacology. 2016;(5):881-893
Abstract
PURPOSE Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis. METHODS A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion. RESULTS Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis. CONCLUSIONS IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
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8.
Preventing and Managing Toxicities of High-Dose Methotrexate.
Howard, SC, McCormick, J, Pui, CH, Buddington, RK, Harvey, RD
The oncologist. 2016;(12):1471-1482
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Abstract
UNLABELLED : High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. IMPLICATIONS FOR PRACTICE High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
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Myelodysplastic syndromes: 2015 Update on diagnosis, risk-stratification and management.
Garcia-Manero, G
American journal of hematology. 2015;(9):831-41
Abstract
DISEASE OVERVIEW The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic. Risk-stratification: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly used system still is probably the International Prognostic Scoring System (IPSS). IPSS is being replaced by the new revised score IPSS-R. RISK-ADAPTED THERAPY Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, and more recently cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5-Azacitidine and decitabine have activity in higher risk MDS. 5-Azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. Management of progressive or refractory disease: At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include participation in a clinical trial or cytarabine based therapy and stem cell transplantation.
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Consistent efficacy and safety of gemcitabine-paclitaxel in patients with metastatic breast cancer: a retrospective comparison of East Asian and global studies.
Xu, B, Zhang, XQ, Chi, HD, Liu, Z, Quinlivan, M, Orlando, M
Asia-Pacific journal of clinical oncology. 2014;(4):330-9
Abstract
AIMS: The incidence of breast cancer in China is increasing at a rate greater than the global average. For treatment of metastatic breast cancer, a phase 3 trial of 529 patients (study JHQG) found that the combination of gemcitabine, a cytotoxic nucleoside analog, and paclitaxel, a taxane, significantly improved both overall and progression-free survival compared with paclitaxel monotherapy. As ethnic differences in the safety and efficacy of some anticancer therapies have been reported, this review provides oncologists treating East Asian patients with an evidence base to extrapolate results of the predominately Caucasian phase 3 JHQG study to their patients. METHODS Three phase 2 studies in Chinese or Japanese patients with metastatic breast cancer are reviewed with reference to the global study JHQG. The results of pharmacokinetic, efficacy and safety analyses are descriptively compared between the global and Asian studies. RESULTS Peak and total drug exposure values differed by less than 10% across the studies. Response rate, overall and progression-free survival values were similar, although values from the Asian studies for each of these parameters were slightly higher. Asian patients had higher rates of hematologic toxicities but lower rates of other adverse events. CONCLUSION Examination of the data from three studies of the gemcitabine-paclitaxel combination reveals no clinically significant ethnic differences in efficacy and safety between East Asian patients and their global counterparts. Given its demonstrated efficacy and safety profile, the gemcitabine-paclitaxel regimen should be one of the standard treatments for East Asian patients with metastatic breast cancer.