Vaccine effectiveness against COVID-19 hospitalisation in adults (≥ 20 years) during Alpha- and Delta-dominant circulation: I-MOVE-COVID-19 and VEBIS SARI VE networks, Europe, 2021.

IntroductionTwo large multicentre European hospital networks have estimated vaccine effectiveness (VE) against COVID-19 since 2021.AimWe aimed to measure VE against PCR-confirmed SARS-CoV-2 in hospitalised severe acute respiratory illness (SARI) patients ≥ 20 years, combining data from these networks during Alpha (March-June)- and Delta (June-December)-dominant periods, 2021.MethodsForty-six participating hospitals across 14 countries follow a similar generic protocol using the test-negative case-control design. We defined complete primary series vaccination (PSV) as two doses of a two-dose or one of a single-dose vaccine ≥ 14 days before onset.ResultsWe included 1,087 cases (538 controls) and 1,669 cases (1,442 controls) in the Alpha- and Delta-dominant periods, respectively. During the Alpha period, VE against hospitalisation with SARS-CoV2 for complete Comirnaty PSV was 85% (95% CI: 69-92) overall and 75% (95% CI: 42-90) in those aged ≥ 80 years. During the Delta period, among SARI patients ≥ 20 years with symptom onset ≥ 150 days from last PSV dose, VE for complete Comirnaty PSV was 54% (95% CI: 18-74). Among those receiving Comirnaty PSV and mRNA booster (any product) ≥ 150 days after last PSV dose, VE was 91% (95% CI: 57-98). In time-since-vaccination analysis, complete all-product PSV VE was > 90% in those with their last dose < 90 days before onset; ≥ 70% in those 90-179 days before onset.ConclusionsOur results from this EU multi-country hospital setting showed that VE for complete PSV alone was higher in the Alpha- than the Delta-dominant period, and addition of a first booster dose during the latter period increased VE to over 90%.

Effect of Prophylactic Fibrinogen Concentrate In Scoliosis Surgery (EFISS): a study protocol of two-arm, randomised trial.

INTRODUCTION: Fibrinogen is one of the essential coagulation factors. Preoperative lower plasma fibrinogen level has been associated with higher blood loss. Scoliosis surgery presents a challenge for the anaesthetic team, one of the reasons being blood loss and transfusion management. Recently, the prophylactic fibrinogen administration has been a debated topic in various indications. It has been described for example, in urological or cardiovascular surgery, as well as in paediatrics. This pilot study is focused on verifying the feasibility of potential large randomised trial and verifying the safety of prophylactic fibrinogen administration in paediatric scoliosis surgery. METHODS AND ANALYSIS: A total of 32 paediatric patients indicated for scoliosis surgery will be recruited. Participants will be randomised into study groups in a 1:1 allocation ratio. Patients in the intervention group will receive prophylactic single dose of fibrinogen, in addition to standard of care. Patients in the control group will receive standard of care without study medication prior to skin incision. The primary aim is to assess the safety of prophylactic fibrinogen administration during scoliosis surgery in children, the incidence of any adverse events (AEs) and reactions will be monitored during participation in the study. The secondary objective is to investigate the additional safety information, feasibility and efficacy of a prophylactic fibrinogen administration. The incidence of AEs and reactions according to selected adverse events of special interest will be monitored. All collected data will be subjected to statistical analysis according to a separate statistical analysis plan. ETHICS AND DISSEMINATION: This trial follows the applicable legislation and requirements for good clinical practice according to the International Conference on Harmonisation E6(R2). All essential trial documents were approved by the relevant ethics committee and national regulatory authority (State Institute for Drug Control) and their potential amendments will be submitted for approval. TRIAL REGISTRATION NUMBER: NCT05391412.

The risk of second primary malignancies in colorectal cancer patients using calcium channel blockers.

Calcium channel blockers are among the most commonly used agents in the treatment of cardiovascular diseases. There are several known side-effects associated with their long-term use, whereas other potential adverse effects are yet to be proven. This study aims to evaluate the association between calcium channel blockers exposure and the incidence of second primary malignancy. We established a cohort of 1401 patients with colorectal cancer diagnosed in our institution between January 2003 and December 2016. Patients were followed-up until December 2020. The tumor characteristics and basic clinical data including medication information were obtained from the hospital information system database. Second malignancy was detected in 301 patients (21.5%), and occurred in 27.8% of patients who used calcium channel blockers compared to only 19.9% among non-users. Their use was associated with an increased incidence of bladder cancer in particular. Subanalysis of patients with second malignancy displayed a higher proportion of right-sided colon cancer compared to rectal carcinoma in non-users. Survival analysis revealed significantly better outcomes in early-stage colorectal cancer patients without a history of calcium channel blockers treatment or second primary malignancy.

Emergency medicine pharmacotherapy compromises accuracy of plasma creatinine determination by enzyme-based methods: real-world clinical evidence and implications for clinical practice.

Background: Assessment of kidney function in emergency settings is essential across all medical subspecialties. Daily assessment of patient creatinine results from emergency medical services showed that some deviated from expected values, implying drug-related interference. Methods: Real-time clinical evaluation of an enzyme method (Roche CREP2) in comparison with the Jaffé gen. 2 method (Roche CREJ2) was performed. During the period of December 2022 and January 2023, we analyzed 8,498 patient samples, where 5,524 were heavily medicated STAT patient specimens, 500 were pediatric specimens, and 2,474 were from a distant general population in a different region using the same methods. Results: In 109 out of 5,524 hospital specimens (1.97%, p < 0.001), the CREP2 value was apparently (25% or more) lower than CREJ2. Suspect interfering medication was found in a sample of 43 out of 46 reviewed patients where medication data were available. This phenomenon was not observed in the general population. Conclusion: In a polymedicated urgent care hospital population, a creatinine enzyme method produces unreliable results, apparently due to multiple drug-related interferences.

Identifying obstacles hindering the conduct of academic-sponsored trials for drug repurposing on rare-diseases: an analysis of six use cases.

BACKGROUND: Academic-sponsored trials for rare diseases face many challenges; the present paper identifies hurdles in the set-up of six multinational clinical trials for drug repurposing, as use cases. METHODS: Six academic-sponsored multinational trials aiming to generate knowledge on rare diseases drug repurposing were used as examples to identify problems in their set-up. Coordinating investigators leading these trials provided feedback on hurdles linked to study, country, and site set up, on the basis of pre-identified categories established through the analysis of previous peer-reviewed publications. RESULTS: Administrative burden and lack of harmonization for trial-site agreements were deemed as a major hurdle. Other main identified obstacles included the following: (1) complexity and restriction on the use of public funding, especially in a multinational set up, (2) drug supply, including procurement tendering rules and country-specific requirements for drug stability, and (3) lack of harmonization on regulatory requirements to get trial approvals. CONCLUSION: A better knowledge of the non-commercial clinical research landscape and its challenges and requirements is needed to make drugs-especially those with less commercial gain-accessible to rare diseases patients. Better information about existing resources like research infrastructures, clinical research programs, and counseling mechanisms is needed to support and guide clinicians through the many challenges associated to the set-up of academic-sponsored multinational trials.

Use of Hypolipidemic Drugs and the Risk of Second Primary Malignancy in Colorectal Cancer Patients.

An increasing number of studies has brought evidence of the protective role of statin use against different types of cancer. However, data on their association with second primary malignancies (SPMs) are lacking. The purpose of this study was to determine the role of hypolipidemic treatment in the prevention of second primary cancer in colorectal cancer (CRC) survivors. We conducted a retrospective single-institution study of 1401 patients with newly diagnosed colorectal cancer from January 2003 to December 2016, with follow-up until December 2020. An SPM was detected in 301 patients (21%), and the incidence was significantly lower in patients with statin medication. However, stratification by cancer types revealed an increased incidence of bladder and gastric cancer in hypolipidemic users. A Kaplan-Meier analysis of early-stage CRC survivors with an SPM showed a significant survival benefit in patients without a history of hypolipidemic treatment. Despite the protective role of statins on overall second cancer incidence, these data indicate that CRC survivors treated with hypolipidemic drugs should be screened more cautiously for SPMs, especially for gastric and bladder cancer.

Effect of dexamethasone in patients with ARDS and COVID-19 (REMED trial)-study protocol for a prospective, multi-centre, open-label, parallel-group, randomized controlled trial.

BACKGROUND: Since December 2019, SARS-CoV-2 virus has infected millions of people worldwide. In patients with COVID-19 pneumonia in need of oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. However, the dose of 6 mg of dexamethasone is currently being reappraised and may miss important therapeutic potential or may prevent potential deleterious effects of higher doses of corticosteroids. METHODS: REMED is a prospective, open-label, randomised controlled trial testing the superiority of dexamethasone 20 mg (dexamethasone 20 mg on days 1-5, followed by dexamethasone 10 mg on days 6-10) vs 6 mg administered once daily intravenously for 10 days in adult patients with moderate or severe ARDS due to confirmed COVID-19. Three hundred participants will be enrolled and followed up for 360 days after randomization. Patients will be randomised in a 1:1 ratio into one of the two treatment arms. The following stratification factors will be applied: age, Charlson Comorbidity Index, CRP levels and trial centre. The primary endpoint is the number of ventilator-free days (VFDs) at 28 days after randomisation. The secondary endpoints are mortality from any cause at 60 days after randomisation; dynamics of the inflammatory marker, change in WHO Clinical Progression Scale at day 14; and adverse events related to corticosteroids and independence at 90 days after randomisation assessed by the Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days. The study will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. DISCUSSION: We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety. TRIAL REGISTRATION: EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020.

Cannabidiol and the possibilities of its use in veterinary medicine of dogs and horses: A brief review.

In connection with the use of cannabinoids for therapeutic purposes in human medicine, there is increased attention for their use in veterinary medicine, particularly by the owners of companion animals and horses. Therefore, veterinarians are expected to face this interest and have the corresponding knowledge on these substances. Presently, it is not possible to use medical marijuana (in terms of the dried cannabis flowers) for veterinary purposes in many countries, but there is increasing evidence that isolated cannabinoids also have beneficial effects (namely cannabidiol - CBD). Thus, this review summarises the possible therapeutic implications of CBD within the scope of evidence-based medicine, particularly in dogs and horses in association with the treatment of pain, epilepsy and anxiety in order to provide veterinarians with a concise overview of scientific findings in this field.

European survey on national harmonization in clinical research.

BACKGROUND: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and "research infrastructures" for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. METHODS: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action. RESULTS: Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know-how and documents. Since harmonization was mainly a bottom-up approach up until now, the extent and topics dealt with are diverse and there is only little cross-networking and cross-country exchange so far. CONCLUSIONS: Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country.

Penis as a primary site of an extraskeletal Ewing sarcoma: A case report.

RATIONALE: The Ewing sarcoma family of malignant tumors is a group of tumors characterized by morphologically similar round-cell neoplasms and by the presence of a common chromosomal translocation; Ewing sarcoma family of tumors typically occur in children and young adults between 4 to 15 years of age. The primary tumor usually originates in the bone, extraskeletal localization is rare. PATIENT CONCERN: We present a case report concerning a 32-year-old male patient with a primary involvement of the penis. DIAGNOSIS: The histopathology from the first penile biopsy showed a small-cell neuroendocrine carcinoma; however, that result was based on a sample obtained at a different facility than the Sarcoma Center, where the investigating pathologist did not have the adequate expertise. The patient then underwent a radical penectomy and a second reading of the histology was demanded after a radical penile amputation when Ewing sarcoma with R1 resection was confirmed. INTERVENTIONS: The patient was referred to the national Sarcoma Center, where - using a multidisciplinary approach - the treatment was started with curative intent. However, it was preceded by a non-standard initiation of the therapy due to the poor primary diagnosis. OUTCOMES: The non-standard therapy at the onset of the disease caused a poor prognosis of an otherwise curable diagnosis. Despite all that, the patient survived for a relatively long time. LESSONS: The treatment of sarcomas with atypical localizations should be conducted by an experienced multidisciplinary team in a center with experience in sarcoma treatment.

Effect of dexamethasone in patients with ARDS and COVID-19 - prospective, multi-centre, open-label, parallel-group, randomised controlled trial (REMED trial): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Second primary malignancies in colorectal cancer patients.

The prevalence of second primary malignancies (SPMs) in the western world is continually increasing with the risk of a new primary cancer in patients with previously diagnosed carcinoma at about 20%. The aim of this retrospective analysis is to identify SPMs in colorectal cancer patients in a single-institution cohort, describe the most frequent SPMs in colorectal cancer patients, and discover the time period to occurrence of second primary tumors. We identified 1174 patients diagnosed with colorectal cancer in the period 2003-2013, with follow-up till 31.12.2018, and median follow-up of 10.1 years, (median age 63 years, 724 men). A second primary neoplasm was diagnosed in 234 patients (19.9%). Older age patients, those with early-stage disease and those with no relapse have a higher risk of secondary cancer development. The median time from cancer diagnosis to development of CRC was 8.9 years for breast cancer and 3.4 years for prostate cancer. For the most common cancer diagnosis after primary CRC, the median time to development was 0-5.2 years, depending on the type of malignancy. Patients with a diagnosis of breast, prostate, or kidney cancer, or melanoma should be regularly screened for CRC. CRC patients should also be screened for additional CRC as well as cancers of the breast, prostate, kidney, and bladder. The screening of cancer patients for the most frequent malignancies along with systematic patient education in this field should be the standard of surveillance for colorectal cancer patients.

PET/CT-tailored treatment of locally advanced oesophago-gastric junction adenocarcinoma: a report on the feasibility of the multicenter GastroPET study.

BACKGROUND: Perioperative chemotherapy is a recommended treatment approach for localised oesophago-gastric junction adenocarcinoma, but not all patients respond to neoadjuvant chemotherapy. Early identification of non-responders and treatment adaptation in the preoperative period could improve outcomes. GastroPET is a national, multicentre phase II trial evaluating a 18FDG-PET/CT-guided preoperative treatment strategy with the R0 resection rate as a primary endpoint. Here, we report on the accuracy of the methodology, the feasibility of the study design and patient safety data after enrolment of the first 63 patients. METHODS: Patients with locally advanced oesophago-gastric junction adenocarcinoma (Siewert I - III) stage Ib-IIIc underwent baseline 18FDG-PET/CT scanning and re-evaluation after 14 days of oxaliplatinum-5FU-(docetaxel) chemotherapy. Responders were defined by a ⩾ 35% decrease in tumour FDG standardised uptake value (SUV)average from baseline. Responders continued with the same chemotherapy for 2 to 3 months prior to surgery. PET-non-responders switched to preoperative chemoradiotherapy [weekly carboplatin and paclitaxel with concurrent radiotherapy (45 Gy in 25 fractions)]. Here, we aim to confirm the feasibility of FDG-PET-based response assessment in a multicenter setting and to compare local versus central reading. In addition, we report on the feasibility of the study conduct and patient safety data. RESULTS: A total of 64 patients received baseline and sequential 14-day 18FDG-PET/CT scanning. And, 63 were allocated to the respective treatment arm according to PET-response [35 (56%) responders and 28 (44%) non-responders]. The concordance of local versus central reading of SUV changes was 100%. Until the date of this analysis, 47 patients (28 responders and 19 non-responders) completed surgery. Postoperative complications of grade ⩾ 3 (Common Terminology Criteria for Adverse Events, CTCAE Version 5.0) were reported in five responders (18%; 95% CI: 7.9-36%) and two non-responders (11%; 95% CI: 2.9-31%), with no statistical difference (p = 0.685). One patient in each arm died after surgery, leading to a postoperative in-hospital mortality rate of 4.3% (2/47 patients; 95% CI: 1.2-14%). CONCLUSION: Local and central FDG-SUV quantification and PET-response assessment showed high concordance. This confirms the accuracy of a PET-response-guided treatment algorithm for locally advanced oesophago-gastric junction cancer in a multicenter setting. Preoperative treatment adaptation revealed feasible and safe for patients.

Everolimus-related unilateral abdominal lymphedema in a renal cancer patient: A case report.

RATIONALE: Unilateral manifestation of lymphedema during everolimus therapy has been described only rarely, mostly in transplant recipients. PATIENT CONCERNS: We report the first case of a patient who developed unilateral abdominal lymphedema, during a short period of everolimus treatment for renal cancer. DIAGNOSIS: The abdominal asymmetry occurred only on the right side of the abdomen, neither ultrasound nor CT scan detected ascites but showed enlargement of the abdominal wall. The Naranjo Adverse Drug Reaction Probability scale was evaluated, in this case, a score of 6 indicated a probable adverse reaction to everolimus. INTERVENTIONS: Discontinuation of everolimus therapy led to immediate alleviation and reduction of the lymphedema, with worsening once again after initiating retreatment with everolimus at a reduced dose. OUTCOMES: The patient's lymphedema recovered after discontinuation of everolimus. LESSONS: This rare case demonstrates the importance of the selection of mammalian target of rapamycin inhibitors using caution, especially for patients with a high risk of developing lymphedema.

Effects of Early and Systematic Integration of Specialist Palliative Care in Patients with Advanced Cancer: Randomized Controlled Trial PALINT.

Background: A broad consensus on the optimal structure, intensity, and timing of early specialist palliative care (SPC) intervention is lacking. Objective: To evaluate the benefit of an early and systematic palliative intervention alongside standard oncology care compared with standard oncology care alone in patients with advanced solid tumors. Design: PALINT, a single-center RCT, conducted at the Masaryk Memorial Cancer Institute, the largest comprehensive cancer center in the Czech Republic (CR). Setting/Subjects/Measurements: Patients with newly diagnosed advanced cancer within six weeks from the start of the palliative systemic therapy were randomly assigned to the integration of SPC (intervention; a consultation with a PC physician every six to eight weeks) or to the standard oncology care (control). The primary endpoint was the quality of life (QOL) assessed by EORTC QLQ C30 and Hospital Anxiety and Depression Scale (HADS) at three and six months. Results: From 2015 to 2017, a total of 126 patients were randomly assigned to intervention (60) or to control (66) arm. At baseline, at three and six months, the global QOL scores (mean, 95% CI) in the intervention and control arm were 58.6 (53.9-63.3), 61.9 (56.4-67.4) and 66.7 (60.2-73.2) versus 54.2 (49.4-58.9), 59.0 (53.7-64.3), and 62.8 (56.7-68.9), respectively. The prevalence of anxiety (HADS-A; value >7) was 36.7%, 27.5%, and 18.9% versus 34.8%, 23.5%, and 16.3% and the prevalence of depression (HADS-D; value >7) was 28.3%, 25.4%, and 29.7% versus 28.8%, 29.4%, and 27.9%, respectively. There was no significant difference between the two arms. The overall survival was similar in both arms (347 vs. 310 days; p = 0.203). Conclusions: A model of early integration of SPC consisting of a consultation with a PC physician alone every six to eight weeks did not increase the QOL of patients with advanced cancer compared with routine oncology care in a center with widely available supportive services. These negative results underline the importance of the multidisciplinary patient centered approach in the early SPC.

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment.

AIMS: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. METHODS: This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment. RESULTS: Thirty-one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. CONCLUSION: Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.

The Impact of Diabetes Mellitus on the Second Primary Malignancies in Colorectal Cancer Patients.

INTRODUCTION: All colorectal cancer (CRC) survivors have an increased risk of developing second primary malignancies (SPMs). The association between diabetes mellitus (DM) and the risk of cancer is well known. However, the role of DM and its therapy in the development of SPMs in CRC patients is not well described. METHODS: In this single-institutional retrospective analysis we identified 1,174 colorectal carcinoma patients, median follow-up 10.1 years, (median age 63 years, 724 men). All patients over 18 years with histologically confirmed CRC who were admitted in the period 1.1. 2003- 31.12.2013 and followed-up till 31.12. 2018 at the Masaryk Memorial Cancer Institute (MMCI) were screened for eligibility. The exclusion criteria were CRC diagnosed at autopsy, lost to follow-up and high risk of development of SPMs due to hereditary cancer syndrome. Tumours are considered multiple primary malignancies if arising in different sites and/or are of a different histology or morphology group. Comparisons of the basic characteristics between the patients with SPM and the patients without SPM were performed as well as comparison of the occurrence of SPMs by the site of diagnosis between the DM and non-DM cohorts and survival analyses. RESULTS: A SPM was diagnosed in 234 (20%) patients, DM in 183 (15%) patients. DM was diagnosed in 22.6% of those with SPM vs. in 13.8% of those without SPM (p=0.001). The most common types of SPMs in DM patients were other CRC, kidney, lung, bladder and nonmelanoma skin cancer, but only carcinoma of the liver and bile duct tracts was significantly more common than in the group without DM. Although breast cancer was the second most common in the group with DM, its incidence was lower than in the group without DM, as well as prostate cancer. A significantly higher incidence of SPMs was found in older CRC patients (≥ 65 years) and in those with lower stage colon cancer and DM. No significant difference in DM treatment between those with and without a SPM was observed including analysis of type of insulin. CONCLUSION: CRC patients with diabetes mellitus, especially those with older age, and early stages of colon cancer, should be screened for second primary malignancies more often than the standard population. Patients without DM have longer survival. According to the occurrence of the most common second malignancies, a clinical examination, blood count, and ultrasound of the abdomen is appropriate, together with standard breast and colorectal cancer screening, and lung cancer screening under certain conditions, and should be recommended in CRC survivors especially in patients with intercurrent DM, however the necessary frequency of screening remains unclear.

Therapeutic Drug Monitoring of Sunitinib in Gastrointestinal Stromal Tumors and Metastatic Renal Cell Carcinoma in Adults-A Review.

BACKGROUND: Sunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal cell carcinoma and a second-line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients, and many face adverse effects and/or toxicity. One of the possible causes of the interindividual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite. This review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib. METHODS: The authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed. RESULTS: There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. To avoid toxicity, the total trough levels should not exceed 100 ng/mL. CONCLUSIONS: According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinib toxicity.

Assessment of Immune Response Following Dendritic Cell-Based Immunotherapy in Pediatric Patients With Relapsing Sarcoma.

Monocyte-derived dendritic cell (DC)-based vaccines loaded with tumor self-antigens represent a novel approach in anticancer therapy. We evaluated DC-based anticancer immunotherapy (ITx) in an academic Phase I/II clinical trial for children, adolescent, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors. The primary endpoint was safety of intradermal administration of manufactured DCs. Here, we focused on relapsing high-risk sarcoma subgroup representing a major diagnosis in DC clinical trial. As a part of peripheral blood immunomonitoring, we evaluated quantitative association between basic cell-based immune parameters. Furthermore, we describe the pattern of these parameters and their time-dependent variations during the DC vaccination in the peripheral blood immunograms. The peripheral blood immunograms revealed distinct patterns in particular patients in the study group. As a functional testing, we evaluated immune response of patient T-cells to the tumor antigens presented by DCs in the autoMLR proliferation assay. This analysis was performed with T-cells obtained prior to DC ITx initiation and with T-cells collected after the fifth dose of DCs, demonstrating that the anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens. Finally, we present clinical and immunological findings in a Ewing's sarcoma patient with an interesting clinical course. Prior to DC therapy, we observed prevailing CD8+ T-cell stimulation and low immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSC) and regulatory T-cells (Tregs). This patient was subsequently treated with 19 doses of DCs and experienced substantial regression of metastatic lesions after second disease relapse and was further rechallenged with DCs. In this patient, functional ex vivo testing of autologous T-cell activation by manufactured DC medicinal product during the course of DC ITx revealed that personalized anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens and that the T-cell reactivity persisted for the period without DC treatment and was further boosted by DC rechallenge. Trial Registration Number: EudraCT 2014-003388-39.