Drugs in Context

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Authors: Chiara Dallagiovanna, Laura Mensi, Luca Di Gesaro, Irene La Vecchia, Marco Reschini

Background: Due to high purity, recombinant human chorionic gonadotropin (hCG) is suitable for subcutaneous injection, and hence for self-administration, in assisted reproduction. To increase usability and reduce the risk of dosing errors, a prefilled pen was produced. We investigated the ease of administration and satisfaction with the product amongst patients and healthcare professionals. Methods: A survey was conducted amongst women with infertility who underwent in vitro fertilization treatments with recombinant hCG to trigger ovulation in various clinics in Italy. Results: A total of 276 Italian women were interviewed. The median score of preference for the prefilled pen in comparison with hCG powder to be reconstituted in the solvent was rated as 9 (range 8–10), and 125 women answered that the prefilled pen had major advantages. Reasons for preference of the prefilled pen were linked to ease of use and safety: avoidance of dosage mistakes and of concern of such, ease of administration, certainty that the drug is correctly taken, safe administration and no anxiety. The procedure for recombinant hCG administration through the prefilled pen was judged as easy by 80% of respondents, with a median score of 9 (range 8–10) for easiness on a 1–10 scale. Out of 276 respondents, 249 (90%) had no problem with the injection. Conclusion: Overall, the respondents reported a favourable perception of the prefilled pen with hCG, which was reported to be easy to use and perceived to prevent dosage mistakes.

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Authors: Agnes Aghetti, Peggy Reiner

Introduction: Anticoagulation therapy is used for the management of atrial fibrillation to prevent new clots from developing. However, neurologists face the challenge of when to initiate/reintroduce treatment after a recent episode of stroke without increasing haemorrhagic risk, especially if the stroke is large and/or complicated with haemorrhagic transformation. Case presentation: This report describes the case of a 72-yearold man who had an ischaemic stroke of the right posterior cerebral artery. The patient had permanent atrial fibrillation, discovered in hospital. He was not on chronic anticoagulation therapy before stroke. His anticoagulation therapy was postponed due to a haemorrhagic lesion, leading to new ischaemic stroke. The patient suddenly had right hemiplegia with aphasia for which a mechanical thrombectomy was performed but complicated by embolization into the left posterior cerebral artery with failure of thromboaspiration of this clot. Finally, the patient presented with intracranial hypertension due to ischaemic lesions and died 3 days after his readmission. Conclusion: When to start anticoagulation therapy after ischaemic stroke is an unresolved question but should be discussed at least twice weekly in a stroke unit based on the clinical evolution of the patient.

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Authors: Marco Vincenzo Lenti, Federico Sottotetti, Gino Roberto Corazza

Clinical complexity (CC) is an increasingly recognized feature of internal medicine patients who are often characterized by complex needs determined by both biological (i.e. intrinsic to the patient or disease biology) and non-biological (i.e. socioeconomic, cultural, environmental, behavioural) factors. Breast cancer, one of the most common malignancies worldwide, certainly represents an example of a complex disease. Nonetheless, the concept itself of CC and its possible determinants in breast cancer have been poorly addressed. We herein provide our view about the possible factors triggering CC, the key issues of CC and the related unmet needs in breast cancer.

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Authors: Francisco Nohales Alfonso

Three women with diverse gynaecological medical histories (one with endometriosis, one having had an episiotomy and obstetric anal sphincter injury during a recent delivery, and one having had a recent cystectomy of the left Bartholin gland) developed acute episodes of gynaecological pelvic pain. In each case, clinical investigations (including objective tools for assessing the source, nature and severity of the pain) were conducted early on, and a multimodal approach to therapy was introduced to control the pain and avoid central sensitization or chronicity. The multimodal approach included hormone therapy, antineuropathic medications, and corticosteroid or botulinum neurotoxin infiltrations in some of the patients according to their medical conditions but consistently included behavioural adjustments, physical interventions and a nutraceutical supplement (alpha-lipoic acid, palmitoylethanolamide and myrrh). In each case, the pelvic pain and associated dyspareunia (Marinoff scale 2 or 3) were largely resolved. These clinical cases support the results of clinical trials showing the benefits of alpha-lipoic acid + palmitoylethanolamide + myrrh for the management of gynaecological pelvic pain, enabling the reduction or withdrawal of other analgesic, anti-inflammatory and antineuropathic medications.

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Authors: Zoe Apalla, Marc Perrussel, Efstathios Rallis

Psoriasis is a chronic inflammatory disease affecting about 100 million people worldwide. Around 80% of patients can be treated with topical agents, most commonly corticosteroids and vitamin D analogues. A topical foam formulation of calcipotriol (50 μg/g) and betamethasone dipropionate (0.5 mg/g) (Cal/BD foam; Enstilar®) is approved for the daily treatment of psoriasis for up to 4 weeks and twice-weekly thereafter as maintenance treatment (after initial 4-week treatment success). Long-term proactive maintenance with Cal/BD foam for plaque psoriasis has been shown to prolong the time to first relapse, reduce the number of relapses and increase days in remission in the PSO-LONG trial. Four case studies of proactive management with Cal/BD foam for the treatment of plaque psoriasis for up to 12 months from initial presentation are described. These case studies provide real-world evidence on the long-term effectiveness of proactive management with Cal/BD foam as well as the improvement and maintenance of health-related quality of life. Cal/BD foam was well tolerated.

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Authors: T Joseph Mattingly II, Shannon Weathers

Cost-of-illness (COI) studies attempt to measure and describe the costs associated or attributed to a specific disease, but there are several considerations for measuring and interpreting drug costs estimates. The complexity of the pharmaceutical supply chain and contractual relationships between manufacturers, wholesalers, pharmacies and payers create challenges for researchers attempting to include drug costs in COI analyses. This article aims to provide contextual information for a general audience interested in conducting or evaluating COI studies that may include drug costs and to describe key factors to consider when reviewing drug costs in the peer-reviewed literature.

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Authors: Chiara Bertone, Antonella Mollicone, Stefano Russo, Paola Sasso, Romina Fasciani, Cinzia Riccardi, Mirella Lizzano, the ALI working group

Experiences from clinical practice suggest that hypochlorous acid (HOCl) used as adjuvant treatment can shorten the time to clinical resolution of blepharitis, particularly in relation to the ophthalmic complications that often occur with a blepharitis diagnosis. In addition, in clinical practice, HOCl adjuvant treatment also resulted in a viable option for the management of ophthalmic disorders other than blepharitis. This case series presents and discusses real-life experiences with using an HOCl ophthalmic spray to manage eye infections, further characterizing the use of HOCl for ophthalmic applications.

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Authors: Stephanie Spivack, Stephen Pagkalinawan, Rafik Samuel, David E Koren

Although decreasing in prevalence, heavily treatment-experienced (HTE) persons with limited options for HIV treatment present unique complexities, even amongst experienced providers, as there is no single approach to successful management. HTE patients are described as those having two or less antiretroviral (ARV) classes available for use with limited fully active ARV agents within each class. A detailed understanding of the underlying processes that caused previous treatment failures, diagnostics to define resistance, resistance mechanisms and ARV pharmacology should all function in tandem to determine the next steps of clinical care. This narrative review provides an overview of the clinician approach to care, including diagnostics, approaches to regimen creation, relevant resources, and a broad array of both currently available and upcoming ARVs that may be used in regimens for HTE patients.

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Authors: Steven H Abman, Nicholas R Fox, M Ibrahim Malik, Sneha S Kelkar, Shelby L Corman, Sanika Rege, Jenna Bhaloo, Rachel Shah, Ren-Jay Shei, Dana Saporito, Nisreen Shamseddine, Erik DeBoer, George J Wan, on behalf of the NOTICE Study Investigators

Background: Inhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States. Methods: This was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression–Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio. Results: Thirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (n=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (n=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (n=20) of patients improved or remained stable according to the CGI-I. Conclusion: In patients hospitalized with COVID-19 and mild-to- moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit–risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.

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Authors: Khalad Maliyar, Sonya J Abdulla

Rosacea is a common inflammatory skin disorder affecting the face. Common cutaneous symptoms include papules, pustules, persistent centrofacial erythema, telangiectasias, recurrent flushing, phymatous changes and a variety of ocular manifestations. Previous epidemiological studies have demonstrated that the incidence of rosacea is much lower in people with darker Fitzpatrick phototypes compared to fair-skinned individuals. In patients with darker skin, the centrofacial erythema can be masked and difficult to appreciate, impacting the ability for providers to make diagnoses and leading to misdiagnoses. Thus, it is difficult to say with certainty that the disparities in prevalence in rosacea amongst fair-skinned and darker individuals are true. The primary aim of this article is to raise awareness that rosacea is a global disease and to provide healthcare professionals with strategies to identify and manage rosacea amongst individuals with skin of colour.

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Authors: Andrew Smith, Oliver Matthews

Background: Upper respiratory tract infections occur with an annual incidence of 17.2 billion cases globally. The negative impact that symptoms have on sleep is thought to slow the recovery process. Plant-derived aromatics have been used since ancient times to treat respiratory illnesses. In this narrative review, we summarize the use of aromatics for the symptomatic relief of upper respiratory tract infections and how this affects sleep quality. Methods: Literature searches were conducted using a series of search terms and results were screened for relevance. Additional references were included according to the expert knowledge of the authors. Discussion: Multiple studies have observed that essential oil mixtures of aromatics enhance symptom relief for upper respiratory tract infections and their inhalation has been reported to have antitussive effects. Clinical trials assessing the efficacy of an ointment containing menthol, eucalyptus and camphor found patients to experience faster nasal cooling and decongestion times. Treatment with the same ointment also resulted in significant improvements in reported sleep quality. Aromatic treatment did not improve objective nasal airway measures in any of the studies. Conclusion: Whilst not affecting objective measures of nasal airway resistance, the use of aromatics leads to improvements in a number of subjective sensations associated with the common cold. Such benefits result in better sleep, which likely aids recovery. Therefore, aromatics remain a well tolerated and effective option for the symptomatic relief of upper respiratory tract infections.

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Authors: Giovanna Malara, Chiara Verduci, Maria Altomonte, Maria Cuzzola, Caterina Trifirò, Cristina Politi, Giovanni Tripepi Article Type

Background: The anti-inflammatory drug, thalidomide, is often administered off-label especially in dermatology patients with diseases refractory to different medications. The drug’s mechanism of action is not well understood but clinical evidence suggests an immunomodulatory function. Although this drug is a useful tool for several dermatoses, there are associations between its use and neurotoxic and teratogenic side effects. Consequently, it is reserved only for severe and refractory cases. Methods: Herein, we present a review about thalidomide focusing on its application in dermatology, particularly on discoid lupus erythematosus (DLE) treatment. We analyzed four cases of people who had a regression of DLE with a dosage of 50 mg thalidomide. Patients were followed to determine the conditions treated with thalidomide, dosage, efficacy, duration of treatment, side effects, adverse events and follow-up. A low dose of 50 mg/day induced a notable and rapid improvement within 1–2 months of treatment and no side effects have been reported so far. Results: We report four cases of DLE treated previously with the most common immunomodulatory agents with no results and finally successfully treated with thalidomide. In all four patients, despite a low dose of 50 mg/day, a notable and rapid improvement was obtained within a few months of treatment with no side effects. Conclusions: Notwithstanding the small cohort size, our experience confirms the efficacy of thalidomide for the treatment of DLE.

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Authors: Jennifer N Clements

Background: Chronic kidney disease (CKD) is a prevalent and progressive condition worldwide, and diabetes is a leading risk factor of this renal disorder. People with diabetes and CKD are at high risk of complications such as cardiovascular events and death. CKD is often unrecognized and undiagnosed amongst people with diabetes. To manage CKD, multiple existing and newer agents have been studied in trials and recommended in clinical practice guidelines. Methods: A narrative review of primary and/or secondary renal outcomes from randomized, controlled trials is summarized in this article. The main objective was to provide the most up-to-date information regarding existing and new pharmacotherapy for the management of CKD amongst people with diabetes, specifically type 2 diabetes (T2D). Discussion: Traditional agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have been used for 20 years to preserve kidney function. Other existing agents have received approval by the FDA for the management of CKD such as dapagliflozin, with a role in reducing intraglomerular pressure. Evidence with sodium–glucose cotransporter 2 inhibitors show a potential class effect on improving renal outcomes, independent on their effect on glycaemic parameters. Recently, finerenone was approved for people with T2D and CKD based on clinical evidence as a non-steroidal mineralocorticoid receptor antagonist. Overall, primary and secondary prevention trials have influenced changes in clinical practice guidelines regarding the use of existing and new pharmacotherapy for CKD. Additional considerations include lifestyle modifications, blood pressure management and achievement of glycaemic targets for people with diabetes and CKD, following adequate screening of glomerular filtration rate and/or severity of albuminuria. Conclusion: Due to more robust evidence, clinical practice guidelines have been modified to reflect high-level recommendations for the management of CKD in people with diabetes, specifically T2D. Additional evidence is needed amongst people with lower glomerular filtration rates and in comparison with the standard of care.

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Authors: Antonio J García Ruiz, Nuria García-Agua Soler, Enrique Herrera Acosta, Iris Zalaudek, Josep Malvehy

Background: Sonidegib and vismodegib are Hedgehog pathway inhibitors (HhIs) that play a relevant role in the management of locally advanced basal cell carcinoma (laBCC). This study compared the efficacy and safety of both HhIs based on their available data using effect size measures such as number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Methods: We reviewed data from pivotal trials of sonidegib (BOLT) and vismodegib (ERIVANCE). The NNT for sonidegib and vismodegib was calculated from objective response rate (ORR) values. The NNH was calculated from data relating to treatment discontinuation due to adverse events (AEs) and incidence of AEs. The LHH was calculated as the ratio between the corresponding NNH and NNT. Results: For sonidegib (200 mg), the NNT for ORR at 18 months was 1.65 (95% CI 1.35–2.01) whilst that for vismodegib (150 mg) at 21 months was 2.10 (95% CI 1.65–2.82). The NNH related to treatment discontinuation due to AEs was 1.9 (95% CI 1.6–2.5) for sonidegib and 1.8 (95% CI 1.4–2.2) for vismodegib. The LHH for sonidegib and vismodegib related to treatment discontinuation due to AEs was 1.14 and 0.84, respectively, whilst the LHH according to AEs of grade ≥3 was 1.41 for sonidegib and 0.85 for vismodegib. Conclusions: Sonidegib showed a better benefit–risk ratio compared to vismodegib, being more likely to achieve therapeutic response than to AEs leading to discontinuation. These results should be confirmed in clinical practice and/or in a direct comparison study.

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Authors: Federico Sottotetti, Elisa Ferraris, Barbara Tagliaferri, Raffaella Palumbo, Erica Quaquarini, Cristina Teragni, Emanuela Balletti, Claudia Leli, Andrea Premoli, Ludovica Mollica, Silvia Puglisi, Silvia Sardi, Alberto Malovini, Paolo Pedrazzoli, Antonio Bernardo

Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.

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Authors: Chrysanthi Batistaki, Michal Graczyk, Marcin Janecki, Agata Anna Lewandowska, Rita Moutinho, Kiriaki Vagdatli

The assessment and treatment of breakthrough cancer pain (BTcP) remain a major challenge in medicine due to its high impact on several aspects of health-related quality of life. BTcP should be carefully monitored in all cancer care settings by a multidisciplinary team to provide an appropriate and personalized clinical approach. The aim of this paper is to provide healthcare professionals involved in cancer pain management with a review of the relevant literature on the relationship between background cancer pain and BTcP which, by definition, occurs despite adequately controlled background cancer pain. The clinical cases presented contribute to a better understanding of this issue and underline its impact in daily clinical practice. This article is part of the Management of breakthrough cancer pain Special Issue: https://www.drugsincontext.com/special_issues/management-of-breakthrough-cancer-pain

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Authors: Wai Kwong Cheong, Alson Wai Ming Chan, Chin Chwen Ch’ng, Wen Hung Chung, Ma Teresita Gabriel, Kiran Godse, Wat Mitthamsiri, Hao Trong Nguyen, Marysia Tiongco-Recto, Dinesh Nagrale

Urticaria is a disabling condition, resulting in an impaired quality of life and sleep disruption, and can have an adverse impact on work-related or school-related performance and attendance. It is defined according to the presence of unknown (chronic spontaneous urticaria) or known (inducible urticaria) eliciting factors. Guidelines recommend second-generation H1-antihistamines for the first-line treatment of urticaria. Bilastine is indicated in adults, adolescents (aged ≥12 years) and children (aged ≥2 years (Mexico and some African countries), ≥4 years (Canada) or ≥6 years (Europe)) with a body weight of at least 20 kg for the symptomatic treatment of urticaria and allergic rhino-conjunctivitis. The aim of the Original Real-world cases of Bilastine In Treatment (ORBIT) study was to review real-world cases from across the Asia- Pacific region supported by evidence-based literature. Eight diverse, real-world, difficult-to-treat cases with urticaria in people aged 10–75 years are presented. Once-daily bilastine (20 mg (adults/adolescents) or 10 mg (children)) was found to be well tolerated and effective in the long-term management of chronic spontaneous urticaria and inducible urticaria.

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Authors: S Mimi Mukherjee, Aimee Dawson

Due to worldwide increases in obesity and average maternal age, the incidence of gestational diabetes mellitus (GDM) is increasing. The primary treatment of GDM is medical nutrition therapy but approximately 15–30% of individuals need pharmacotherapy to reach blood glucose goals to minimize the adverse consequences of hyperglycaemia. In the past, regular and neutral protamine Hagedorn insulin were the mainstays of pharmacological treatment for GDM due to their well-established safety; however, because they are administered as injections and require strict timing of doses and meals to minimize hypoglycaemia, alternatives are often sought. The research around the treatment of GDM continues to evolve as insulin analogues and oral agents are studied in clinical trials. The short-term and long-term effects of treatment choices on both mothers and progeny are being evaluated, and this narrative review summarizes the current state of information available regarding the treatment of GDM.

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Authors: Biagio Ricciuti, Alessia Mira, Elisa Andrini, Pietro Scaparone, Sandra Vietti Michelina, Federica Pecci, Luca Cantini, Andrea De Giglio, Giuseppe Lamberti, Chiara Ambrogio, Giulio Metro

Constitutive KRAS signalling drives tumorigenesis across several cancer types. In non-small-cell lung cancer (NSCLC) activating KRAS mutations occur in ~30% of cases, and the glycine to cysteine substitution at codon 12 (G12C) is the most common KRAS alteration. Although KRAS mutations have been considered undruggable for over 40 years, the recent discovery of allelic-specific KRAS inhibitors has paved the way to personalized cancer medicine for patients with tumours harbouring these mutations. Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC.

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Authors: Andrea L Monteiro, Mary Smart, Christopher D Saffore, Todd A Lee, Sarette T Tilton, Michael A Fischer, A Simon Pickard

Introduction: Academic detailing (AD) is an educational outreach strategy to provide clinicians with current evidence-based information, which has been shown to change prescribing behaviours. The overall effectiveness of AD interventions is associated with prescriber satisfaction; however, most approaches use single items or nonvalidated measures. This study aims to develop and validate an instrument to assess prescriber satisfaction with AD interventions. Methods: A group of candidate items was generated and refined based on constructs identified through a literature review and in consultation with an expert panel. The initial instrument was piloted with 183 primary care providers who participated in an AD intervention on opioid-related pain management. To support the validity and reliability of the measure, psychometric properties were examined. Results: Ten candidate items were developed based on the following themes: acceptability, feasibility of implementation, usefulness, perception of efficacy, overall satisfaction, willingness to repeat and willingness to change. One item related to willingness to change did not contribute to assessing an individual’s ability and lowered the measure’s internal consistency and was therefore dropped. Conclusion: Results supported the validity and reliability of a refined 9-item measure of Provider Satisfaction with Academic Detailing (the PSAD). This measure should be considered for broad use across educational outreach programmes as a standardized measure to assess provider satisfaction and provide continuous quality improvement.

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Authors: Yuliya Lytvyn, Muskaan Sachdeva, Asfandyar Mufti, Jensen Yeung

Psoriasis is a chronic inflammatory skin condition that affects diverse ethnic groups with a wide spectrum of skin colours. There are significant differences in how psoriasis presents and impacts the quality of life in non-White individuals. Genetic variations as well as cultural and socioeconomic factors all play a role in such differences and have important implications for the management of psoriasis in skin of colour. Despite these differences, the current psoriasis management is similar across different ethnic backgrounds and is mainly guided by factors such as disease severity, medical comorbidities and patient preferences. This is largely due to the lack of sufficient evidence for psoriasis treatment tailored for patients with skin of colour as most clinical trials are composed of mainly White individuals. Therefore, the focus of this article is to review the current evidence on how epidemiology, clinical presentation and genetic differences in patients with skin of colour with psoriasis may impact treatment strategies. Additionally, pharmacological therapies available to date in these diverse patient cohorts are summarized in this article. The limited data published on this topic reveal a significant need for more investigations with the ultimate goal of incorporating recommendations for patients with skin of colour into the current guidelines for psoriasis treatment. Moreover, awareness of differences in psoriasis presentation amongst individuals with skin of colour may support patients to seek medical care sooner, which could result in earlier diagnosis and lead to improved patient outcomes.

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Authors: Megan Wesling, Jennifer J D’Souza

The prevalence of obesity worldwide continues to increase substantially. Obesity is a chronic disease that can lead to other health conditions, including type 2 diabetes mellitus (T2DM). A variety of treatment options are available to treat T2DM. With its prevalence increasing, it is essential that healthcare professionals assess how their patients’ current diabetes treatment is being managed to avoid further weight gain in those with overweight or obesity.

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Authors: Elisa Andrini, Mirta Mosca, Linda Galvani, Francesca Sperandi, Biagio Ricciuti, Giulio Metro, Giuseppe Lamberti

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1–2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET-positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically ‘cold’ tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to off-target effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET-positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood–brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients.

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Authors: Annalisa Schiepatti, Andrea Premoli, Stiliano Maimaris, Mimma Rizzo, Maria Marples, Laura Villani, Nigel Scott, Federico Sottotetti, David S Sanders, Federico Biagi, Clare Donnellan

The differential diagnosis of non-coeliac enteropathies (NCEs) is challenging and includes a wide range of aetiologies. Drug-induced NCEs are relatively common and characterized by duodenal villous atrophy, which resolves upon suspension of the offending drug. Immune-checkpoint inhibitors (ICIs), targeting molecules involved in the activation of cytotoxic T cells by targeting, for example, PD-1, PD-L1 and CTLA4, are increasingly used for many types of cancers. Adverse events occurring in the gastrointestinal tract have been described, predominantly in the form of immune-mediated colitis mimicking inflammatory bowel disease. Small bowel involvement whilst on ICI therapy is also possible, though less well described. Herein, we describe two cases of enteropathy with villous atrophy and negative coeliac serology due to ICIs: a 65-year-old man affected by stage IV pulmonary adenocarcinoma under treatment with pembrolizumab and an 18-year-old woman affected by stage IV auricular melanoma who was treated with nivolumab. We also provide a review of the current literature describing small bowel involvement during therapy with ICIs, alone or in combination, for different types of solid tumours. Implications for clinical practice include considering the possibility of small bowel involvement in oncological patients treated with ICIs and the inclusion of ICIs amongst the iatrogenic causes of NCE with villous atrophy. Enteropathies due to ICIs may also represent a pathogenetic model for the understanding of the molecular mechanisms leading to villous atrophy in NCE.

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Authors: Siddiq Moolla, Yvette Miller-Monthrope

Hyperpigmentation disorders, such as post-inflammatory hyperpigmentation and melasma, are common conditions affecting all skin types. These conditions are largely benign and are influenced by numerous endogenous and exogenous factors impacting melanocyte activity and melanin production. Current treatment modalities for these conditions fall into broad categories, including photoprotection, topical and systemic therapies, chemical peels, and laser or light-based therapies. Biological differences in skin of colour require additional consideration when deciding on treatment and management. This narrative review provides an inclusive summary of these conditions and compares the current treatment options with a specific focus on skin of colour. Photoprotection and sunscreens protective against both UV and visible light are recommended for all individuals. Topical therapy is the recommended first-line treatment, with the gold standard being hydroquinone, which can be used alone or in combination with other agents. Chemical peels and laser or light-based therapies are also effective adjunctive methods of treatment; however, caution should be taken when used in patients with richly pigmented skin due to the increased risk of post-inflammatory hyperpigmentation.

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Authors: Flor Cristina Ortiz Rios, Itzel Guadalupe Dávila Ruiz, Elisa Sacal Dumani

Anxiety-related disorders are one of the most common mental health issues worldwide. Mexico has reported an increase in the prevalence of these ailments secondary to the confinement derived from the COVID-19 pandemic. Given the limitations of commonly used treatments for these disorders, a need arises to develop new pharmacological treatments for these patients. This paper has the primary objective of evaluating the efficacy and safety of cannabidiol isolate in drug compounding used as a personalized treatment in patients with anxiety disorders through the presentation of four clinical cases.

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Authors: Sergey V Efimov, Natallia V Matsiyeuskaya, Olga V Boytsova, Luydmila Yu Akhieva, Elena V Kuntsevich, Anastasia A Troshina, Elena I Kvasova, Anton A Tikhonov, Nadezhda F Khomyakova, Francisco Harrison, Jean-François Rossi, Timothy C Hardman

Background: Evidence-based therapies used to treat coronavirus disease (COVID-19) remain limited. Azoximer bromide (AZB; Polyoxidonium®) is an immunomodulating molecule frequently used in the Russian Federation. It offers demonstrable therapeutic benefit in upper respiratory tract infections. This study evaluated the safety and efficacy of AZB when used in combination with standard of care treatment in patients hospitalized with COVID-19. Methods: Hospitalized patients with COVID-19 (n=81; nine sites) received AZB 12 mg intravenously once daily for 3 days then intramuscularly every other day until day 17. The primary endpoint included clinical status at day 15 versus baseline. Historical control data of 100 patients from a randomized, controlled, open-label trial conducted in China were included to serve as a direct control group. Results: Notable clinical improvement, assessed by seven-point ordinal scale (OS) score and National Early Warning Score, was observed. Mean duration of hospitalization was 19.3 days. Indicators of pneumonia and lung function showed gradual recovery to normalization. No patients died but, by day 28, one patient still required respiratory support; this patient died on day 34. A higher proportion of patients receiving AZB required invasive or non-invasive ventilation (OS 5 or 6) at baseline compared with the historical control group. Improvement in mean OS score by day 14/15 was not notable in the control group (OS 3.99–3.87) but was clear in the AZB group (OS 4.36–2.90). Mean duration of hospitalization was similar in the control group (16.0 days); however, day 28 mortality was higher, at 25.0% (n=25). Conclusion: AZB combined with standard of care was safe and well tolerated. An apparent clinical improvement could not be fully evaluated due to the lack of a direct control group; further assessment of AZB for the treatment of COVID-19 in a randomized, placebo-controlled study is warranted.

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Authors: Daniele Marinelli, Marco Siringo, Giulio Metro, Biagio Ricciuti, Alain J Gelibter

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK, ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK, ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK-rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1-rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/ RNA-based next-generation sequencing testing is therefore crucial to identify positive cases. This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

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Authors: Alexander KC Leung, Benjamin Barankin, Joseph M Lam, Kin Fon Leong, Kam Lun Hon

Background: Early recognition of xeroderma pigmentosum is important to minimize the complications arising from the harmful effects of exposure to ultraviolet radiation. This narrative review aims to familiarize physicians with the clinical features, diagnosis and management of xeroderma pigmentosum. Methods: A search was conducted in December 2021 in PubMed Clinical Queries using the key term “xeroderma pigmentosum”. The search strategy included all clinical trials, observational studies and reviews published within the past 10 years. The information retrieved from the search was used in the compilation of this article. Results: Xeroderma pigmentosum is a condition of abnormal DNA repair of ultraviolet radiation-induced and oxidative DNA damage, which leads to increased skin cancer susceptibility. Approximately 50% of patients with xeroderma pigmentosum have increased photosensitivity and certain types of xeroderma pigmentosum are more prone to ocular disease and progressive neurodegeneration depending on the causative mutation. The diagnosis should be suspected in patients with increased photosensitivity and characteristic cutaneous, ophthalmological and neurological findings. A definite diagnosis can be made by the identification of biallelic mutation in one of the causative genes. Strict and consistent sun avoidance and protection and early detection and treatment of premalignant and malignant skin lesions are the mainstays of management. Treatment options for actinic keratosis include cryotherapy, topical imiquimod, topical 5-fluorouracil, chemical peeling, excision, CO2 laser resurfacing, fractional/pulsed laser therapy, and photodynamic therapy. Cutaneous malignancy can be treated by photodynamic therapy, curettage and electrodesiccation, or surgical excision. Oral isotretinoin, oral niacinamide, topical imiquimod and topical fluorouracil can be used for the prevention of skin malignancy. Treatment options for poikiloderma include chemical peeling, dermabrasion and laser resurfacing. Methylcellulose eyedrops and soft ultraviolet-protective contact lenses may be used to keep the cornea moist and protect against the harmful effects of keratitis sicca. Investigational therapies include the use of T4 endonuclease-V liposome lotion and oral nicotinamide to reduce the rate of actinic keratoses and non-melanoma skin cancers and gene therapy for radical cure of this condition. Conclusion: Although currently there is no cure for xeroderma pigmentosum, increased awareness and early diagnosis of the condition, followed by rigorous sun avoidance and protection and optimal management, can dramatically improve the quality of life and life expectancy.

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Authors: Alireza FakhriRavari, Brenda Simiyu, Taylor Morrisette, Yewande Dayo, Jacinda C Abdul-Mutakabbir

Antimicrobial resistance is a global public health threat due to its associated increase in mortality, and the most appropriate treatment algorithms for resistant and persistent Gram-positive and Gram-negative infections have yet to be elucidated. Whilst combination therapy has been touted as a viable method to overcome prominent resistant mechanisms represented amongst these microbes, the optimal agents to utilize remains controversial. Beta-lactams have a safe profile and are bactericidal against most Gram-positive and Gram-negative microorganisms. Thus, the use of dual beta-lactam therapy to overcome multidrug-resistant pathogens is of supreme interest. This article reviews the mechanisms of beta-lactam resistance in Gram-positive and Gram-negative bacteria, discusses the rationale for dual beta-lactam use against multidrug-resistant infections (and other scenarios in which this strategy may be most utilized in clinical practice), explores the available in vitro, in vivo and clinical data, and provides considerations for the use of dual beta-lactam therapy against Enterococcus faecalis, Listeria monocytogenes, Staphylococcus aureus, Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii pathogens.

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Authors: George Kassianos, Joan Puig-Barberà, Hannah Dinse, Martin Teufel, Özlem Türeci, Shanti Pather

Immunization programmes have been globally recognized as one of the most successful medical interventions against infectious diseases. Despite the proven efficacy and safety profiles of coronavirus disease 2019 (COVID-19) vaccines, there are still a substantial number of people who express vaccine hesitancy. Factors that influence vaccine decision-making are heterogenous, complex, and context specific and may be caused or amplified by uncontrolled online information or misinformation. With respect to COVID-19, the recent emergence of novel variants of concern that give rise to milder disease also drives vaccine hesitancy. Healthcare professionals remain one of the most trusted groups to advise and provide information to those ambivalent about COVID-19 vaccination and should be equipped with adequate resources and information as well as practical guidance to empower them to effectively discuss concerns. This article seeks to summarize the currently available information to address the most common concerns regarding COVID-19 vaccination.

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Authors: Emily K Hanners, Jessica Benitez-Burke, Melissa E Badowski

Background: People living with HIV (PLWH) and receiving antiretroviral therapy (ART) have a goal of achieving and maintaining viral suppression; however, low-level viraemia (LLV) (HIV-RNA viral load levels of 50–999 copies/mL) persists in certain patients despite consistent medication adherence, lack of drug interactions and no genotypic resistance. This is a narrative review of the growing evidence of LLV in PLWH to determine risk factors and ART management strategies and to discuss the implications of LLV on the development of future virological failure. Methods: A systematic, comprehensive literature search was completed in the English language using PubMed, Google Scholar and bibliography review to gather information about LLV in PLWH between July 2014 and June 2021. The following keywords were used as search terms: “low-level viremia”, “HIV”, “viral blip”, “intensification”, “genotyping”, “adherence” and “resistance.” Results: Of 66 studies examined, 39 were analysed and included in this review. All trials included were published between 2014 and 2021. Eleven studies assessed risk factors for LLV. Identified risk factors were low CD4+ T cell nadir counts at baseline, higher baseline viral load measurements, medication non-adherence, non-nucleoside reverse transcriptase inhibitor use and others. Three studies assessed genotyping and concluded that the interpretation of both historical RNA genotype resistance testing and current proviral DNA genotype resistance testing in patients with LLV is appropriate. Seven studies were evaluated and determined that modifying or intensifying ART regimens resulted in decreased incidence of virological failure. Conclusion: This compilation of reviewed data gives a framework for the management of PLWH with LLV. Currently, there are no clear or definitive treatment directions for LLV provided in guidelines. Complicating this topic further is the unclear and varying definitions of LLV. Future research is needed on this topic but patients presenting with LLV should have their medication adherence assessed, drug interactions checked and ART intensified, where appropriate.