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

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

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

Background: This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in women with HER2-negative metastatic breast cancer (MBC) in China Methods: The mNC regimen was administered to the enrolled cases, including oral vinorelbine (VNR) 40 mg three times weekly (on days 1, 3 and 5 every week) and capecitabine (CAP) 500 mg three times a day, until disease progression or intolerable toxicity. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and treatment-related adverse events (TRAEs). Stratified factors included treatment lines and hormone receptor (HR) status. Results: Between June 2018 and March 2023, 29 patients were enrolled into the study. The median follow-up time was 25.4 months (range, 2.0-53.8). In the entire group, the 1-year PFS rate was 54.1%. ORR, DCR and CBR were 31.0%, 96.6% and 62.1%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). Subgroup analysis revealed that ORRs were 29.4% and 33.3% in first- and =second-line chemotherapy, respectively. ORRs were 29.2% (7/24) and 40.0% (2/5) for HR-positive MBC and metastatic triple-negative breast cancer (mTNBC), respectively. Grade 3/4 TRAEs were neutropenia (10.3%) and nausea/vomiting (6.9%). Conclusions: The dual oral mNC regimen showed very good safety features and improved compliance without loss of efficacy in both first- and second-line treatments. The regimen also reached an excellent ORR in the mTNBC subgroup. [ABSTRACT FROM AUTHOR]

An 82‐year‐old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune‐related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine‐based immunosuppressant was effective against irAE hepatitis, therefore thiopurine‐based immunosuppressants may be effective against steroid‐refractory hepatitis. [ABSTRACT FROM AUTHOR]

Irinotecan‐induced hepatotoxicity can cause severe clinical complications in patients; however, the underlying mechanism and factors affecting hepatotoxicity have rarely been investigated. In this cross‐sectional study, we screened all clinical, demographic, medication, and genetic variables among 126 patients receiving irinotecan and explored potential associations with the incidence and time to onset of irinotecan‐induced hepatotoxicity. Approximately 38.9% of the patients suffered from hepatotoxicity after irinotecan administration. The presence of cardiovascular diseases increases the incidence of hepatotoxicity ≈2.9‐fold and doubles the hazard of time to hepatotoxicity. Patients with liver metastasis had a >4‐fold higher risk of hepatotoxicity and a 3.5‐fold increased hazard of time to hepatotoxicity compared to those without liver metastasis. Patients who took cytochrome P450 (CYP) 3A inducers had a 4.4‐fold increased incidence of hepatotoxicity, and furthermore, concomitant use of platinum‐based antineoplastics revealed 4.2 times the hazard of time to hepatotoxicity compared to those receiving antimetabolites. The cumulative dose of irinotecan (5‐9 cycles) increased hepatotoxicity by 8.5 times. However, the genotypes and phenotypes of UGT1A1*28/*6 failed to be predictive factors of hepatotoxicity. The findings of this study suggest that irinotecan‐induced hepatotoxicity is not directly associated with genetic variables but is mostly related to concomitant use of CYP3A4 inducers and platinum, as well as the presence of liver metastasis and cardiovascular disease. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using CYP3A inducers and platinum antineoplastic drugs, which may be the best way to prevent hepatotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: Management of immunosuppression in a kidney transplant recipient with a failed allograft is complex; continuation carries infectious and metabolic risks, and discontinuation can lead to sensitization. Methods: We evaluated risk factors for sensitization in 89 kidney or simultaneous kidney‐pancreas recipients, whose kidney transplant failed after January, 2013 and who were subsequently re‐evaluated for kidney transplantation. Results: Among recipients with pre graft failure cPRA < 50%, calcineurin inhibitor (CNI) continuation (OR.11, P =.003) and steroid continuation (OR.17, P =.04) were associated with significantly lower odds of developing an absolute increase in cPRA of ≥50%. Each additional HLA mismatch was associated with OR of 2.16 (P =.02). CNI use was associated with OR of.09 (P =.001) for increase in cPRA to ≥80% if pre graft failure cPRA was <50%, and OR of.08 (P =.02) for increase in cPRA to ≥98% if pre graft cPRA was <80%. Anti‐metabolites were continued more often among recipients who had a <50% increase (P =.006); however, the association was lost on multivariate analyses. Weaning off immunosuppression and higher number of HLA mismatches are associated with greater likelihood of sensitization. Conclusion: While both CNI and steroid continuation conferred some protection against increase in cPRA, CNI continuation was the only factor protecting against becoming highly sensitized. [ABSTRACT FROM AUTHOR]

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co‐administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration‐time curve from zero to infinity (AUC0‐inf) and analyzed by a linear mixed effect model. Twenty‐two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0‐inf of capecitabine (95% confidence interval (CI) −10.0% to 57.0%, P = 0.36). In addition, capecitabine half‐life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI −16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI‐cotreated patients with cancer. [ABSTRACT FROM AUTHOR]

Background Information: Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5‐year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5‐fluorouracil, irinotecan (SN‐38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long‐term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient‐derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO. Results: We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi‐compartmental elimination models of oxaliplatin and SN‐38. We then treated PaTa‐1818x naive PDAC organoids with six cycles of 72 h‐FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa‐1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness. Conclusions: We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa‐1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse. Significance: To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Over the recent years there has been a noticeable upsurge of interest in aza‐analogs of tryptophan which are isosteric to the latter and found numerous applications in medicinal, bioorganic chemistry, and peptide research. In the present review article, five aza‐tryptophan derivatives are profiled, including aza‐substitution in the positions 2, on the five‐membered ring, as well as in positions 4, 5, 6, and 7 on the six‐membered ring. A detailed and comprehensive literature overview of the synthetic methods for the preparation of these aza‐tryptophans is presented and general facets of the biological properties and most promising applications are discussed. [ABSTRACT FROM AUTHOR]

Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single‐locus analysis showed that the single‐nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P <.0038). The gene‐gene interaction analysis identified the overall best models, including a 2‐way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P =.0022) and a 3‐locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P =.0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene‐gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine‐induced hematological toxicity. Moreover, we propose a promising data‐mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene‐gene interactions. [ABSTRACT FROM AUTHOR]

Background: Thiopurine methyltransferase (TPMT) polymorphism is one of the causes of the toxicity of thiopurines, but this is rarely seen in Asian populations. Rather, the nucleoside diphosphate‐linked X‐component motif 15 (NUDT15) gene is frequently linked to mercaptopurine (MP) intolerance and myelotoxicity in children with acute lymphoblastic leukemia (ALL) in East Asians; however, little is known about the NUDT15 polymorphism in healthy children, especially in ethnic minorities in China. Methods: A total of 162 cases of healthy children with Bai nationality were enrolled for NUDT15 genotyping. Results: Three coding variants were identified in the NUDT15 gene including rs186364861, rs746071566 and rs116855232. Notably, the rs746071566 and rs116855232 in NUDT15 showed much higher frequencies in healthy children with Bai nationality compared with healthy East Asian populations, suggesting a concentrated distribution of these variants in the Bai ethnic group. Conclusions: This finding reveals the genetic polymorphism of NUDT15 in children with Chinese Bai nationality, providing a biological genetic background for the individualized therapy of thiopurines for children with Bai nationality in China. [ABSTRACT FROM AUTHOR]

A 72‐year‐old man, diagnosed with advanced lung squamous cell carcinoma, was administered of cisplatin plus gemcitabine with necitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), as a sixth‐line treatment. Tumor shrinkage was observed, but asymptomatic grade 4 hypomagnesemia occurred on day 8 of the second cycle. He received magnesium replenishment and hypomagnesemia recovered on day 40, but tumor progression was observed during the period of magnesium correction. Hypomagnesemia is known as a major adverse event of treatment with anti‐EGFR antibodies, but there have been no case reports of severe hypomagnesemia or its clinical course. [ABSTRACT FROM AUTHOR]

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML. [ABSTRACT FROM AUTHOR]

Figures from the Editors selected issue highlights will be displayed each month in the journal image carousel on the BJCP homepage http://bpspubs.onlinelibrary.wiley.com/hub/journal/10.1111/(ISSN)1365-2125/. B On precision dosing of oral small molecule drugs in oncology b Alex K. Lyashchenko and Serge Cremers DOI: 10.1111/bcp.14454 B Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom b Shelby Barnett, Jordon Kong, Guy Makin and Gareth J. Veal DOI: 10.1111/bcp.14419 B Is there scope for better individualisation of anthracycline cancer chemotherapy? And further interesting cohort data come from Scotland's methadone prescription cohort and showed age, female gender and high dose of methadone were associated with increased risk of methadone-specific drug related death. [Extracted from the article]

Despite advances in targeted cancer therapy, the fluoropyrimidines 5‐fluorouracil (5FU) and capecitabine continue to play an important role in oncology. Historically, dosing of these drugs has been based on body surface area. This approach has been demonstrated to be an imprecise way to determine the optimal dose for a patient. Evidence in the literature has demonstrated that precision dosing approaches, such as DPD enzyme activity testing and, in the case of intravenous 5FU, pharmacokinetic‐guided dosing, can reduce toxicity and yield better patient outcomes. However, despite the evidence, there has not been uniform adoption of these approaches in the clinical setting. When a drug such as 5FU has been used clinically for many decades, it may be difficult to change clinical practice. With the aim of facilitating change of practice, issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed. [ABSTRACT FROM AUTHOR]

Background: COVID‐19 has been spreading worldwide with a significant death toll. Solid‐organ transplantation (SOT) recipients are at higher risk due to their suppressed immune system. In this study, we aimed to conduct a systematic review on COVID‐19 clinical manifestations and treatment strategies in SOT recipients. Methods: We searched three databases for relevant terms related to COVID‐19 and transplantation. 50 studies, including 337 patients, were reviewed. Results: Two hundred thirty six patients were male, with a mean age of 49.9 years. The most prevalent group was the kidney 57.0%, followed by 17.2% heart and 13.6% liver. Fever and cough were the most reported clinical presentations. Infiltration (55.4%) in chest x‐ray and ground‐glass opacity (67.1%) in CT scans were the most radiological findings. It was found that 96.8% and 72.4% of patients present with CRP level and lymphocytopenia, respectively, and 70.6% of kidney recipients patients presented with high creatinine levels. The most common baseline immunosuppressants were calcineurin inhibitors (88.9%) and antimetabolites (73.2%). Antimetabolites (84.3%) and calcineurin inhibitors (54.3%) were discontinued/decreased 84.3% whereas glucocorticoids dosage almost has no change (77.9%) or even increased. 18.4% of cases had died, and 65.9% were discharged. Conclusions: Patients' demographics, signs, symptoms, and radiographic findings in SOT recipients are almost similar to the general population. However, gastrointestinal symptoms appear to be more common. There are different treatment strategies, but in most of them, antimetabolite and calcineurin inhibitors were decreased or discontinued, while corticosteroids were increased. Finally, COVID‐19 seems to be more severe and has higher mortality in SOT recipients compared to the general population. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide, with 9.6 million cancer‐related deaths in 2018. Cancer incidence has increased over time, and so has the prescription rate of chemotherapeutic drugs. These pharmaceuticals, known as antineoplastic agents, enter the aquatic environment via human excretion and wastewater. The objectives of the present critical review were to investigate the risk of antineoplastics to aquatic species and to summarize the current state of knowledge regarding their levels in the environment, because many antineoplastics are not adequately removed during wastewater treatment. We conducted 2 separate literature reviews to synthesize data on the global environmental prevalence and toxicity of antineoplastics. The antineoplastics most frequently detected in the environment included cyclophosphamide, ifosfamide, tamoxifen, methotrexate, and 5‐fluorouracil; all were detectable in multiple water sources, including effluent and surface waters. These antineoplastics span 3 different mechanistic classes, with cyclophosphamide and ifosfamide classified as alkylating agents, tamoxifen as a hormonal agent, and methotrexate and 5‐fluorouracil as antimetabolites. Studies that characterize the risk of antineoplastics released into aquatic environments are scarce. We summarize the biological impacts of the most environmentally prevalent antineoplastics on aquatic organisms and propose an adverse outcome pathway for cyclophosphamide and ifosfamide, 2 widely prescribed drugs with a similar immunotoxic mode of action. Acute and chronic ecotoxicity studies using aquatic models are needed for risk characterization of antineoplastics. Environ Toxicol Chem 2020;39:967–985. © 2020 SETAC [ABSTRACT FROM AUTHOR]

The aim of the study was to research the biological functions of circRNA (hsa_circ_0079662) and its underlying mechanism in colorectal cancer. Drug‐resistant cell lines (HT29‐LOHP, HCT116‐LOHP, HCT8‐LOHP) were separately dealt with oxaliplatin concentration gradient (0.1‐10 μmol/L). Real‐time PCR, Western blotting, dual‐luciferase assay, miRNA pull‐down assay, coimmunoprecipitation and ELASA were performed to explore the mechanism of chemotherapy drug oxaliplatin resistance in CRC. The results showed that the expression of hsa_circ_0079662 was increased in drug‐resistant cell lines by RT‐PCR. The expression of HOXA9, TRIP6, Vcam‐1, VEGFC, MMP3, MMP9 and MMP14 was higher by Western blotting. Interaction between HOXA9 and TRIP6 in CO‐IP detection. Additionally, the cytokines TNF‐α, IL‐1 and IL‐6 were also found. In conclusion, hsa_circ_0079662, as a ceRNA binding with hsa‐mir‐324‐5p, can regulate target gene HOXA9 and induced the mechanism of chemotherapy drug oxaliplatin resistance in CRC through the TNF‐α pathway in human colon cancer. [ABSTRACT FROM AUTHOR]

Background: There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6‐MP). Xanthine oxidase inhibition increases concentrations of AZA and 6‐MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6‐MP, dose reduction of AZA or 6‐MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout. Objective: To determine the clinical impact of the febuxostat‐thiopurine DI. Design and Setting: Case series derived from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and published medical literature. Patients: Nineteen patients who received concomitant febuxostat and either AZA or 6‐MP. Measurements: Laboratory and clinical data. Results: Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6‐MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization; 15 reported administration of blood products. Thirteen cases reported resolution of the event with discontinuation of both drugs, two reported discontinuation of the thiopurine only, and one reported discontinuation of febuxostat only. Limitations: Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real‐world morbidity and mortality associated with the febuxostat‐thiopurine DI were not examined. Finally, FAERS data are limited by the voluntary nature of reporting. Conclusion: Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6‐MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling. [ABSTRACT FROM AUTHOR]

Cardiovascular side effects of broadly used chemotherapeutic drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) among cancer survivors are well established. Nitric oxide (NO) is known to protect cardiovascular tissues under conditions of stress. NO can act through cyclic guanosine monophosphate (cGMP)‐dependent and ‐independent pathways. Particularly, the S‐nitrosylation of SH‐groups in a protein by NO falls under cGMP‐independent effects of NO. TC, CP, and EP are hypothesized as interfering with cellular protein S‐nitrosylation, which, in turn, may lead to endothelial dysfunctions. The results show that all three drugs attenuate nitrosylated proteins in endothelial cells. A significant reduction in endogenous S‐nitrosylated proteins was revealed by Saville–Griess assay, immunofluorescence and western blot. Incubation with the drugs causes a reduction in endothelial migration, vasodilation and tube formation, while the addition of S‐nitrosoglutathione (GSNO) has a reversal of this effect. In conclusion, results indicate the possibility of decreased cellular nitrosothiols as being one of the reasons for endothelial dysfunctions under TC, CP and EP treatment. Identification of the down‐regulated S‐nitrosylated proteins so as to correlate their implications on fundamental vascular functions could be an interesting phenomenon. [ABSTRACT FROM AUTHOR]

This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug‐drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady‐state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04‐1.49), 1.30 (1.11‐1.53) and 1.28 (1.11‐1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration‐time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16‐1.66), minimum plasma concentration (1.53; 1.10‐2.12) and area under the concentration‐time curve from time zero to 8 hours (1.41; 1.19‐1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients. [ABSTRACT FROM AUTHOR]

Aims: Drug‐induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify suspected drugs. Methods: Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed. Results: In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti‐inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45–55% of neutrophils +45–55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms. Conclusion: The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM. [ABSTRACT FROM AUTHOR]

Background: Drug‐eluting beads bronchial arterial chemoembolization (DEB‐BACE) can embolize the tumor‐feeding artery and also be loaded with antitumor drugs, which can be released slowly into the local tumor environment. The effect of DEB‐BACE in patients with lung cancer remains unclear. We evaluated the efficacy and safety of DEB‐BACE with gemcitabine‐loaded CalliSpheres beads in patients with non‐small cell lung cancer (NSCLC). Methods: From May 2017 to December 2018, six patients with NSCLC who were ineligible or refused to receive standard treatment underwent DEB‐BACE with gemcitabine‐loaded CalliSpheres beads. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression‐free survival (PFS), overall survival (OS), and quality of life. Safety was evaluated by the occurrences of adverse events and serious adverse events. Results: All patients were treated with DEB‐BACE loaded with gemcitabine (800 mg) using CalliSpheres beads. Five patients also received transarterial infusion with nedaplatin (80–100 mg). Of the six patients, five underwent a second session of DEB‐BACE, with intervals of one month between the first and second session. The median follow‐up time was 16.5 months (7.0–23.0 months). ORR and disease control rate were 50.0% and 100.0%, 50.0% and 83.3%, 50.0% and 66.7% respectively at 2, 4, and 6 months after DEB‐BACE. One patient maintained a partial response and the other five had progressive disease, of whom two patients died and the other three remained alive receiving targeted therapy, radiotherapy, transarterial infusion or thermal ablation. The median PFS was 8.0 months (4–23 months), and the 6‐ and 12 month PFS rates were 66.7% and 16.7%, respectively. The median OS was 16.5 months (7–23 months), and the six and 12 month OS rates were 100.0% and 66.7%, respectively. Hemoptysis, cough and dyspnea disappeared after DEB‐BACE in four patients. Global quality of life, physical and emotional functioning were all significantly improved at two months (P < 0.05). There were no serious adverse events. Conclusions: DEB‐BACE with gemcitabine‐loaded CalliSpheres beads is a feasible and well‐tolerated treatment for patients with NSCLC who are ineligible or refuse to receive standard treatment. [ABSTRACT FROM AUTHOR]

Background: 6‐Mercaptopurine (6‐MP) is considered the backbone of therapy in the maintenance phase of acute lymphoblastic leukemia (ALL). Gene polymorphisms involved in thiopurine degradation are predictors of toxicity in patients treated with 6‐MP. We investigated the effects of nucleoside diphosphate linked moiety X (nudix) type motif 15 (NUDT15) polymorphism NUDT15c.415C>T on neutropenia incidence, dose adjustment for 6‐MP, and survival rates in Thai children with ALL. Methods: Children diagnosed with ALL who received 6‐MP in the maintenance phase of treatment, in 2005–2016, were retrospectively enrolled. Results: The subjects consisted of 102 patients (median age, 5.2 years; 58 boys). On genetic testing 78, 22, and two patients were normal (CC), heterozygous (CT), and homozygous (TT), respectively. The incidence of neutropenia at 3 months was significantly higher in the CT/TT than CC polymorphism groups (OR, 12; 95%CI: 3.781–38.085, P < 0.001). The mean dose of 6‐MP at 3, 6, and 12 months was significantly lower in the CT/TT versus the CC group (P < 0.001). The 5 year overall survival (OS) rate for CC was 80.4%, and for CT/TT, 95.5% (P = 0.34). The 5 year event‐free survival (EFS) for CC and CT/TT was 75.1% and 85.7%, respectively (P = 0.17). After adjusted risk classification, no significant differences were observed for OS or EFS between the CC and CT/TT groups. Conclusion: Patients harboring the CT/TT polymorphism of NUDT15 had a significantly higher incidence of neutropenia during the first 3 months of maintenance, resulting in significantly lower doses of 6‐MP. [ABSTRACT FROM AUTHOR]

Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma.Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m2 gemcitabine on days 1 and 8 and 75 mg/m2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts.Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated.Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone. [ABSTRACT FROM AUTHOR]

Background: 5‐Fluorouracil (5‐FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all‐in‐one, pH neutral stable solution of 5‐FU plus LV with β‐cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first‐in‐human phase I trial. Methods: Patients with advanced solid malignancy received Deflexifol as weekly bolus (375–575 mg/m²) or two‐weekly 46 h infusion (1200–3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. Results: Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose‐limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m2 (maximum tolerated dose 525 mg/m²), whereas none were reported for the infusional schedule. The recommended phase II infusional dose was declared as 3,000 mg/m², >25% that of 5‐FU used in standard‐of‐care regimens. Pharmacokinetic analyses showed evidence of inter‐patient variability, with no evidence of saturation in clearance, and a trend to linear increase in AUC with dose. Disease control rate was 64% despite most patients having failed previous 5‐FU regimens. Conclusion: Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5‐FU and LV. A phase II study evaluating Deflexifol is planned. [ABSTRACT FROM AUTHOR]

Pretubulysin (PT), a potent tubulin‐binding antitumoral drug, and the well‐established antimetabolite methotrexate (MTX) were tested separately or in combination (PT+MTX) for antitumoral activity in L1210 leukemia cells or KB cervix carcinoma cells in vitro and in vivo in NMRI‐nu/nu tumor mouse models. In cultured L1210 cells, treatment with PT or MTX displays strong antitumoral effects in vitro, and the combination PT+MTX exceeds the effect of single drugs. PT also potently kills the MTX resistant KB cell line, without significant MTX combination effect. Cell cycle analysis reveals the expected arrest in G1/S by MTX and in G2/M by PT. In both cell lines, the PT+MTX combination induces a G2/M arrest which is stronger than the PT‐triggered G2/M arrest. PT+MTX does not change rates of apoptotic L1210 or KB cells as compared to single drug applications. Confocal laser scanning microscopy images show the microtubule disruption and nuclear fragmentation induced by PT treatment of L1210 and KB cells. MTX changes the architecture of the F‐actin skeleton. PT+MTX combines the toxic effects of both drugs. In the in vivo setting, the antitumoral activity of drugs differs from their in vitro cytotoxicity, but their combination effects are more pronounced. MTX on its own does not display significant antitumoral activity, whereas PT reduces tumor growth in both L1210 and KB in vivo models. Consistent with the cell cycle effects, MTX combined at moderate dose boosts the antitumoral effect of PT in both in vivo tumor models. Therefore, the PT+MTX combination may present a promising therapeutic approach for different types of cancer. [ABSTRACT FROM AUTHOR]

Background: The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB).Methods: A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment.Results: A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring <1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P = .0001). For patients with tumors measuring <1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P = .54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring <1 cm.Conclusions: The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC. [ABSTRACT FROM AUTHOR]

Abstract: Hypoglycemia is the most important complication of antidiabetic medications. Most patients with diabetes mellitus take multiple medications. In this study, we explored clinical drug‐drug interactions that result in hypoglycemia by analyzing the Japanese Adverse Drug Event Report (JADER) database. The primary outcome was the report of hypoglycemia. The Norén and Gosho methods, which quantitatively measure the discrepancy between the observed and expected number of adverse events under the combination of 2 drugs, were used as the criteria for detecting drug‐drug interactions. The JADER database contained patient characteristics with 468 292 records, drug information with 2 973 172 records, and adverse reactions with 741 016 records. We noted that hypoglycemia was reported in 6208 patients. Concomitant use of linagliptin/glibenclamide, sitagliptin/glibenclamide, sitagliptin/buformin, exenatide/voglibose, mitiglinide/perindopril, repaglinide/barnidipine, alogliptin/cilnidipine, teneligliptin/barnidipine, teneligliptin/urapidil, exenatide/candesartan, voglibose/barnidipine, voglibose/guanabenz, or exenatide/tocopherol was noted using the 2 criteria for drug‐drug interactions. Concomitant use of teneligliptin and barnidipine produced the highest values for the 2 criteria. The second‐and third‐highest values were observed for teneligliptin/urapidil and exenatide/candesartan combinations, respectively. The same analysis was performed using the US Food and Drug Administration Adverse Event Reporting System database to assess the validity of the result from the JADER database. The concomitant use of sitagliptin/buformin, exenatide/voglibose, repaglinide/barnidipine, teneligliptin/barnidipine, teneligliptin/urapidil, exenatide/candesartan, voglibose/barnidipine, voglibose/guanabenz, or exenatide/tocopherol was detected in both the JADER and Food and Drug Administration Adverse Event Reporting System databases. Combination therapy with the drugs listed above would show potential interactions that could result in hypoglycemia in patients with diabetes mellitus. [ABSTRACT FROM AUTHOR]

Abstract: 6‐Thioguanine (6TG) is a DNA‐targeting therapeutic used in the treatment of various cancers. While 6TG was rationally designed as a proof of concept for antimetabolite therapy, it is also a rare thioamide‐bearing bacterial natural product and critical virulence factor of Erwinia amylovorans, plant pathogens that cause fire blight. Through gene expression, biochemical assays, and mutational analyses, we identified a specialized bipartite enzyme system, consisting of an ATP‐dependent sulfur transferase (YcfA) and a sulfur‐mobilizing enzyme (YcfC), that is responsible for the peculiar oxygen‐by‐sulfur substitution found in the biosynthesis of 6TG. Mechanistic and phylogenetic studies revealed that YcfA‐mediated 6TG biosynthesis evolved from ancient tRNA modifications that support translational fidelity. The successful in vitro reconstitution of 6TG thioamidation showed that YcfA employs a specialized sulfur shuttle that markedly differs from universal RNA‐related systems. This study sheds light on underexplored enzymatic C−S bond formation in natural product biosynthesis. [ABSTRACT FROM AUTHOR]

Background: Platinum‐based chemotherapy is the standard first‐line treatment for patients with advanced pan‐negative non‐squamous (non‐Sq) non‐small cell lung cancer (NSCLC). However, it is unknown which chemotherapy regimen confers the greatest benefit in such patients. This study explored which chemotherapy regimens were advantageous in non‐Sq NSCLC patients. Methods: A retrospective study was conducted on 114 patients with advanced non‐Sq NSCLC using platinum‐based chemotherapy in a first‐line setting between January 2013 and December 2015. The study evaluated the most common first‐line regimens including pemetrexed/platinum (PP), paclitaxel/carboplatin, gemcitabine/platinum, and vinorelbine/cisplatin. The primary endpoint was progression‐free survival (PFS), and secondary endpoints were the objective response rate and disease control rate (DCR). Univariate and multivariate logistic analysis was carried out. Results: Sixty of the 114 patients were administered PP regimens and 54 non‐pemetrexed plus platinum (NPP) regimens. The median PFS was significantly longer in the PP than in the NPP group (7.2 months, 95% confidence interval [CI] 5.3–9.1 vs. 4.9 months, 95% CI 3.2–6.6; P = 0.031). The DCR of the PP regimen was better than that of the NPP regimen (90.0% vs. 74.1%; P = 0.026). Smoking status was an independent predictor of PFS (hazard ratio 2.1, 95% CI 1.4–3.3; P = 0.001) in a final multivariate Cox regression model. Conclusions: A PP regimen tends to be more beneficial than an NPP regimen for patients with pan‐negative advanced non‐Sq NSCLC. Smoking status may be a valuable predictor for the selection of a chemotherapy regimen in such patients. [ABSTRACT FROM AUTHOR]

The article reports on the history of cancer research in the U.S. Topics discussed include cancer laboratory research focusing on the use of surgery and radiotherapy for treating cancer; medical research on tissue histology and animal xenograft; and advances made in chemotherapy such as development of novel antimetabolites, alkylating agents, and nucleoside analogs.

Abstract: Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin‐resistant non‐small human cell lung cancer and ovarian cancer cell lines. Cisplatin‐resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin‐sensitive controls. The susceptibility of cisplatin‐resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin‐resistant clones, and glutamine supplementation rescued cisplatin‐resistant clones from starvation‐induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin‐resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin‐resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism. [ABSTRACT FROM AUTHOR]

Summary: The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher‐risk disease treated with azacitidine (AZA) in the ‘real‐world’ remains largely unknown. We evaluated 1101 consecutive higher‐risk MDS patients (International Prognostic Scoring System intermediate‐2/high) and low‐blast count acute myeloid leukaemia (AML; 21–30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5‐2‐2. Overall, median number of cycles was 6 (range 1–67) and 8 (range 6–14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7–12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6–19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML. [ABSTRACT FROM AUTHOR]

Abstract: Raltitrexede (RTX) is a folate analogue that belongs to the antimetabolites family and has antineoplastic activity correlated to inhibition of the thymidylate synthase (TS) enzyme. This study addresses the electrochemical characterization of RTX at a glassy carbon electrode, on a wide interval of pH, using voltammetric techniques. The interaction between RTX and double helix DNA (dsDNA) in physiological medium is also addressed, using a DNA‐electrochemical biosensor. A mechanism for the electrochemical oxidation of RTX is proposed. RTX is irreversibly electroxidized under a predominantly diffusion controlled and pH‐dependent process. The oxidation process in acid and physiological media occurs in two consecutive steps. The first oxidation step is pH‐independent and associated with the transfer of one electron of the nitro group at N10 position by releasing a methyl cation. The second oxidation step is pH‐dependent and occurs with the transfer of one electron and one proton from the carbon at C9 position, followed by a direct attack by a water molecule leading to an irreversible dissociation of an oxidation product of RTX. A strong interaction between RTX and dsDNA was revealed by using a multilayer dsDNA electrochemical biosensor. The experiments demonstrated that RTX interacts and binds to the dsDNA helix by different interaction modes, suggesting an intercalation in between the DNA base pairs leading to defects in its secondary structure. [ABSTRACT FROM AUTHOR]

Summary: Background: Elbasvir‐grazoprevir is indicated for chronic hepatitis C virus (HCV) genotypes 1 and 4. Aim: To evaluate the utilization and outcomes of chronic HCV patients treated with elbasvir‐grazoprevir in the United States. Methods: We conducted a retrospective cohort study of adults treated with elbasvir‐grazoprevir with or without ribavirin for chronic HCV genotypes 1 or 4 infection. Data were collected from healthcare providers and specialty pharmacies through Innervation Platform, a proprietary, cloud‐based disease management program from Trio Health. The primary endpoint was per protocol sustained virological response 12 weeks post‐treatment (SVR12). Results: Among 470 patients treated in 2016, 95% had HCV genotype 1 infection, 80% (373/468) were HCV treatment naïve and 70% (327/468) had non‐cirrhotic disease. Almost 3 quarters (73%) of patients received care in community practices. The majority (89%) of patients received elbasvir‐grazoprevir for 12 weeks. Per protocol SVR12 rates were 99% (396/402) for HCV genotype 1 and 95% (21/22) for HCV genotype 4. Among patients with Stage 4 or 5 chronic kidney diseases, 99% (113/114) achieved SVR12. In univariate analyses, variables significantly associated with per protocol SVR12 for the entire sample were therapy duration (P = 0.001), treatment experience (P = 0.016), and cirrhosis status (P = 0.001). However, among HCV genotype 1 patients, no variables were significant. Intent‐to‐treat SVR12 rates were 89% (396/447) for HCV genotype 1 and 91% (21/23) for HCV genotype 4. Conclusion: Elbasvir‐grazoprevir is highly effective, and in this 2016 cohort, its use was predominantly in patients with HCV genotype 1 and as a 12‐week therapy without ribavirin. [ABSTRACT FROM AUTHOR]

Summary: Treatment with azacitidine (AZA) has been suggested to be of benefit for higher‐risk myelodysplastic syndrome (HR‐MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR‐MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time‐varying variable in multivariable analysis. A Cox Regression model with time‐interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non‐CK) and International Prognostic Scoring System risk (high versus intermediate‐2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non‐CK patients, P < 0·05 for all). AZA also significantly improved progression‐free survival (P < 0·01). This study confirms a time‐dependent benefit of AZA on outcome in patients with HR‐MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK. [ABSTRACT FROM AUTHOR]

The aim of this retrospective cohort study was to investigate the incidence of delayed methotrexate elimination in patients treated with high-dose methotrexate (≥1 g/m2 ) for haematological malignancy and to identify the impact of interacting drugs, especially proton-pump inhibitors (PPIs) and ranitidine. All patients treated with high-dose methotrexate over a 6 year period in the haematology department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) were included. Potential risk factors for delayed methotrexate elimination were tested in a generalized linear model by univariate analysis: patient age, gender, methotrexate dose, administration of PPI or ranitidine, and concomitant nephrotoxic drugs. A total of 412 cycles of methotrexate were administered to 179 patients. Proton-pump inhibitors were co-administered with methotrexate in 127 cycles and ranitidine in 192 cycles. Ninety-three cycles included no antacid drugs. A total of 918 plasma methotrexate assays were performed. Methotrexate concentrations were checked at 24 hours in 92% of cycles. Delayed methotrexate elimination was observed in 20.9% of cycles. A total of 63 cycles with delayed methotrexate elimination were only identified on plasma methotrexate measures at 72 hours: ie, plasma methotrexate was in the normal range at 24 and 48 hour post injection. Use of PPI/ranitidine or no antacid drugs did not increase risk of delayed elimination, with respectively delayed methotrexate elimination in 20.5%, 21.9%, and 19.4% of cycles (P = .89). Impaired baseline creatinine clearance showed significant association in univariate analysis. Fifteen patients showed grade 1 acute kidney injury, 1 grade 2, 2 grade 3, and none grade 4. For half of these cases, delayed methotrexate elimination was observed and the 2 grade 3 events appeared in patients treated with PPIs. This retrospective study suggests that there is no association between concomitant use of proton-pump inhibitors (pantoprazole and esomeprazole) or ranitidine and delayed methotrexate elimination. [ABSTRACT FROM AUTHOR]

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 × 103 cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 × 103 cells/μL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC ≤ 2 × 103 cells/μL at 6 m (5y OS 85% vs 48%, P = .004) and ALC ≤ 1.8 × 103 cells/μL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (≤4 × 103 cells/μL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted Treg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored. [ABSTRACT FROM AUTHOR]

Background The purpose of this retrospective study was to evaluate the feasibility and efficacy of definitive concurrent chemoradiotherapy (CCRT) with capecitabine and cisplatin for elderly patients with locally advanced esophageal squamous cell carcinoma. Methods A total of 90 patients were included from two different centers. Forty-nine patients were treated with CCRT consisting of capecitabine (850 mg/m2, oral, twice a day for 1-14 days) and cisplatin (20 mg/m2) weekly during radiotherapy (RT). The remaining 41 patients were treated with RT alone. The overall response, overall survival, progression-free survival, and toxicity rates were recorded. Results Compared to the RT group (51.2%; P = 0.029), the overall response rate in the CCRT group (73.5%) was obviously higher. A complete response was achieved in 34.7% and 14.6% of patients in the CCRT and RT groups, respectively ( P = 0.030). Median progression-free and median overall survival rates were significantly higher in the CCRT group (24.7 and 30.6 months; P < 0.05) compared to the RT group (16.6 and 18.7 months). Acute toxic effects were more severe in the CCRT group, but no significant difference in grade 3 or 4 acute toxicities was observed between the groups. Conclusion Both CCRT with capecitabine and cisplatin and RT alone are feasible to treat elderly patients and yield a good performance status with locally advanced esophageal squamous cell carcinoma. CCRT improved the tumor response without increasing the side effects compared to RT alone. CCRT is recommended for patients over 65 with good performance status. [ABSTRACT FROM AUTHOR]

Thiopurines are part of a clinical regimen used for the treatment of autoimmune disorders and childhood acute lymphoblastic leukemia. However, despite these successes, there are also unintended consequences such as therapy‐induced cancer in long‐term survivors. Therefore, a better understanding of cellular responses to thiopurines will lead to improved and personalized treatment strategies. RAD51D is an important component of homologous recombination (HR), and our previous work established that mammalian cells defective for RAD51D are more sensitive to the thiopurine 6‐thioguanine (6TG) and have dramatically increased numbers of multinucleated cells and chromosome instability. 6TG is capable of being incorporated into telomeres, and interestingly, RAD51D contributes to telomere maintenance, although the precise function of RAD51D at the telomeres remains unclear. We sought here to investigate: (1) the activity of RAD51D at telomeres, (2) the contribution of RAD51D to protect against 6TG‐induced telomere damage, and (3) the fates of Rad51d‐deficient cells following 6TG treatment. These results demonstrate that RAD51D is required for maintaining the telomeric 3′ overhangs. As measured by γ‐H2AX induction and foci formation, 6TG induced DNA damage in Rad51d‐proficient and Rad51d‐deficient cells. However, the extent of γ‐H2AX telomere localization following 6TG treatment was higher in Rad51d‐deficient cells than in Rad51d‐proficient cells. Using live‐cell imaging of 6TG‐treated Rad51d‐deficient cells, two predominant forms of mitotic catastrophe were found to contribute to the formation of multinucleated cells, failed division and restitution. Collectively, these findings provide a unique window into the role of the RAD51D HR protein during thiopurine induction of mitotic catastrophe. Environ. Mol. Mutagen. 59:38–48, 2018. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML).Methods: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine.Results: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]).Conclusions: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Key Clinical Message Methotrexate-induced leukoencephalopathy is to be considered as a potential etiology in any patient presenting with stroke-like symptoms after receiving methotrexate. One of our cases suggests that the method of administration of the methotrexate can be IV or intrathecal and still results in leukoencephalopathy. [ABSTRACT FROM AUTHOR]

Background This study was conducted to evaluate the value of gemcitabine combined with cisplatin as adjuvant chemotherapy for radical resection of non-small cell lung cancer. Methods Data of 100 patients who had undergone radical resection of non-small cell lung cancer and were treated with cisplatin/gemcitabine as adjuvant chemotherapy between June 2007 and December 2010 at the Chinese Academy of Medical Sciences were reviewed. Results The median age was 59 years (range 36-73); 82% of the patients were male. Forty-two percent had adenocarcinoma and 55% had squamous cell carcinoma. Most patients had pathologic IIB (29%) and IIIA (44%) stage disease. Eighty-five percent of patients completed four cycles of chemotherapy, with 76% completing the planned full dose. The main reason for a reduced gemcitabine dose in 13 patients was grade 3/4 neutropenia or thrombocytopenia. The median dose and dose intensity were 8377.1 mg/m2 and 708 mg/(m2/week) for gemcitabine and 293.38 mg/m2 and 25.24 mg/(m2/week) for cisplatin, respectively. During follow-up the median disease-free survival was 33.8 months (95% confidence interval [ CI] 15.938-51.676). Patients with squamous cell carcinoma (hazard ratio [ HR] 0.404, 95% CI 0.241-0.676; P = 0.001) and pathologic stage I ( HR 4.379, 95% CI 1.721-11.142; P = 0.002) achieved better disease-free survival. The survival rates at one, two, and five years were 94%, 77%, and 55%, while the survival rates without recurrence were 64%, 53%, and 39%, respectively. Conclusion As an adjuvant chemotherapy regimen, gemcitabine with cisplatin is well tolerated. Patients with squamous cell carcinomas or pathologic stage I achieve better results. [ABSTRACT FROM AUTHOR]

Hand-foot syndrome (HFS) is a frequent dose-limiting adverse reaction of capecitabine in patient with gastrointestinal cancers. Silymarin is a polyphenolic flavonoid extracted from the Silybum marianum that exhibits strong antioxidant and antiinflammatory activities. In this study, we evaluated silymarin efficacy in prevention of capecitabine-induced HFS in patients with gastrointestinal cancers, as the first human study. During this pilot, randomized, double-blinded, placebo-controlled clinical trial, the effect of silymarin gel 1%, which is applied on the palms and soles twice daily starting at the first day of chemotherapy for 9 weeks, on HFS occurrence was assessed. Forty patients fulfilled the inclusion criteria assigned to the silymarin or placebo group. World Health Organization HFS grading scale scores were recorded at baseline and every 3 weeks during these 9 weeks. The median WHO HFS scores were significantly lower in silymarin group at the end of the 9th week (p < 0.05). The scores increased significantly in both placebo and silymarin groups during chemotherapy, but there was a delay for HFS development and progression in silymarin group. Prophylactic administration of silymarin topical formulation could significantly reduce the severity of capecitabine-induced HFS and delays its occurrence in patients with gastrointestinal cancer after 9 weeks of application. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile.Methods: To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468).Results: At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease.Conclusions: Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML. Cancer 2017;123:2671-79. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Improvement of the biosynthetic capabilities of industrially relevant microbes to produce desired metabolites in higher quantities is one of the important topics of modern biotechnology. In this article, different strategies of improvement of mutated microbial strains are briefly described. This is followed by the first comprehensive review of the literature on obtaining high yielding microorganisms, that is, mutants exhibiting resistance to antimetabolites, nutritional repression, and abiotic stresses as well as tolerance to solvents and toxic substrates or products. Furthermore, the efficiency of the microbial metabolites produced by improved microbial strains, advantages, and limitations, as well as future prospects for strategies of strain development are discussed. [ABSTRACT FROM AUTHOR]

Objective: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2-/- ) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy.Methods: To test these hypotheses, we assessed two therapies in Tk2-/- mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP.Results: We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2-/- animals compared to dCMP+dTMP.Interpretation: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652. [ABSTRACT FROM AUTHOR]

Aim The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. Methods Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations. Results The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin ( n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. Conclusion The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen. [ABSTRACT FROM AUTHOR]