Non-conventional dosing of oral anticancer agents in oncology and malignant haematology: a systematic review protocol

Background. Recent advances in cancer therapeutics have resulted in significantly improved overall survival and progression-free survival for patients. Targeted oral systemic anticancer therapies (SACT) offer a range of treatment approaches that differ from traditional cytotoxic chemotherapy: non-cytotoxic oral SACT target malignant disease continuously, have less broad and more favourable safety profiles, which can improve patients’ quality of life (QoL). Toxicities associated with daily oral SACT administration can, however, result in non-adherence and a reduced QoL. Non-conventional dosing of oral SACT, where unlicensed doses/schedules of drugs are prescribed, is one approach increasingly adopted by clinicians to reduce toxicities and subsequent non-adherence and to improve QoL. Guidance governing this practice is, however, limited. This systematic review aims to identify evidence about prescribing practices of, and outcomes from, non-conventional dosing of oral SACT in oncology and malignant haematology. Methods. A search using the following electronic databases will be conducted: Ovid MEDLINE, Ovid EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Registry of Controlled Trials. Studies will be selected based on predefined inclusion/exclusion criteria. Critical appraisal will be conducted to identify potential biases, strengths and limitations of included studies. Extracted data will be tabulated to sort and summarise key findings. An initial literature search indicated that studies reporting non-standard dosing of oral SACT intervention studies are diverse and heterogeneous in study design. Extracted data will, therefore, be tabulated, and together with a narrative synthesis of integrated key findings, will be presented and discussed in reference to the strengths and weaknesses of the evidence base. If sufficient stratified data is available (e.g. age group, tumour type, disease stage) or intervention (drug, dosing schedule), sub-group analysis will be conducted to inform prescribing practice. Discussion. This review will identify relevant literature on the topic to inform prescribers working in oncology and malignant haematology. It will also analyse any evidence of the following outcomes: toxicity, treatment adherence and/or QoL outcomes for patients receiving non-standard doses of oral SACT. Limitations in the evidence base may arise from variability in both the type and quality of studies reviewed. Systematic Review Registration. PROSPERO CRD42017076195

A systematic review of non-standard dosing of oral anticancer therapies

Background. The use of oral systemic anticancer therapies (SACT) has increased and led to improved cancer survival outcomes, particularly with the introduction of small molecule targeted agents and immunomodulators. Oral targeted SACT are, however, associated with toxicities, which might result in reduced quality of life and non-adherence. To reduce treatment-related toxicity, the practice of non-standard dosing is increasing; however guidance to govern this practice is limited. A systematic review was conducted to identify evidence of, and outcomes from, non-standard dosing of oral SACT in oncology and malignant haematology. Methods. A comprehensive search of 78 oral SACT was conducted in the following databases: MEDLINE®, EMBASE®, Cochrane Library©, and Cumulative Index to Nursing and Allied Health Literature (CINAHL©). Studies were selected based on predefined inclusion/exclusion criteria, and were critically appraised. Extracted data were tabulated to summarise key findings. Due to diversity of study designs and heterogeneity of reported outcomes, studies were categorised and evidence was synthesised in three main themes: dose interruption; dose reduction; and other dosing strategies. Results. Thirty-four studies were eligible for inclusion: four clinical trials, fifteen cohort studies and fifteen case reports. Evidence for non-standard dosing was reported for eleven oral SACT. Dose interruptions were the most commonly reported strategy (14 studies); nine studies reported dose reductions; and eleven reported other dosing strategies. Eight retrospective cohort studies reported dose interruption of sunitinib in renal cell carcinoma and showed either similar or improved responses and survival outcomes, and fewer or equivalent high grade toxicities, compared to the standard schedule. Four cohort studies retrospectively evaluated dose reductions of imatinib, gefitinib or erlotinib, for chronic myeloid leukaemia and non-small cell lung cancer, respectively. Other dosing strategies included alternate-day dosing. The quality of the evidence was limited by the small sample size in many studies, retrospective study designs, and lack of reported toxicity and/or QoL outcomes. Conclusions. This review identified limited evidence to support current non-standard dosing strategies, but some of findings, e.g. dose interruption of sunitinib, warrant further investigation in large-scale prospective clinical trials

NEUROBEHAVIORAL FUNCTIONS, SERUM PROLACTIN AND PLASMA RENIN ACTIVITY OF MANGANESE-EXPOSED WORKERS

Objective of this study was to assess effects of manganese (Mn) exposure on 56 workers employed in a Mn welding workshop of a machine building factory in Taiyuan (Shanxi Province, P.R. China) for a mean period of 16.1 years. The mean air Mn level in the workshop was 138.4 μg/m3. Neurobehavioral Core Test Battery (NCTB), including the Profile of Mood States (POMS), was performed. Blood pressure (BP) increase following immediate stand-up (BP-IS), serum prolactin (PRL) and plasma renin activity (PRA) in supine position were also determined. Most of the NCTB scores of the Mn-exposed workers were lower than those of the controls, while the POMS scores were higher, indicating a Mn-induced impairment of neurophysiological functions and a deflection of mood towards negative emotion states. PRL values of the Mn-exposed workers were higher than those of the controls. BP-IS of Mn-exposed workers was significantly lower than that of the controls. PRA of the same workers was augmented more than 200 %. In the Mn-exposed workers, the higher PRL values are possibly due to a reduced inhibitory effect on pituitary lactotrope cells by the tubero-infundibular dopamine system; the decreased BP-IS was referred to imbalance between the sympathetic and parasympathetic activities, whereas the higher basal PRA was thought to depend on neuroendocrine changes (including increased central sympathetic tone) and/or on a direct effect of Mn on renal juxta-glomerular cells. On the whole, this study demonstrates that occupational Mn exposure is responsible for neurobehavioral changes coexisting with alterations of neuroendocrine and humoral systems

Asthma worsened by benzoate contained in some antiasthmatic drugs.

Here, we report our experience on benzoate hypersensitivity. Drug and food additives are known to induce pseudo-allergic reactions such as urticaria, eczema, asthma and rhinitis. These reactions are often under-diagnosed, above all in allergic patients treated with additive containing drugs. On the contrary, attention to additives present in some drug formulations and foods may often permit more correct diagnosis

Immunotoxicity and Sensitizing Capacity of Metal Compounds Depend on Speciation

Immunotoxicity of metal compounds is an issue of great importance due to the recent industrial application of metals with unknown toxicity on the immune system and the discovery of metal intermediary compounds not sufficiently studied yet. In this report we show results of our study on the immunotoxicity of the following metals: the Platinum group elements (Platinum, Palladium, Rhodium), Titanium and Arsenic. We applied functional and non functional assays and investigated both innate and adaptive immune systems, in particular, cell proliferation, cytokine production by PBMCs and O−2 production by neutrophils. We obtained the following results: only some Ti compounds (Titanocene, Ti ascorbate and Ti oxalate) show immunotoxicity. Trivalent As compounds (Sodium arsenite and tetraphenyl arsonium chloride) are more immunotoxic than the other investigated As compounds. Genotoxicity of Pt group compounds is in the following order: Pt < Rh < Pd. Immunotoxicity of Pt group compounds is in the following order: Pd < Pt < Rh. Lymphocytes and macrophages show a different reaction of neutrophils to metal toxicity. We can conclude that these studies show that metal immunotoxicity depends on speciation. In general speciation provides additional and often essential information in evaluating metal toxicity. However, there are many difficulties in applying speciation in investigating toxico-kinetic aspects to many metals, mainly due to the lack of information about the existence and significance of species and to the lack of analytical methods for measuring species in biological samples

"In vitro" comparative immune effects of different titanium compounds.

Exposure to Ti compounds is today an occupational and environmental health hazard. Object of this study was to determine "in vitro" effects of different Ti salts on cultured human peripheral blood mononuclear cells (PBMC) proliferation and cytokine release. 10−4 and 10−7 M Ti compounds did not modify spontaneous PBMC proliferation. Ti dioxide (a biocompatible material and sunscreen component) did not exert effects on phytoemagglutinin (PHA) stimulated PBMC proliferation and on PHA stimulated IFN-γ and TNF-α release from PBMC. On the other hand, 10−4 M Ti oxalate (with wide industrial applications) and Ti ascorbate (used mainly in agriculture) inhibited about 70 % the PHA stimulated PBMC proliferation; both these Ti compounds at 10−4 and 10−7 M concentrations significantly inhibited TNF-α release, while only Ti oxalate inhibited that of IFN-γ. Titanocene (used in chemotherapy) did not exert effects on PBMC proliferation but markedly inhibited IFN-γ and TNF-α release. On the whole, this study demonstrates that Ti dioxide is not immunotoxic; Ti oxalate shows marked immunotoxicity; titanocene exerts selective toxicity on cytokine release but not on PBMC proliferation, while Ti ascorbate affects TNF-α release from PBMC but not IFN-γ release. In conclusion, these data show that immunotoxicity of Ti depends on speciation

Identification of the target self-antigens in reperfusion injury

Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients