Accidental Ixazomib Overdose in a Patient With Multiple Myeloma.

Multiple myeloma is the second most common hematological malignancy. Ixazomib is the first oral proteasome inhibitor approved in the United States for the management of multiple myeloma who have received at least one prior treatment. The availability of oral chemotherapeutic agents for the management of multiple myeloma has made it easier for patients who do not have to come to the hospital for chemotherapy infusions. However, many barriers are associated with oral chemotherapy, and one of them is a misinterpretation of instruction which can have deleterious effects. In this case report, we present a case of a 69-year-old male with multiple myeloma who accidentally took ixazomib daily for 3 days instead of the weekly regimen and thus coming into the hospital with an overdose. In this report, we focus on the adverse effects associated with ixazomib toxicity and how to manage the adverse reactions. Although there is no antidote available for ixazomib, supportive care is very essential in these patients.

Non-medical caregivers and the use of intraperitoneal chemotherapy in the operating theatre: A survey on the perception of safety.

BACKGROUND: In the last two decades, intraperitoneal(IP) chemotherapy during surgery achieved recognition in the management of peritoneal metastases. Occupational hazard became a concern leading to standardized safety measures. The aim of this study is to evaluate the perceived level of information and protection among the non-medical caregivers involved in HIPEC and PIPAC in a high-volume center. METHODS: All non-medical caregivers in the operating theatre of our institution were asked to answer a questionnaire between April and May 2018. The questionnaire included multiple choice questions and open questions structured in four parts: demographic variables, perceived level of information, perceived level of protection, interest in further education. RESULTS: Forty-nine caregivers agreed to answer the questionnaire. All identified IP chemotherapy as an occupational risk. Thirty-eight persons (77.55%) trusted the protective value of safety measures during HIPEC compared to 32 (65.3%) during PIPAC. A total of 29 persons (59.18%) used some of the measures while 16 (32.65%) used all of them. Main reasons of non-use were slips and lapses (7 persons) and lack of comfort (4 persons). A total of 34 caregivers considered the level of information about safety protocols as good or very good (69%). A total of 46 persons considered the level of protection as satisfying or excellent (93.87%). A total of 36 (73.47%) interviewees expressed the need of receiving more information. CONCLUSIONS: The present study shows that non-medical caregivers in the operating theatres are aware of the occupational hazards related to the use of IP chemotherapy. The use of protective measures is associated with decreased level of perceived risk. However there is a high need of continuous education on this subject for the involved personnel.

Pharmacological inhibition of androgen receptor expression induces cell death in prostate cancer cells.

The androgen receptor (AR) plays an important role in the pathogenesis and development of prostate cancer (PCa). Mostly, PCa progresses to androgen-independent PCa, which has activated AR signaling from androgen-dependent PCa. Thus, inhibition of AR signaling may be an important therapeutic target in androgen-dependent and castration-resistant PCa. In this study, we determined the anticancer effect of a newly found natural compound, sakurasosaponin (S-saponin), using androgen-dependent and castration-resistant PCa cell lines. S-saponin induces mitochondrial-mediated cell death in both androgen-dependent (LNCaP) and castration-resistant (22Rv1 and C4-2) PCa cells, via AR expression. S-saponin treatment induces a decrease in AR expression in a time- and dose-dependent manner and a potent decrease in the expression of its target genes, including prostate-specific antigen (PSA), transmembrane protease, serin 2 (TMPRSS2), and NK3 homeobox 1 (NKX3.1). Furthermore, S-saponin treatment decreases B-cell lymphoma-extra large (Bcl-xL) and mitochondrial membrane potential, thereby increasing the release of cytochrome c into the cytosol. Moreover, Bcl-xL inhibition and subsequent mitochondria-mediated cell death caused by S-saponin were reversed by Bcl-xL or AR overexpression. Interestingly, S-saponin-mediated cell death was significantly reduced by a reactive oxygen species (ROS) scavenger, N-acetylcystein. Animal xenograft experiments showed that S-saponin treatment significantly reduced tumor growth of AR-positive 22Rv1 xenografts but not AR-negative PC-3 xenografts. Taken together, for the first time, our results revealed that S-saponin induces mitochondrial-mediated cell death in androgen-dependent and castration-resistant cells through regulation of AR mechanisms, including downregulation of Bcl-xL expression and induction of ROS stress by decreasing mitochondrial membrane potential.

Cultura de segurança dos profissionais de enfermagem no manuseio das drogas antineoplásicas / Safety culture of nursing professionals when handling antineoplastic drugs

O objeto da pesquisa foi a cultura de segurança dos trabalhadores de enfermagem de um hospital geral universitário, no manuseio das drogas antineoplásicas. Objetivo: Descrever o conhecimento e experiência dos profissionais de enfermagem acerca dos riscos ocupacionais e da proteção individual do cliente e do ambiente relacionados às drogas antineoplásicas em hospital geral; analisar os mecanismos de proteção utilizados pelos profissionais de enfermagem no manuseio dos antineoplásicos e discutir a cultura de segurança adotada pelos profissionais de enfermagem, relacionada às drogas antineoplásicas, na perspectiva da saúde do trabalhador. Metodologia: Estudo descritivo, exploratório, de abordagem qualitativa, desenvolvido em um hospital geral público federal da Região Sudeste do Brasil, com 35 trabalhadores de enfermagem. Foram utilizadas entrevistas semiestruturadas como técnica de coleta de dados para traçar o perfil sociodemográfico, profissional e laboral dos participantes e saber sobre a cultura de segurança com as drogas antineoplásicas. Utilizou-se a análise temática de conteúdo no tratamento dos dados, gerando seis categorias de análise: conhecimento dos profissionais de enfermagem sobre as drogas antineoplásicas e seus efeitos para a saúde do trabalhador; experiências dos trabalhadores de enfermagem com as drogas antineoplásicas e situações de exposição; conhecimento sobre os mecanismos de proteção ao cliente , ao ambiente, e ao trabalhador; Medidas preventivas no manuseio com drogas antineoplásicas pelos trabalhadores e instituições ­ uma questão educativa e percepção sobre condutas em caso de ocorrência de acidentes com as drogas antineoplásicas. Resultados: Constatou-se que a equipe de enfermagem não tinha experiência nem conhecimento sobre as recomendações para o manuseio seguro das drogas antineoplásicas. Não havia protocolos para sua administração e condutas em caso de acidentes, bem como capacitação à equipe de enfermagem dentro da metodologia da educação permanente e para o uso de equipamentos de proteção individual adequado. Evidenciou-se conhecimento sobre os efeitos das Hazardousdrugs e que havia medidas preventivas a serem adotadas. As questões institucionais também foram referidas, como colaboradoras e limitantes para o alcance da cultura de segurança no trabalho. Conclusão: Para a efetivação da cultura de segurança no trabalho com drogas antineoplásicas, é imprescindível que haja envolvimento da equipe de enfermagem, de outros trabalhadores que lidam com as Hazardousdrugs e dos diretores da instituição. Acredita-se que a capacitação os tornam aptos para compreender e seguir as recomendações estabelecidas no manejo adequado e enfoque preventivo com esses fármacos, ações fundamentais, pois repercutem na segurança e na saúde do trabalhador da equipe de enfermagem.

The aim of this research was the safety culture among nursing workers in a general university hospital who handle antineoplastic drugs. Aims: To describe the knowledge and experiences of nursing professionals concerning occupational risks and the client and environmental protection related to antineoplastic drugs in a general hospital; to analyze the protection mechanisms used by nursing professionals in handling antineoplastic agents and to discuss the safety culture adopted by nursing professionals associated to antineoplastic drugs aimed at worker's health. Methodology: A descriptive exploratory qualitative study carried out at a federal public general hospital in the Southeast Brazilian Region with 35 nursing workers. Semi structured interviews were used as data collection technique to establish the sociodemographic, occupational and working profile of the participants and to be aware of safety culture with antineoplastic drugs. Thematic content analysis was used for treatment of data, then emerging six categories of analysis: knowledge of nursing professionals about antineoplastic drugs and their effects on workers' health; prior experiences of nursing workers with antineoplastic drug and exposure to it; understanding the tools to protect the customer, the environment and the worker; preventive measures in handling antineoplastic drugs applied by workers and institutions - an educational issue and perception of behavior in case of accidents with antineoplastic drugs. Results: It was found that the nursing staff lack experience and knowledge of the recommendations for safe handling of antineoplastic drugs. There were neither guidelines for their management nor for the procedures in case of accidents. There was neither training for the nursing teams following the methodology for continuing education nor for the use of appropriate personal protective equipment. The study showed that knowledge about the effects of Hazardousdrugs and that there were preventive measures to be adopted. Institutional issues also emerged as these topics both help and limit the reach of safety culture at work. Conclusion: It is crucial to engage the nursing staff as well as other professional and the directors of the institution in order to implement a safety culture to handle antineoplastic drugs. It is assumed that the training help them to became able to understand and follow the relevant recommendations for appropriate administration and safe handling practices for these drugs, evaluated as essential procedures in view of the impacts on nursing staff security and health.

In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors.

Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence.

Antileukemic effect of paclitaxel in combination with metformin in HL-60 cell line.

Acute promyelocytic leukemia (APL) is a subtype of AML that is a mixture of hematological malignancy, characterized by a specific translocation t(15;17). The using of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapeutic agents or both of these agents, composes main treatment strategy of APL. While it is possible to achieve success in treatment of low-risk APL with current treatment regimens, such success is not mentioned in high-risk APL. So, it may develop new approaches for treatment regimens for high-risk APL. In the present study, we aimed to investigate the effects of combinational of a classic anticancer agent paclitaxel and antidiabetic agent metformin on HL-60 APL cell line. The combination dose of paclitaxel and metformin was determined by WST-1 analysis. The effect of combinational dose on apoptosis was assessed in fluorescence microscope after using AnnexinV-EGFP Apoptosis and JC-1 Assay Kit. The effect of combinational dose on cell cycle, apoptosis and differentiation, and signaling pathways were determined investigating gene expression changes by using real time qRT-PCR. The combinational dose of paclitaxel and metformin was determined as 4.8nM and 398.7µM for 72h, respectively. The combination dose significantly increased apoptosis for 48h. In expression changes of genes associated cell cycle, apoptosis, cytokines, co-stimulator molecules, NF-kB and MAP/MAPK pathways, TLRs (Toll-like receptors) were found to be decreased or increased to provide apoptosis or differentiation. Consequently, we suggest that the combination of paclitaxel and metformin can be used as an option assessable for development of new treatment strategies for APL.

Hospitalization for Toxicity in Patients Treated With Rituximab.

OBJECTIVES: To estimate the rates of hospitalizations in patients within 12 months after the first rituximab administration. METHODS: Patients who received rituximab between 2001 and 2008 for either benign or malignant conditions were identified from Texas Medicare files. The hospitalization rates for these patients with any diagnoses that might represent toxicity were then compared in the 12 months before and after the first infusion of rituximab. Dose-response analyses were performed on the basis of the number of doses received in the 8 weeks after initiating rituximab and also using the cumulative number of doses as a time-dependent covariate. RESULTS: In all, 2623 patients received rituximab as a single agent for malignant indications and 1124 received it for benign indications. Overall inpatient admission rates did not differ significantly between the 12 months before and after rituximab initiation in patients with benign or malignant conditions. Those with malignant conditions had higher rates of hospitalizations for cardiovascular, infectious, pulmonary, and neurological diagnoses after rituximab initiation. In those with nonmalignant conditions, the only increase was in hospitalizations for infections. Neither group of patients showed any clear dose-response relationships with any toxicity. CONCLUSIONS: The increased hospitalizations for potential toxicities seen in patients with malignant disease were presumably because of the underlying disease process and not rituximab. Rituximab does not appear to be associated with hospitalizations for serious toxicity within 12 months after the first infusion, with the possible exception of infection.

Apoptotic Process Induced by Oxaliplatin in Rat Hippocampus Causes Memory Impairment.

Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus-sensitive. Rodents, previously subjected to 2-week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in the hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose-dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in the hippocampus from OX rats cotreated with copper sulphate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co-administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions.

Review of Experience of a Statewide Poison Control Center With Pediatric Exposures to Oral Antineoplastic Drugs in the Nonmedical Setting.

The use of oral antineoplastic agents in nonmedical settings continues to increase. There are limited data available on pediatric exposures to these agents. We sought to identify characteristics of such exposures. We performed a retrospective review of database of a statewide poison system from 2000 to 2009 for all cases of pediatric exposures to oral antineoplastic agents, which took place in a nonmedical setting. Data collected include gender, age, agent of exposure, dose, drug concentration, reason for exposure, symptoms, outcomes, interventions, and length of hospital stay. There were a total of 328 patients. The mean average age was 4.1 years. Eighty-nine percentage (n = 293) was unintentional. Exposures to 21 different antineoplastic agents were identified. Methotrexate (n = 91) and 6-mercaptopurine (n = 47) were the most common agents encountered. Two hundred ninety-nine (91%) cases had no symptoms reported. When reported, gastrointestinal symptoms (n = 17) and central nervous system sedation (n = 6) were most common. One case of pancytopenia was reported. No deaths were reported in this series. Sixty-seven percent (n = 220) were managed at home, whereas 19 (6%) were admitted to a health care facility. Cases were followed by the poison control center for 0.34 days (SD = 1.40). In this study, exposures to oral antineoplastics were primarily unintentional, asymptomatic, and managed at home. Study limitations include possible reporting bias, inability to objectively confirm exposures, and limited duration of monitoring by the poison control center. In this retrospective review, no significant morbidity or mortality was reported from pediatric exposures to oral antineoplastic drugs in the nonmedical setting.

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells.

BACKGROUND: The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. METHODS: Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. RESULTS: TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. CONCLUSIONS: Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may represent a promising new option for the future development of combination therapies. Our data also suggest that RIPK3 expression may serve as a potential predictive marker for the sensitivity of tumor cells to programmed necrosis and extend the previously established role of ceramide as a key mediator of death receptor-induced programmed necrosis (and thus as a potential target for future therapies) also to the tumor cell lines examined here.

Treatment of athracycline extravasations using dexrazoxane

Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane proved to be effective and moderately well tolerated. However, alternative approaches for the management of anthracycline extravasations are available such as topical DMSO and cooling. There appears to be general agreement about dexrazoxane usefulness when extravasations involve large volumes of anthracycline and/or central venous access device. Nevertheless, the non-invasive combination of DMSO and cooling is the most commonly described therapy, particularly in small anthracycline extravasations. Further research is still needed to establish unequivocal situations where dexrazoxane must be initiated (AU)

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Treatment of anthracycline extravasations using dexrazoxane.

Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane proved to be effective and moderately well tolerated. However, alternative approaches for the management of anthracycline extravasations are available such as topical DMSO and cooling. There appears to be general agreement about dexrazoxane usefulness when extravasations involve large volumes of anthracycline and/or central venous access device. Nevertheless, the non-invasive combination of DMSO and cooling is the most commonly described therapy, particularly in small anthracycline extravasations. Further research is still needed to establish unequivocal situations where dexrazoxane must be initiated.

[Accidental poisoning with peach seeds used as anticancer therapy--report of two cases]. / Przypadkowe zatrucie pestkami brzoskwini stosowanymi w celach przeciwnowotworowych--opis dwóch przypadków.

UNLABELLED: We described two cases of poisoning with amygdalin. Clinical signs presented by two females were mild and lasted up to 5 hours. CONCLUSIONS: The usage of amygdalin may be connected with serious side effects. The cyanide and prussic acid which are deliberated in digestive system are responsible for toxicity in such cases. The rarity of poisoning with amygdalin as well as high cost of analysis are responsible for the reason that most labs are not prepare for such procedure.

Biphasic dose-dependent effect of lithium chloride on survival of human hormone-dependent breast cancer cells (MCF-7).

Lithium, the first element of Group I in the periodic system, is used to treat bipolar psychiatric disorders. Lithium chloride (LiCl) is a selective inhibitor of glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine kinase that regulates many cellular processes, in addition to its role in the regulation of glycogen synthase. GSK-3ß is emerged as a promising drug target for various neurological diseases, type-2 diabetes, cancer, and inflammation. Several works have demonstrated that lithium can either inhibit or stimulate growth of normal and cancer cells. Hence, the present study is focused to analyze the underlying mechanisms that dictate the biphasic oncogenic properties of LiCl. In the current study, we have investigated the dose-dependent effects of LiCl on human breast cancer cells (MCF-7) by assessing the consequences on cytotoxicity and protein expressions of signaling molecules crucial for the maintenance of cell survival. The results showed breast cancer cells respond in a diverse manner to LiCl, i.e., at lower concentrations (1, 5, and 10 mM), LiCl induces cell survival by inhibiting apoptosis through regulation of GSK-3ß, caspase-2, Bax, and cleaved caspase-7 and by activating anti-apoptotic proteins (Akt, ß-catenin, Bcl-2, and cyclin D1). In contrast, at high concentrations (50 and 100 mM), it induces apoptosis by reversing these effects. Moreover, LiCl also alters the sodium and potassium levels thereby altering the membrane potential of MCF-7 cells. Thus it is inferred that LiCl exerts a dose-dependent biphasic effect on breast cancer cells (MCF-7) by altering the apoptotic/anti-apoptotic balance.

Deaths reported from the accidental intrathecal administration of bortezomib.

Medication errors due to the inadvertent intrathecal administration of vincristine and other antineoplastic agents continue to occur despite the development of preventative strategies. Three fatalities due to bortezomib being accidentally given intrathecally instead of by the intended intravenous route have recently been reported by the European Medicines Agency. The most effective method for preventing accidental intrathecal administration is to eliminate the syringe as a means of administrating neurotoxic agents and prepare them in a small volume minibag. However due to a lack of stability data for bortezomib in a minibag and the increasing use of bortezomib via the subcutaneous route necessitates the continued preparation of bortezomib in a syringe. A number of recommendations aimed at preventing the possibility of accidental intrathecal administration of bortezomib are made. These need to be incorporated into standard practice internationally and pharmacists must take the lead to ensure this occurs as a matter of urgency.