[Analysis of the work of the Immunohistochemical Quality Control Center of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia in 2023]. / Analiz raboty Tsentra kontrolya kachestva immunogistokhimicheskikh issledovanii FGBOU DPO «RMANPO¼ Minzdrava Rossii v 2023 godu.

The article demonstrates a detailed analysis of the results of the rounds of quality control of immunohistochemical studies conducted by the Central Committee of the Immunohistochemical Quality Control Center of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia in 2023. Typical shortcomings and errors in the immunohistochemical examination of various tumors have been identified and ways to eliminate them are given. Particular attention is paid to defining a panel of standard breast cancer markers and eliminating the shortcomings of immunohistochemical examination of markers of accompanying diagnosis.

A rapid and sensitive LC-MS/MS method for quantifying oxycodone, noroxycodone, oxymorphone and noroxymorphone in human plasma to support pharmacokinetic drug interaction studies of oxycodone.

A sensitive and reliable LC-MS/MS method was developed and validated for the quantification of oxycodone and metabolites in human plasma. The method has a runtime of 6 min and a sensitivity of 0.1 µg/L for all analytes. Sample preparation consisted of protein precipitation. Separation was performed on a Kinetix biphenyl column (2.1 × 100 mm, 1.7 µm), using ammonium formate 5 mm in 0.1% aqueous formic acid and methanol LC-MS grade 100% in gradient elution at a flow rate of 0.4 ml/min. Detection was performed in multiple reaction monitoring mode using positive electrospray ionization. The method was linear over the calibration range of 0.1-25.0 µg/L for oxycodone, noroxycodone and noroxymorphone and 0.1-5.0 µg/L for oxymorphone. The method demonstrated good performance in terms of intra- and interday accuracy (86.5-110.3%) and precision (CV 1.7-9.3%). The criteria for the matrix effect were met (CV < 15%) except for noroxymorphone, for which an additional method was applied to compensate for the matrix effect. Whole blood samples were stable for 4 h at room temperature. Plasma samples were stable for 24 h at room temperature and 3 months at -20°C. Furthermore, the method was successfully applied in a pharmacokinetic drug interaction study of oxycodone and enzalutamide in patients with prostate cancer.

The Predicted Outcome of Spinal Cord Stimulation in Patients With a Psychopathological Disorder and Persistent Spinal Pain Syndrome Type 2: A Systematic Review From 2009 to 2021.

OBJECTIVES: Psychologic screening is often included as a mandatory component of evaluation of the impact of psychopathology disorders on the predicted outcome of spinal cord stimulation (SCS) for patients with chronic pain due to persistent spinal pain syndrome type 2 (PSPS type 2). The conclusion of such screenings can influence the decision to offer SCS therapy to a patient. However, evidence on the impact of psychopathology on SCS outcomes is still scarce. MATERIALS AND METHODS: To address this knowledge gap, we systematically reviewed the literature from 2009 to 2021 to explore the correlation between the presence of a psychopathological disorder and the predicted outcome of SCS in patients with PSPS type 2. The literature search was conducted using various online data bases with "failed back surgery syndrome," "psychopathology," and "spinal cord stimulation" used as essential keywords. The identified studies were organized in a Rayyan AI data base, and the quality was analyzed with the Critical Appraisal Skills Program tool. RESULTS: Our search generated the identification of 468 original articles, of which two prospective and four retrospective studies met our inclusion criteria. These studies reported pain relief, a reduction of symptoms of anxiety and depression, and an improvement in rumination on the Pain Catastrophizing Scale in patients with PSPS type 2 after SCS therapy. The studies also found contradictory outcomes measured using the Oswestry Disability Index, and in terms of the impact of psychopathological disorder on the clinical outcome and revision rate of the SCS system. CONCLUSION: In this systematic review, we found no convincing evidence that the presence of a psychopathological disorder affects the predicted outcome of SCS therapy in patients with PSPS type 2.

[Assessment of HER2 status of carcinomas of various localizations]. / Opredelenie HER2-statusa kartsinom razlichnykh lokalizatsii.

A detailed description of the methodological aspects of the evaluation of HER2-status in carcinomas of such localizations as the mammary gland, pancreas, salivary glands, stomach, colon, endometrium, bladder, lungs is presented. Approaches and criteria for assessing HER2 status from methodological and clinical points of view are analyzed. The data are systematized in tables for use in practical diagnostic work.

[Predictive markers of immunotherapy in cervical cancer]. / Prediktivnye markery immunoterapii v rake sheiki matki.

OBJECTIVE: Study of PD-L1 expression in squamous and adenosquamous cell cervical cancer (CC) by immunohistochemical (IHC) method, assessment of the relationship between PD-L1 tumor status and its clinical and morphological characteristics, TILs, MSI/dMMR, and HPV tumor status. MATERIAL AND METHODS: Surgical material was obtained from 41 patients with CC, on which the expression of PD-L1, proteins of the MMR system and p16 was studied by the IHC method, the TILs index was determined. RESULTS: Positive PD-L1 status was found in 51.2% of the studied CC samples. In the study sample, the level of PD-L1 expression depended on the severity of lymphoid infiltration of the tumor (p=0.038), it was shown that a positive PD-L1 status of CC can be expected with a TILs value greater than or equal to 50%. The age of the patients, the histological variant of the tumor, the pT and pN stage, the presence of lymphovascular invasion, and the HPV status did not statistically significantly affect the level of PD-L1 expression, however, there was an association between the PD-L1 status and the grade of CC malignancy (p=0.027). The presence of the MSI/dMMR phenomenon was detected in a small percentage of carcinomas (4.9%), the PD-L1 status of these tumors was determined as positive. CONCLUSION: A positive PD-L1 status is determined in a significant number of cases of CC, regardless of most of the studied clinical and morphological characteristics; there is a statistically significant relationship between PD-L1 expression and the degree of tumor differentiation and TILs. It has been shown that CC with the MSI/dMMR phenomenon is characterized by a positive PD-L1 status. The authors consider it necessary to study the expression of PD-L1 in patients with cervical carcinomas in order to determine the possibility of prescribing personalized therapy with immune checkpoint inhibitors.

[Updated CAP guidelines for determining molecular biological subtypes of breast cancer]. / Obnovlennye rekomendatsii CAP po opredeleniyu molekulyarno-biologicheskikh podtipov raka molochnoi zhelezy.

Updated 2023 guidelines from the College of American Pathologists (CAP) on immunohistochemical detection of human epidermal growth factor receptor type 2 (HER2), receptors of estrogen (ER) and progesterone (PgR), and the cell proliferation marker Ki-67 in breast cancer are presented. Attention is drawn to the emergence of two new terms «ER Low Positive¼ and «HER2 Low¼ to characterize tumors with low expression of estrogen receptors and HER2.

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.

BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

[Investigation of the mutational status of the FGFR3 gene in urothelial bladder carcinoma]. / Issledovanie mutatsionnogo statusa gena FGFR3 v urotelial'noi kartsinome mochevogo puzyrya.

OBJECTIVE: To study the somatic mutational status of the FGFR3 gene in urothelial bladder cancer (BC) and evaluate its relationship with the clinical and morphological characteristics of the tumor, deficiency of the DNA mismatch repair (dMMR), PD-L1 tumor status, and immunohistochemical (IHC) expression of the p16 protein. MATERIAL AND METHODS: Surgical material of 40 patients with BC, on which the mutational status of the FGFR3 gene was studied using the molecular genetic method, as well as the MMR status, PD-L1 and p16 expression by the IHC method. RESULTS: FGFR3 mutations, such as G370C, S249C, S371C/Y373C, R248C, were detected in 35.0% of the studied BC samples. FGFR3 status did not depend on the gender and age of patients, as well as on the degree of tumor lymphoid infiltration (TILs). Statistically significant differences were found in the analysis of FGFR3 status depending on the histological structure and degree of tumor differentiation, as well as on the pT stage. The FGFR3 status of BC was not associated with the IHC expression of the studied proteins of the MMR system, as well as with the PD-L1 status. Higher levels of PD-L1 expression were demonstrated by BC tumor cells, in which no aberrations in FGFR3 were detected. There was no significant association between p16 status and the presence of FGFR3 mutations, but for FGFR3-positive carcinomas, the basal pattern of p16 staining by IHC was noted. CONCLUSION: A positive somatic mutational status of the FGFR3 gene was statistically significantly more common in the group of papillary low-grade non-muscle-invasive BC, demonstrating basal p16 IHC staining. In the study sample, there was no statistically significant relationship between the FGFR3 status of BC and gender and age differences, TILs, MMR status, PD-L1 status (SP142 and 22C3), and p16 status. The results of the study indicate the need to determine the FGFR3 status in patients with BC for further prescription of personalized therapy.

[External quality control of immunohistochemical studies in pathomorphology: tasks, problems, solutions, development prospects]. / Vneshnii kontrol' kachestva immunogistokhimicheskikh issledovanii v patomorfologii: zadachi, problemy, puti resheniya, perspektivy razvitiya.

In 2022, the Quality Control Center for Immunohistochemical Studies of the Russian Medical Academy of Continuing Professional Education conducted 12 rounds of markers for breast, lung, prostate, bladder cancer with the participation of 83 laboratories. For the first time, a round was held to control the method of in situ hybridization in the diagnosis of breast cancer, and a digital round. Typical problems in carrying out immunohistochemical studies in oncomorphology have been identified and the importance of participation of laboratories in external control has been shown.

Spinal Cord Stimulation for Failed Back Surgery Syndrome: to Trial or Not to Trial?

Spinal cord stimulation (SCS) is a recommended therapy to treat failed back surgery syndrome (FBSS). A trial period is practiced to enhance patient selection. However, its fundamental evidence is limited, especially concerning long-term benefit and therapy safety. We compared the long-term (5.3 ± 4.0 years) clinical outcome and therapy safety of a trialed and nontrialed implantation strategy, including multidimensional variables and pain intensity fluctuations over time. A multicenter cohort analysis was performed in 2 comparable groups of FBSS patients. Regarding eligibility, patients had to be treated with SCS for at least 3 months. While the Trial group comprised patients who underwent an SCS implantation after a successful trial, the No-Trial group encompassed patients who underwent complete implantation within 1 session. The primary outcome measures were pain intensity scores and complications. The Trial and No-Trial groups consisted of 194 and 376 patients (N = 570), respectively. A statistically but not clinically significant difference in pain intensity (P = .003; effect = 0.506 (.172-.839)) was found in favor of the Trial group. No interaction between a time dependency effect and pain intensity was noted. Whereas trialed SCS patients were more likely to cease opioid usage (P = .003; OR = .509 (.326-.792)), patients in the No-Trial group endured fewer infections (P = .006; proportion difference = .43 (.007-.083)). Although the clinical relevance of our findings should be proven in future studies, this long-term real-world data study indicates that patient-centered assessments on whether an SCS trial should be performed have to be investigated. According to the current ambiguous evidence, SCS trials should be considered on a case-by-case basis. PERSPECTIVE: The currently available comparative evidence, together with our results, remains ambiguous on which SCS implantation strategy might be deemed superior. An SCS trial should be considered on a case-by-case basis, for which further investigation of its clinical utility in certain patient populations or character traits is warranted.

Effectiveness of a vitamin D regimen in deficient multiple myeloma patients and its effect on peripheral neuropathy.

PURPOSE: Peripheral neuropathy (PN) is common in multiple myeloma (MM) patients. More insight has been gained concerning the role of vitamin D in preventing PN. However, studies evaluating the effects of vitamin D3 supplementation on PN are lacking. The aims of this study are to (1) evaluate the effectiveness of a vitamin D3 regimen on achieving adequate vitamin D levels in deficient MM patients and to (2) exploratively evaluate the effect of vitamin D3 supplementation on PN. METHODS: Thirty-nine MM patients with inadequate (< 75 nmol/L [= 30 ng/mL]) 25-hydroxyvitamin D (25(OH)D) levels were included in this multicenter, prospective, single-arm study, of whom 35 patients completed the study. They received oral vitamin D3 for 6 months according to a dose escalation regimen that consisted of one or two loading doses of 200,000 international units (IU), and maintenance doses of 800, 1600, or 3200 IU/day depending on the 25(OH)D level. A validated questionnaire was used to measure PN. RESULTS: Median 25(OH)D increased from 38 (IQR 32-52) nmol/L at baseline to 77 (IQR 72-87) nmol/L after 6 months (P < 0.001). Adequate 25(OH)D levels were achieved by 66% of the subjects, and 34% were within the range of 50-75 nmol/L. Furthermore, in 37% of the participants, PN severity decreased (P = 0.007). CONCLUSION: The use of substantially higher vitamin D3 doses than recommended in current guidelines resulted in a significant increase in vitamin D levels in MM patients. Furthermore, evaluation of PN showed a significant decrease in PN grading. However, this exploratory evaluation needs further confirmatory research.

Lean Body Mass and Total Body Weight Versus Body Surface Area as a Determinant of Docetaxel Pharmacokinetics and Toxicity.

AIM: This study examined whether anthropometric and body composition parameters such as body surface area (BSA), lean body mass (LBM), and total body weight (TBW) are correlated with docetaxel clearance and exposure by analyzing area under the curve. In addition, LBM, TBW, and a fixed dose were compared with BSA as dosing parameters for dose individualization of docetaxel. METHODS: Thirty-six patients receiving docetaxel chemotherapy for breast or metastatic castration-resistant prostate carcinoma were included. Before treatment, LBM was measured using a dual-energy X-ray absorptiometry scanner. Blood samples were collected up to 180 minutes after dosing to analyze docetaxel concentrations and determine individual pharmacokinetic parameters. RESULTS: No significant correlations were found between docetaxel clearance and the anthropometric and body composition variables (BSA, LBM, and TBW). The area under the curve was significantly but poorly correlated with BSA [r = 0.452 ( P = 0.016)] and TBW [r = 0.476 ( P = 0.011)]. The mean absolute percentage error and mean error of simulated dosing based on LBM and fixed dosing were not significantly different from those of BSA. For TBW, only mean absolute percentage error was significantly higher compared with dosing based on BSA (24.1 versus 17.1, P = 0.001). CONCLUSIONS: There was no clinically relevant correlation between docetaxel pharmacokinetics and the anthropometric and body composition variables BSA, LBM, and TBW. Therefore, dose individualization of docetaxel based on LBM, TBW, or fixed dosing cannot be recommended over BSA-based dosing.

Differences in Evidentiary Requirements Between European Medicines Agency and European Health Technology Assessment of Oncology Drugs-Can Alignment Be Enhanced?

OBJECTIVES: National health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies' evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences. METHODS: Interviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted. RESULTS: Acceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements. CONCLUSIONS: Differences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed.

Evidence- and consensus-based guidelines for drug-drug interactions with anticancer drugs; A practical and universal tool for management.

Drug-drug interactions (DDIs) with anticancer drugs are common and can significantly affect efficacy and toxicity of treatment. Therefore, a Dutch Multidisciplinary Expert group is assessing the clinical significance of DDIs in oncology and provides recommendations for the management of these DDIs. We present an overview of methodology and outcome of an evidence- and consensus-based assessment of DDIs between anticancer drugs and non-anticancer drugs. A literature search was performed through PubMed and EMA and FDA assessment reports, to identify potential DDI's involving anticancer drugs. For each potential DDI a concept report for risk analysis and practical advice for management was created. Subsequently, this risk analysis and the corresponding advice were assessed and weighed. A total of 290 potential DDIs have been identified in the literature thus far. Of these 290 potential DDIs, the Expert Group has identified 94 (32%) DDIs as clinically relevant, with a need for an automated alert and a suggested intervention. Furthermore, 110 DDIs have been identified as clinically not relevant. For 86 potential DDIs evidence supporting a relevant DDI was insufficient and in these cases neither an alert nor advice regarding a suggested intervention were formulated. A transparent risk analysis is presented for identification of clinically relevant DDIs with anticancer drugs. Integration of DDI guidelines into the national electronic prescribing system is essential to achieve optimal efficacy and minimal toxicity in patients receiving anticancer therapy. A clear overview of clinically relevant DDIs with anticancer therapy provides clinicians with a structured, evidence-based and consensus-built tool for anticancer therapy surveillance.

[Results of the work of the Russian Medical Academy of Continuous Professional Education Center for quality control of immunohistochemical studies for 2019-2021]. / Itogi raboty Tsentra kontrolya kachestva immunogistokhimicheskikh issledovanii FGBOU DPO «RMANPO¼ za 2019­2021 gg.

In 2019-2021 the Russian Medical Academy of Continuous Professional Education Center for quality control of immunohistochemical studies conducted rounds on the most used tumour markers of various localizations. The deficiencies in the conduct of immunohistochemical studies were identified and the importance of the participation of medical organizations in measures to improve the quality control of immunohistochemical studies in oncomorphology was shown.

Clinical implications of germline variations for treatment outcome and drug resistance for small molecule kinase inhibitors in patients with non-small cell lung cancer.

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer.

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 µg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured Cmin at steady-state. The geometric mean (GM) Cmin at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM Cmin at the start dose was 1456 µg/L (95% CI: 1185-1789) vs 682 µg/L (95% CI: 572-812) (P < .001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (Cmin 971 µg/L [95% CI: 790-1193] vs 669 µg/L [95% CI: 568-788]) (P = .005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM Cmin at BTD were comparable between the SGC and the RCC group, 694 µg/L (95% CI: 584-824) vs 583 µg/L (95% CI: 496-671) (P = .1). The observed cabozantinib exposure at BTD of approximately 600 µg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity.

[Immunohistochemical study of MSI markers in breast cancer]. / Immunogistokhimicheskoe issledovanie markerov MSI pri rake molochnoi zhelezy.

OBJECTIVE: To investigate the expression of microsatellite instability (MSI) markers, which is detected by an immunohistochemical technique, and to compare the expression with the PD-L1 status in luminal B, HER2-negative and triple-negative breast cancer. MATERIAL AND METHODS: The investigation included tumors from 40 patients with triple-negative and luminal B, HER2-negative subtypes. Immunohistochemical study was performed using Ventana antibodies: anti-MLH1 (clone M1), anti-MSH2 (clone G219-1129), anti-PMS2 (clone A16-4), and anti-MSH6 (clone SP93). MSI was assessed according to the standard criteria. RESULTS: The PD-L1-positive status was present in 14 (35%) of the 40 patients. Moreover, MSI-H was detected in only 1 (2.50%) case. The two-year survival rate was 87.5%; it should be noted that the median survival rate was not reached either in the study sample or in the groups divided according to PD-L1 and MSI statuses. The overall survival rate for patients with MSI was 75% (3/4). CONCLUSION: The first comparative study of the expression of PD-L1 and immunohistochemical MSI markers, which has been conducted on a small sample, fails to draw unambiguous conclusions, but shows the need to investigate this phenomenon on large samples and by using genetic methods.

The impact of a 1-hour time interval between pazopanib and subsequent intake of gastric acid suppressants on pazopanib exposure.

Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (Cmin ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

Prevalence and follow-up of potentially inappropriate medication and potentially omitted medication in older patients with cancer - The PIM POM study.

OBJECTIVES: To determine the prevalence of Potentially Inappropriate Medication (PIMs) and Potentially Omitted Medication (POMs) in older patients with cancer. MATERIALS AND METHODS: In this prospective observational study (hospital) pharmacists conducted comprehensive medication reviews in older patients with cancer (aged ≥65 years) receiving parenteral chemotherapy and/or immunotherapy at the Deventer Hospital. PIMs and POMs were identified using the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP), the Screening Tool to Alert doctors to the Right Treatment (START), and pharmacists' expert opinion. Recommendations regarding PIMs and POMs were communicated to the patient's oncologist/haematologist and follow-up was measured. Associations between covariates and the prevalence of PIMs and POMs were statistically analysed. RESULTS: For the 150 patients included, 180 PIMs and 86 POMs were identified with a prevalence of 78%. Using pharmacists' expert opinion in addition to only STOPP/START criteria contributed to 49% of the PIMs and 23% of the POMs. A follow-up action was required in 73% of the 266 PIMs and POMs. Number of medicines and Charlson Comorbidity Index score were both associated with having at least one PIM and/or POM (p = .031 and p = .016, respectively). CONCLUSION: The prevalence of PIMs and POMs and subsequent follow-up in older patients with cancer is high. A pharmacist-led comprehensive medication review is a good instrument to identify these PIMs and POMs and to optimize patients' treatment. A complete approach, including pharmacists' expert opinion, is recommended to identify all PIMs and POMs in clinical practice.