Development of an Administration Guideline of Oral Medicines to Patients with Dysphagia.

Background and Objectives: There is increasing evidence that patients with dysphagia often have limited access to suitable oral dosage forms, especially when administered via an enteral feeding tube (FT). In addition, there is a lack of clear and readily available information from drug manufacturers on how to administer medications to patients with dysphagia. This study aimed to develop a practical guide for healthcare professionals to increase the safe and effective administration of oral medications to patients with dysphagia. Materials and Methods: The data were collected from existing English databases and handbooks available to develop an easy-to-use tabular guideline presenting all relevant information using keywords and short expressions. The working group differentiated 514 formulation types, and the information was collected and added to the guideline separately. In addition, the instructions for the patients taking the medicines orally or via FT were described separately. Results: The guideline consisted of 24 keywords or short expressions developed by the working group and described the instructions to use them. The guideline contained 343 active pharmaceutical ingredients and 19 fixed-dose combinations. Conclusions: Knowledge about proper medication preparation and administration for patients with swallowing difficulties is limited but essential. It is crucial to encourage drug manufacturers to provide this information as a standard to ensure the safe and effective use of medications for all patient groups.

Exploring the Molecular Players behind the Potentiation of Chemotherapy Effects by Durvalumab in Lung Adenocarcinoma Cell Lines.

Immune checkpoint inhibitors are increasingly used in combination with chemotherapy for the treatment of non-small cell lung cancer, yet the success of combination therapies is relatively limited. Thus, more detailed insight regarding the tumor molecular markers that may affect the responsiveness of patients to therapy is required. Here, we set out to explore the proteome of two lung adenocarcinoma cell lines (HCC-44 and A549) treated with cisplatin, pemetrexed, durvalumab, and the corresponding mixtures to establish the differences in post-treatment protein expression that can serve as markers of chemosensitivity or resistance. The mass spectrometry study showed that the addition of durvalumab to the treatment mixture resulted in cell line- and chemotherapeutic agent-dependent responses and confirmed the previously reported involvement of DNA repair machinery in the potentiation of the chemotherapy effect. Further validation using immunofluorescence also indicated that the potentiating effect of durvalumab in the case of cisplatin treatment was dependent on the tumor suppressor RB-1 in the PD-L1 weakly positive cells. In addition, we identified aldehyde dehydrogenase ALDH1A3 as the general putative resistance marker. Further studies in patient biopsy samples will be required to confirm the clinical significance of these findings.

Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells.

Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are increasingly used in combination with cytotoxic treatments, such as chemotherapy. Although combined treatments are more effective, not all patients respond to the therapy; therefore, a detailed understanding of the effect of treatment combinations at the tumour level is needed. The present study aimed to explore whether ICIs could affect the cytotoxic effects of chemotherapy on lung adenocarcinoma cell lines with different PD-L1 expression levels (high, HCC-44; low, A-549). Using the resazurin-based assay, the efficacy of seven chemotherapeutic agents (cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel and paclitaxel) was compared in the presence or absence of the individually chosen single doses of four ICIs (nivolumab, pembrolizumab, atezolizumab and durvalumab). The results revealed that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or lung adenocarcinoma cell line used. Durvalumab was the most promising ICI, which potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. By contrast, nivolumab, exhibited depotentiating trends in several combinations. The immunostaining of γH2AX in treated cells confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage; however, this effect was strongly dependent on the chemotherapy agent and cell line used. Our future studies aim to address the specific mechanisms underlying the observed ICI-induced potentiation or depotentiation.

Solid oral medications' suitability for use in enteral feeding tubes.

BACKGROUND: There is a lack of specific data about the efficacy and safety of medications administered via feeding tubes, although there is a general awareness that not all drug formulations are suitable. AIMS AND OBJECTIVES: To overview the current situation with solid medications administered through feeding tubes in the Tartu University Hospital intensive care units. To evaluate the availability of information on the suitability of drug formulations for administration via feeding tubes. DESIGN: This was a descriptive retrospective document analysis study. METHODS: During visits to the intensive care units, medication data for current patients were collected from paper medical charts and nurses. In addition, package information leaflets, summaries of product characteristics, and two practical handbooks were used for evaluating the medicines' suitability for administration via feeding tubes. A request for information was also sent to manufacturers or marketing authorization holders. RESULTS: In 3 months, data were collected from 113 intensive care patients' medical charts. A total of 306 medication administrations via feeding tubes were documented and analysed, 67% of which were solid oral dosage forms. Exactly 91.2% of these were conventional tablets. After the analysis of information availability, 88% of the medications were classified as suitable for administration via feeding tubes, but only 48% had the manufacturer-provided information. CONCLUSION: This study showed that the information about the suitability of formulations administration through a feeding tube is not readily available for almost half of the medications. The manufacturers seem to have the relevant information, but it is not always added to their medications' official information, putting these patients at higher risk for errors. RELEVANCE TO CLINICAL PRACTICE: This study shows that if there is no clear statement about administration through feeding tubes on official manufacturers' information, this should be sought directly from manufacturers or marketing authorization holders, and the data could be incorporated into local guidelines.

Expression of immune checkpoint PD-1 in non-small cell lung cancer is associated with tumor cell DNA-dependent protein kinase.

Immunotherapy using immune checkpoint inhibitors has demonstrated durable responses and has significantly improved survival in patients with non-small cell lung cancer (NSCLC). Moreover, immunotherapy is increasingly used in combination with cytotoxic treatments such as chemotherapy and radiotherapy. Although the combined treatments are more effective, the underling mechanisms that lead to higher antitumor activity are not fully understood. Therefore, the aim of the current retrospective study was to determine the relationship between expression of immune checkpoints [programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1)] and the enzyme DNA-dependent protein kinase (DNA-PK), which is part of a key pathway involved in the repair of cytotoxic cancer therapy induced damage. Surgically excised NSCLC tissues (n=121) were histologically examined for overall extent of inflammation (score 0-3). Expression levels of PD-1 (number of PD-1 positive cells), PD-L1 [tumor proportion score (TPS); %] and DNA-PK (proportion of DNA-PK positive tumor cells; %) were determined using immunohistochemistry. Expressions of these markers were compared in different clinicopathological subgroups and later used for nonparametric Spearman correlation analysis to determine associations. In patients with NSCLC, PD-1 was significantly expressed in males (P=0.030) and in patients with no or trivial inflammation scores (P=0.030). PD-L1 expression was also significantly higher in current smokers (P=0.025). Correlation analysis was based on the individual values of patients and revealed a significant association between one of the targets of immune checkpoint inhibitors and tumor cell DNA-PK. Tumors with higher numbers of PD-1 positive cells also demonstrated higher tumor cell DNA-PK expressions (P=0.027). The results demonstrated a significant positive correlation between the PD-1/PD-L1 axis and tumor cell DNA-PK expression in patients with NSCLC. Further studies are required to clarify the significance of this correlation and its effect on the efficacy of immunotherapy and cytotoxic cancer therapy combinations.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC): Lung cancer.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Lung cancer is the leading cause of cancer mortality and has a wide variation in treatment and outcomes in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must only be carried out in lung cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

Prospective Risk Assessment of Medicine Shortages in Europe and Israel: Findings and Implications.

INTRODUCTION: While medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice. METHODOLOGY: A semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns. RESULTS: The participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy. CONCLUSION: The study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe.

Suppression of Taxanes Cytotoxicity by Citrus Flavonoid Hesperetin in PPC-1 Human Prostate Cancer Cells.

BACKGROUND/AIM: More than half of prostate cancer patients use, in addition to conventional therapies, some kind of complementary medicine, including flavonoid-rich products. However, knowledge about the co-effects of flavonoids with cytotoxic chemotherapies is still rather poor. Therefore, this study was undertaken to assess the cytotoxic activity of flavonoids and their interactions with taxanes in human advanced prostate cancer cells. MATERIALS AND METHODS: Cytotoxicity of different flavonoids and their effects on the efficacy of docetaxel and cabazitaxel were studied in the human metastatic prostate cancer cell line PPC-1, using MTT colorimetric assay. RESULTS: Both taxanes suppressed the viability of PPC-1 cells with IC50 values in the nanomolar range. Tested flavonoids exerted cytotoxic activity only at high micromolar concentrations or revealed no remarkable effect on cell survival. Simultaneous treatment of cells with taxanes and flavonoids baicalein, chrysin, luteolin, fisetin, quercetin, genistein or daidzein did not lead to any change in chemotherapy-induced cytotoxicity. However, simultaneous exposure of cells to hesperetin and taxanes resulted in 9.8- and 13.1-fold reduction in cytotoxicity of docetaxel and cabazitaxel, respectively. CONCLUSION: Flavonoid hesperetin remarkably suppressed the cytotoxic efficacy of taxanes in prostate cancer cells. Therefore, caution is required from prostate cancer patients who take hesperetin-containing oral supplements.