Brentuximab-induced splinter nail haemorrhages in a patient with Sézary syndrome: A case report.

Sézary syndrome is a systemic variant of cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy and circulating atypical lymphocytes (Sézary cells). It may present with nonspecific lesions on multiple digits. We describe an atypical case of brentuximab-induced splinter nail haemorrhages in a patient with Sézary syndrome, associated with a poor prognosis during follow-up. Concomitantly with the appearance of nail lesions, significant lymphocytosis was detected as well as infiltration of bone marrow and nail matrices. The lesions followed a precise sequence, which can be traced back to the monthly application of brentuximab and its direct cytotoxic effect on CD30+ T lymphocytes in the nail matrix. Brentuximab-induced nail lesions might be associated with decreased efficacy of brentuximab in this patient with advanced cutaneous T-cell lymphoma.

Global Warming and Prescribing: A Review on Medicines' Effects and Precautions.

INTRODUCTION: Global warming is slowly but surely becoming one of the greatest problems of the modern world. Heatwaves with extremely high temperatures and humidity changes are particularly dangerous as they can lead to increased mortality rates and increased side effects of certain medications. The goal of this study was to give a short review of the most critical issues healthcare professionals should be mindful of when it comes to prescription of medicines during high temperature periods. METHODS: A PubMed literature search was conducted in January 2021 in order to identify studies showing stability changes of most prescribed drugs in high temperatures as well as studies demonstrating impact of some drugs on human thermoregulation. RESULTS: A vast majority of the commonly prescribed drugs, including Simvastatin, Levothyroxine, Omeprazole and Atorvastatin aren't susceptible to heat. However, some studies found that Amlodipine and Lansoprazole degrade following heat exposure. A study demonstrated the effects of low relative humidity environment on Levothyroxine tablets. While Levothyroxine remained stable at high temperatures, it significantly degraded with the decrease in humidity. Since all vaccines, both viral and bacterial, are most stable at exactly 2-8 °C, providing adequate storage has turned out to be an immense challenge. In general, killed whole-cell bacterial vaccines, like pertussis vaccine, show a higher degree of stability of potency compared to live attenuated vaccines, such as BCG. However, when tested in high-temperature conditions, BCG vaccine has proven to be more stable than Pertussis vaccine. Also, diphtheria and tetanus toxoids have proven to be most stable during exposure to various conditions. Many medicines can potentially have their side effects enhanced during heatwaves and cause serious health issues. Using the percutaneous form of nitroglycerin could lead to an additional decrease in blood pressure in warm weather. Subdermally injected insulin could create a severe hypoglycemia in diabetic patients. Studies have shown that schizophrenic patients on antipsychotic treatment have much lower heat tolerance, with a higher possibility of developing hyperthermic syndromes such as febrile catatonia or neuroleptic malignant syndrome. CONCLUSION: Heatwave periods are not to be taken lightly and should be approached with utmost caution when prescribing therapy. It is of critical importance to inform and educate vulnerable populations early in the season and promote proper hydration throughout the periods when temperatures exceed local averages.

The development of biologics to target SARS-CoV2: Treatment potential of antibodies in patient groups with poor immune response.

Development of novel antibodies to combat the novel SARS-CoV-2 virus is ongoing. Importantly, particular subgroups are more prone to severe disease, namely patients with poor immune responses. This includes cancer patients with solid and haematological disease, solid organ transplant (SOT) patients and those with congenital or acquired immunodeficiency. Outcomes for patients with poor immune responses receiving antibody therapy for underlying disease and SARS-CoV-2 severe infection are undergoing investigation. The objective of this study was to perform a search on patients with poor immune responses with severe SARS-CoV-2 infection, to assess if antibody therapy is beneficial in such populations. We performed searches using PubMED and medrXiv up to May 2021 of patients with solid and hematologic malignancy, SOT patients and acquired or congenital immunodeficiency. The primary outcome was to assess if antibody therapy was included during SARS-CoV-2 infection and the clinical outcomes of such treatment in this population. Here we find that there is a repurposing of monoclonal antibodies to target cytokine release syndrome, along with the use of convalescent plasma (CP). Despite CP demonstrating promising results, we reiterate evidence that CP forces mutational escape and subsequent variant development. Repurposing of antibody therapies (such as Tocilizumab) proved effective, especially in SOT patients. This also potentially opens an avenue for the use of anti-SARS-CoV-2 spike protein neutralizing monoclonal antibodies; however, studies have yet to focus on patients with poor immune responses as a subpopulation.

Effect of adjunctive lidocaine-based scalp block and laryngotracheal local anesthesia vs general anesthesia only on plasma and cerebrospinal fluid pro-inflammatory cytokine concentrations in patients with cerebral aneurysm: a randomized controlled trial.

AIM: To compare the effect of adjunctive lidocaine-based scalp block and laryngotracheal local anesthesia vs general anesthesia only on pro-inflammatory cytokine concentrations in patients with non-ruptured brain aneurysms undergoing elective open surgery. METHODS: This parallel, randomized, controlled, open-label trial was conducted at Clinical Hospital Center Zagreb between March 2019 and March 2020. At the beginning of anesthesia, lidocaine group received 40 mg of 2% lidocaine for laryngotracheal topical anesthesia and 4 mg/kg for the scalp block. Control group underwent general anesthesia only. Plasma concentrations of IL-6, TNF-α, and IL-1ß were measured before anesthesia (S0); at the incision (S1); at the end of surgery (S2); 24 hours postoperatively (S3). Cerebrospinal fluid (CSF) cytokine concentrations were measured at the incision (L1) and the end of surgery (L2). RESULTS: Forty patients (each group, 20) were randomized; 37 were left in the final analysis. IL-6 plasma concentrations increased significantly compared with baseline at S3 in lidocaine group, and at S2 and S3 in control group. In both groups, changes in TNF-α and IL-1ß were not significant. CSF cytokine concentrations in lidocaine group did not change significantly; in control group IL-6 and IL-1ß were significantly higher at L2 than at L1. CSF IL-6 in control group significantly increased at L2, but TNF-α and IL-1ß did not. No differences in clinical outcome and complication rates were observed. CONCLUSION: Adjunctive lidocaine-based scalp block and laryngotracheal local anesthesia might attenuate CSF IL-6 concentration increase in patients with brain aneurysm.

Pembrolizumab-induced vitiligo in a patient with lung adenocarcinoma: A case report.

Pembrolizumab is an immune checkpoint inhibitor designed to block the interaction between programmed cell death-1 and programmed cell death-ligands 1 and 2. It shows efficacy in the treatment of patients with advanced nonsmall-cell lung cancer, among others. Side effects may involve immune-related adverse events, including vitiligo. We hereby present a 63-year-old Caucasian female with metastatic nonsmall-cell lung cancer. Immunohistochemical analysis showed programmed death-ligand 1 expression on 100% of tumour cells. The patient was eligible for immunotherapy and received pembrolizumab every 3 weeks as the first-line treatment. Three months after initiation of immunotherapy with pembrolizumab, depigmentation appeared on her upper right thoracic area of the skin overlying the affected lung lobe. Immunotherapy was generally well tolerated. Excellent response in our subject with complete remission during 16 months of follow-up potentially indicates that cutaneous immune-related adverse events, such as vitiligo, might be associated with increased efficacy of pembrolizumab in metastatic lung adenocarcinoma.

Safety and efficacy of nivolumab as a second line therapy in metastatic renal cell carcinoma: a retrospective chart review.

AIM: To assess diseases outcomes and tolerability of real-life second-line nivolumab in a series of metastatic renal cell carcinoma (mRCC) patients. METHODS: This retrospective chart review involved prospectively monitored patients (named patient program) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from February 2016 to March 2018. RESULTS: The study enrolled 30 patients, 5 of whom (16.7%) had a complete response. The mean ± standard deviation therapeutic response time to nivolumab treatment was 14.07 ± 8.92 months, with a minimum treatment duration of 2 months and a maximum of 24 months. The median duration of therapy was 17 months (mean: 15.8 months; range: 3-24 months), and 50% (n=15/30) of patients remained alive at the end of follow up. The most common adverse events associated with nivolumab were fatigue (26.67%; n=8/30), anemia (10.0%; n=3/30), adrenal insufficiency (6.67%; n=2/30: G1=1, G2=1), grade 2 pneumonitis (6.67%; n=2/30), grade 2 neuropathy (6.67%; n=2/30), rash (6.67%; n = 2/30: G1=1, G2=1), and hepatitis (3.33%; n=1/30). CONCLUSION: The present study indicates acceptable patient responses and tolerability of nivolumab in mRCC.

Effect of local anesthesia with lidocaine on perioperative proinflammatory cytokine levels in plasma and cerebrospinal fluid in cerebral aneurysm patients: Study protocol for a randomized clinical trial.

BACKGROUND: Cerebral aneurysm surgery has significant mortality and morbidity rate. Inflammation plays a key role in the pathogenesis of intracranial aneurysms, their rupture, subarachnoid hemorrhage and neurologic complications. Proinflammatory cytokine level in blood and cerebrospinal fluid (CSF) is an indicator of inflammatory response. Cytokines contribute to secondary brain injury and can worsen the outcome of the treatment. Lidocaine is local anesthetic that can be applied in neurosurgery as regional anesthesia of the scalp and as topical anesthesia of the throat before direct laryngoscopy and endotracheal intubation. Besides analgesic, lidocaine has systemic anti-inflammatory and neuroprotective effect.Primary aim of this trial is to determine the influence of local anesthesia with lidocaine on the perioperative levels of pro-inflammatory cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor-α in plasma and CSF in cerebral aneurysm patients. METHODS: We will conduct prospective randomized clinical trial among patients undergoing craniotomy and cerebral aneurysm clipping surgery in general anesthesia. Patients included in the trial will be randomly assigned to the lidocaine group (Group L) or to the control group (Group C). Patients in Group L, following general anesthesia induction, will receive topical anesthesia of the throat before endotracheal intubation and also regional anesthesia of the scalp before Mayfield frame placement, both done with lidocaine. Patients in Group C will have general anesthesia only without any lidocaine administration. The primary outcomes are concentrations of cytokines interleukin-1ß, interleukin-6 and tumor necrosis factor-α in plasma and CSF, measured at specific timepoints perioperatively. Secondary outcome is incidence of major neurological and infectious complications, as well as treatment outcome in both groups. DISCUSSION: Results of the trial could provide insight into influence of lidocaine on local and systemic inflammatory response in cerebrovascular surgery, and might improve future anesthesia practice and treatment outcome. TRIAL IS REGISTERED AT CLINICALTRIALS.GOV:: NCT03823482.

Skin autoimmunity might be associated with increased efficacy of atezolizumab in metastatic urothelial carcinoma: a case report.

Atezolizumab is a monoclonal antibody immune checkpoint inhibitor that binds to programmed death ligand 1 to selectively prevent its interaction with programmed cell death-1 (PD-1) and B7.1 (CD80) receptors. We present a case of a 61-year-old man with metastatic urothelial carcinoma of the right ureter and urinary bladder. After gemcitabine/cisplatin as the first-line chemotherapy and surgery, the patient received atezolizumab 1200 mg i.v. q3w. Following the first atezolizumab administration, he noted vitiligo periorally, on his hands, legs, and the scalp. The patient's overall survival (OS) of >26 months and continuing response to atezolizumab treatment is considerably better than median OS in the SAUL study of 8.7 months (IMvigor211-like patients' OS 10.0 months). This case indicates that increased efficacy of atezolizumab can be associated with cutaneous immune related adverse events, reflecting the known Th17 polarization of these diseases and showing that individuals with cutaneous adverse events could benefit from PD-1 checkpoint blockade in the therapy of metastatic urothelial carcinoma.

Evaluation of nurses' workload in intensive care unit of a tertiary care university hospital in relation to the patients' severity of illness: A prospective study.

BACKGROUNDS: Costs of intensive care reach up to 30% of the hospital budget with workforce expenses being substantial. Determining proper nurse-patient ratio is necessary for optimizing patients' health related outcomes and hospitals' cost effective functioning. OBJECTIVES: To evaluate nurses' workload using Nine Equivalents of Nursing Manpower Use Score and Nursing Activities Score scoring systems while assessing correlation between both scores and the severity of illness measured by Simplified Acute Physiology Score II. DESIGN: A Prospective study SETTINGS: Cardiac Surgery Intensive Care Unit of the Clinical Hospital Centre Rijeka, Croatia, from October 2014 to February 2015. This Intensive Care Unit has 3 beds that can be expanded upon need. PARTICIPANTS: The study included 99 patients treated at this Unit during the study's period. The scores were obtained by 6 nurses, working in 12h shifts. METHODS: Measurements were obtained for each patient 24h after admission and subsequently twice a day, at the end of the day shift (7pm) and at the end of the night shift (7 am). The necessary data were obtained from the patient's medical records. RESULTS: Nursing Activities Score showed significantly higher number of nurses are required for one 12h shift (Z=3.76, p<0.001). Higher scores were obtained on day shifts vs. night shifts. (Nursing Manpower Use Score, z=3.25, p<0.001; Nursing Activities Score, z=4.16, p<0.001). When comparing Nursing Activities Score and Nursing Manpower Use Score during the week, we calculated higher required number of nurses on weekdays than on weekends and holidays, (Nursing Manpower Use Score, p<0.001; Nursing Activities Score, p<0.001). Correlation analysis of Nursing Activities Score and Nursing Manpower Use Score with Simplified Acute Physiology Score II has shown that Nursing Manpower Use Score positively associated with severity of disease, while Nursing Activities Score shows no association. CONCLUSION: Both scores can be used to estimate required number of nurses in 12-h shifts, although Nursing Activities Score seems more suitable for units with prolonged length of stay, while Nursing Manpower Use Score appears better for units with shorter duration of stay (up to four days). Higher workload measured by Nursing Manpower Use Score scale can be predicted with higher Simplified Acute Physiology Score II. However, with low Simplified Acute Physiology Score II scores it cannot be assumed that the nursing workload will also be low. Further research is needed to determine the best tool to asses nursing workload in intensive care units.

Budget Impact Analysis of Biosimilar Trastuzumab for the Treatment of Breast Cancer in Croatia.

BACKGROUND AND OBJECTIVE: Breast cancer is the most common cancer in women and has considerable impact on healthcare budgets and patients' quality of life. Trastuzumab (Herceptin®) is a monoclonal antibody directed against the human epidermal growth factor receptor (HER2) for the treatment of breast cancer. Several trastuzumab biosimilars are currently in development. In 2015, trastuzumab was the drug with the highest financial consumption among all drugs in Croatia. This model estimates the 1-year budget impact of the introduction of biosimilar trastuzumab in Croatia. METHODS: A budget impact model, based on approvals for trastuzumab treatment in 2015, was developed for the introduction of biosimilars. Two biosimilar scenarios were developed: biosimilar scenario 1, based on all approvals in 2015, and biosimilar scenario 2, based on approvals after February 2015 and the reimbursement of the subcutaneous formulation of trastuzumab in Croatia. Only trastuzumab-naïve patients and drug-acquisition costs were used in the model. Uptake of biosimilar was assumed at 50 %. Scenarios were calculated with price discounts of 15, 25 and 35 %. The robustness of the model was tested by extensive sensitivity analyses. RESULTS: The projected drug cost savings from the introduction of biosimilar trastuzumab range from €0.26 million (scenario 2, 15 % price discount) to €0.69 million (scenario 1, 35 % price discount). If budget savings were reinvested to treat additional patients with trastuzumab, 14 (scenario 2, 15 % price discount) to 47 (scenario 1, 35 % price discount) additional patients could be treated. Sensitivity analyses showed that the incidence of breast cancer had the highest impact on the model, with a 10 % decrease in incidence leading to an 11.3 % decrease in projected savings. CONCLUSION: The introduction of biosimilar trastuzumab could lead to significant drug cost savings in Croatia.

No Adverse Effects After Radioiodine Treatment at 3 Weeks of Pregnancy.

Radioactive iodine is used for the treatment of hyperthyroidism. Because it accumulates in the fetal thyroid, its administration during pregnancy may cause severe and potentially irreversible hypothyroidism in neonates, with consequent mental retardation, and it is contraindicated during the whole pregnancy. We present a case of a pregnant woman inadvertently treated with 1 mCi (37 MBq) of I in the earliest period of pregnancy and subsequently gave birth to a male infant without signs or symptoms of hypothyroidism or any other damage. This case illustrates that when radioactive iodine administration happens around the third week of gestation pregnancy outcome can be normal.

Online learning applied to a course on rational therapeutics: an international comparison between final year students of two medical schools.

INTRODUCTION: Poor prescribing is probably the most common cause of preventable medication errors and many of these events involve junior doctors. In 2009, an electronic problem-based therapeutics course developed at the University of Michigan Medical School (UMMS) was translated and adapted for use at the University of Zagreb Medical School (UZMS). METHODS: After students from both schools took the course in 2010, we compared their responses with an online questionnaire addressing the course quality and its effectiveness. RESULTS: There were no statistically significant differences in the overall average grades awarded for the course (UZMS 4.11 ± 0.86 vs. UMMS 3.96 ± 0.93; 95% CI mean difference (MD) -0.36, 0.07; P = 0.175) with both student groups expressing high satisfaction rates with its quality, accessibility and overall design. UZMS students reported spending less time working through the course than their American colleagues (2.14 ± 1.01 vs. 2.89 ± 1.02 on a five point Likert scale; 95% CI MD 0.51, 0.99; P < 0.05). Furthermore, Croatian students indicated greater difficulty with course materials (3.54 ± 0.59 vs. 3.25 ± 0.59; 95% CI MD -0.42, -0.15; P < 0,05) and weekly multiple choice questions (3.83 ± 0.62 vs. 3.4 ± 0.61; 95% CI MD -0.58, -0.29; P < 0,05) compared with the UMMS students. CONCLUSION: It is possible to adapt and translate successfully whole online teaching resources and implement them internationally in different countries and health care systems, achieving similar, high student satisfaction rates while decreasing administrative and cost burdens. Web based learning may have great potential to offer a cost effective and safe environment in which prescribing skills can be improved.

Pain relief in medical patients: does clinical judgment and prescribing knowledge suffice?

The aim of this study was to evaluate the quality of pain management in hospitalised patients. A cross-sectional study design that included all medical patients experiencing pain was used. Out of 167 patients hospitalized at the Department of Medicine at the University Hospital Zagreb, 41 patients were experiencing pain and 40 out of them received analgesics. Twenty-two out of 38 patients were treated for malignant pain, 16 for non-malignant pain, and 2 patients could not be classified. Adequate pain relief was reported in less than 25% of patients in both groups. Our study revealed under-prescribing of combination therapy, low utilization rates of strong opioids and prevailing "as needed" prescribing practice. In conclusion, unsatisfactory pain management in medical patients is often present if left solely to the clinical judgement and knowledge of the prescribing physician. Regular pain assessment, evidence-based guidelines, education and regular audits of implementation of these measures are a prerequisite for effective pain treatment, and should all be employed in patients experiencing pain.