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We present 7 years of clinical experience with single-agent pembrolizumab immune checkpoint inhibitor immunotherapy in non-small cell lung cancers (NSCLC) from four UK cancer centres. This multi-institutional retrospective cohort study included 226 metastatic NSCLC patients. Outcomes were number and severity of immune-related adverse events (irAEs), median progression-free survival (mPFS) and median overall survival (mOS). Within our cohort, 119/226 (53%) patients developed irAEs. Of these, 54/119 (45%) experienced irAEs affecting two or more organ systems. The most common irAEs were diarrhoea and rash. The development of an irAE was associated with better mOS (20.7 versus 8.0 months; P < 0.001) and mPFS (12.0 versus 3.9 months; P < 0.001). The development of grade 3/4 toxicities was associated with worse outcomes compared with the development of grade 1/2 toxicities (mOS 6.1 months versus 25.2 months, P < 0.01; mPFS 5.6 months versus 19.3 months, P = 0.01, respectively). Females had a higher proportion of reported grade 3/4 toxicities (13/44 [29.5%] versus 10/74 [13.5%], P = 0.03). Using a multiple Cox regression model, the presence of irAEs was associated with a better overall survival (hazard ratio = 0.42, 95% confidence interval 0.29–0.61; P < 0.01) and better PFS (hazard ratio 0.38, 95% confidence interval 0.27–0.53; P < 0.001). In this multicentre retrospective cohort study, the development of at least one irAE was associated with significantly longer mPFS and mOS; however, more severe grade 3 and 4 irAEs were associated with worse outcomes. Delayed-onset irAEs, after the 3-month timepoint, were associated with better clinical outcomes. • Multi-institution experience (n = 226) of pembrolizumab monotherapy in advanced lung cancer. • Development of immune-related adverse events (irAEs) associated with improved outcomes. • Onset of irAEs at >3 months from treatment start associated with better outcomes. • Patients with CTCAE grade 1–2 toxicity did better than those with grade 3–4 toxicity. [ABSTRACT FROM AUTHOR]

The EPIWATCH artificial intelligence (AI) system scans open-source data using automated technology and can be used to detect early warnings of infectious disease outbreaks. In May 2022, a multicountry outbreak of Mpox in non-endemic countries was confirmed by the World Health Organization. This study aimed to identify signals of fever and rash-like illness using EPIWATCH and, if detected, determine if they represented potential Mpox outbreaks. The EPIWATCH AI system was used to detect global signals for syndromes of rash and fever that may have represented a missed diagnosis of Mpox from 1 month prior to the initial case confirmation in the United Kingdom (7 May 2022) to 2 months following. Articles were extracted from EPIWATCH and underwent review. A descriptive epidemiologic analysis was conducted to identify reports pertaining to each rash-like illness, locations of each outbreak and report publication dates for the entries from 2022, with 2021 as a control surveillance period. Reports of rash-like illnesses in 2022 between 1 April and 11 July (n = 656 reports) were higher than in the same period in 2021 (n = 75 reports). The data showed an increase in reports from July 2021 to July 2022, and the Mann–Kendall trend test showed a significant upward trend (P = 0.015). The most frequently reported illness was hand-foot-and-mouth disease, and the country with the most reports was India. Vast open-source data can be parsed using AI in systems such as EPIWATCH to assist in the early detection of disease outbreaks and monitor global trends. [ABSTRACT FROM AUTHOR]

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product). [ABSTRACT FROM AUTHOR]

Patients with smoldering ATLL often present with a skin eruption due to skin infiltration of ATLL cells. Although skin eruption type is known to be associated with prognosis based on its pattern, it is unknown why different types of skin eruptions are associated with different prognoses. Genomic analysis of patients with skin eruptions of smoldering ATLL will be performed to determine the mechanism of ATLL development and its association with prognosis. DNA from skin biopsy specimens was used for targeted sequencing of 280 genes to examine the association between genomic variation and prognosis. Due to the small number of smoldering ATLL patients (27 cases), we could not find a clear relationship between skin eruption and prognosis in this study. Genomic analysis identified 247 genomic variants (108 genes), with an average of 9.2 variants and 3.2 variants as driver genes. Pathway analysis of the driver genes showed activation of the pathway associated with HTLV-1 infection, as well as activation of the signaling pathway observed throughout ATLL. Furthermore, multivariate analysis identified age>70 years and STAT3 mutation as prognostic risk factors and TBL1XR1 mutation as a risk factor for progression-free survival. Although the small number of patient samples did not allow us to determine a prognostic association with skin eruption, STAT3 mutation was identified as a prognostic risk factor for smoldering ATLL with skin eruption. Further studies are needed to increase the number of patients with this disease. • No correlation between the prognosis and the type of skin lesions in smoldering ATLL. • STAT3 mutation and over 70 y/o as prognostic risk in smoldering ATLL with skin rash. • TBL1XR1 mutation as a risk factor for PFS in smoldering ATLL with skin rash. • Activation of the pathway associated with HTLV-1 infection in smoldering ATLL with skin rash. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe a case of a patient with ocular toxoplasmosis, which has resulted in Kyrieleis plaques formation (segmental periarteritis associated with severe inflammation) and later follow-up and alternative treatment due to documented allergy to sulfonamide. A 33-year-old Brazilian woman diagnosed with acute toxoplasmosis, initially treated with sulfonamide, developed a critical cutaneous rash. Cotrimoxazole was changed to clindamycin and pyrimethamine, and prednisone was started. The medication was maintained for 45 days. Four months later, she developed retinal lesions suggestive of toxoplasmosis with Kyrieleis plaques in the upper temporal vessels. Pyrimethamine, clindamycin, and prednisone were initiated until healing. She presented reactivation months later, and a suppressive treatment with pyrimethamine was instituted for one year. This is the first report to use the combination of clindamycin with pyrimethamine in the treatment and recurrence prophylaxis for OT in a documented allergy to sulfonamide. [ABSTRACT FROM AUTHOR]

• The recovery of the ELISA was 0.63%-4.08%. • The intra-day and inter-day precision were 0.63–4.08% and 3.56%-5.78%. • The LOD and LOQ were 0.023 μg/mL and 0.033 μg/mL. • The method showed no cross-reactivity with soybeans, cashew nuts and sesame. • Ara h 3 can be detected in different food matrices containing peanuts. Peanut is an important food that can cause food allergies, often leading to moderate and severe allergic symptoms such as skin rashes, asthma, and even anaphylactic shock. Research indicates that Ara h 3 is one of the major peanut allergen. In order to establish a simple analytical method for detecting Ara h 3, we developed a sandwich enzyme-linked immunosorbent assay (ELISA) with antibodies that were induced from purified Ara h 3. The experimental results showed that the purified Ara h 3 had good purity, and we successfully prepared capture and detection antibodies. The method established in this study exhibited high specificity and did not cross-react with soybeans, cashew nuts, and sesame. For validation, including precision, recovery and sensitivity were in good condition. We also detected the Ara h 3 in peanut related foods. Overall, the ELISA developed in this study is a reliable method for Ara h 3 detection. [ABSTRACT FROM AUTHOR]

In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC. This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS). A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively. Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC. ClinicalTrials.gov identifier: NCT03712943. • Mismatch repair proficient (pMMR) colon cancer (CRC) is unresponsive to immunotherapy. • Regorafenib (REGO) may enhance the antitumor activity of nivolumab (NIVO). • The dose-limiting toxicity of REGO/NIVO was rash. • REGO/NIVO showed limited anticancer activity in pMMR CRC. • REGO/NIVO showed anticancer activity in non-liver or lung metastatic pMMR CRC. [ABSTRACT FROM AUTHOR]

• RIV4 was made available in NH20/21 in Taiwan via special import. • A total of 200,287 doses of RIV4 were administered in NH20/21 in Taiwan. • AE reporting rate following RIV4 receipt was 3.99 per 100,000 doses administered. • The majority AEs were non-serious in nature. • Our surveillance study supports the safety profiles of RIV4 in Taiwan population. During the COVID-19 pandemic, the need for influenza vaccine significantly increased in the initial weeks of the 2020–2021 influenza vaccination campaign season in Taiwan. To meet this demand, the Taiwanese government therefore purchased additional influenza vaccines via special import, including 350,000 doses of quadrivalent recombinant influenza vaccines (RIV4, Flublok Quadrivalent). Approved in the United States since 2016, there were limited numbers of published studies regarding RIV4 outside America. We utilized the national passive surveillance system consisting adverse event (AE) reports following RIV4 immunization to describe its safety profiles in Taiwan. We obtained the database from the Taiwan National Adverse Drugs Reactions Reporting System and collected reports from January 2021 to July 2021, which was at least one month after RIV4 immunization. AE reporting rates were calculated based on the total administered doses. Eight AEs were reported among 200,287 administered doses, which led to a reporting rate of 3.99 AEs per 100,000 doses administered. The mean age of the reported individuals were 47.53 years, and women (75%) were the predominant gender. Most adverse events started within the first day after immunization, with one reported as starting 4 days after vaccination. Among the 8 cases, 75% (n = 6) were non-serious and the most common symptoms were erythematous skin rashes with pruritus. Two cases were listed as serious based on the criteria of "other clinically significant medical conditions", but neither was judged to have a causal relationship with RIV4 immunization. The Taiwan national passive surveillance data supported the safety profiles of RIV4 in Taiwan population. [ABSTRACT FROM AUTHOR]

Background: Following approval by the US Food and Drug Administration (FDA) in late 2019, cenobamate (Xcopri) has been utilized to treat adults with focal seizures. Based on its robust efficacy from the phase 2 trials, we began using cenobamate in our adolescent and young adult patients whose seizures were not controlled with previously available options. This study expanded its real-world application to this cohort with focal epilepsy and a history of drug-related rash.Methods: We conducted a retrospective study of our patients exposed to cenobamate (n = 45). We evaluated dosage and serum levels, efficacy, drug interactions, and adverse effects.Results: After gradually increasing cenobamate to clinical effect using the FDA-approved dosing protocol, 60% (n = 22) of patients were responders. Adolescents were treated with an average daily dose of 204.0 mg, and adults with 223.4 mg cenobamate, and had serum levels of 20.5 μg/mL and 26.7 μg/mL, respectively. The side effect profile observed was similar to that seen in the phase 2/3 registry trials. Importantly, patients with a prior history of rash to other medications or antiseizure medications (n = 5) experienced no rashes related to cenobamate.Conclusions: This real-world study supports the findings of prior controlled studies regarding the efficacy of cenobamate as a treatment for focal seizures in adolescents and suggests that patients with a history of rash may benefit from this medication. [ABSTRACT FROM AUTHOR]

The BNT162b2 and mRNA-1273 COVID-19 vaccines are the main vaccines that have been used for mass vaccination in Japan. Information on adverse reactions to COVID-19 vaccines in the Japanese population is limited. We conducted an online survey on self-reported adverse reactions in individuals who had received two doses of the BNT162b2 or mRNA-1273 vaccine. The incidence of adverse events after each dose of vaccine was investigated. Propensity score matching was used to compare the incidence of adverse reactions after the second dose of the BNT162b2 and mRNA-1273 vaccines. After the first and second doses of the BNT162b2 vaccine, and the first and second doses of the mRNA-1273 vaccine, 890, 853, 6401, and 3965 individuals, respectively, provided complete responses. Systemic reactions, including fever, fatigue, headache, muscle/joint pain, and nausea were significantly more common in females, individuals aged <50 years, and after the second dose. The incidence of injection site pain did not differ significantly according to the dose. The incidence of delayed injection site reactions after the first dose of mRNA-1273 vaccine was 3.9% and 0.8% among females and males, respectively, and 10.6% among females aged 40–69 years. Local and systemic reactions after the second dose, including fever, fatigue, headache, muscle/joint pain, nausea, and skin rash were more common in individuals who had received the mRNA-1273 vaccine. Adverse reactions were more frequently reported in females, younger individuals, and after the mRNA-1273 vaccine. [ABSTRACT FROM AUTHOR]

TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional doxorubicin liposomal formulations in preclinical models. This phase I first-in-human study aimed to define the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary activity of TLD-1 in patients with advanced solid tumors. We recruited patients with advanced solid tumors who failed standard therapy and received up to 3 prior lines of palliative systemic chemotherapy. TLD-1 was administered intravenously every 3 weeks up to a maximum of 9 cycles (6 for patients with prior anthracyclines) from a starting dose of 10 mg/m2, according to an accelerated titration design followed by a modified continual reassessment method. 30 patients were enrolled between November 2018 and May 2021. No dose-limiting toxicities (DLT) were observed. Maximum administered dose of TLD-1 was 45 mg/m2, RP2D was defined at 40 mg/m2. Most frequent treatment-related adverse events (TRAE) of any grade included palmar-plantar erythrodysesthesia (PPE) (50% of patients), oral mucositis (50%), fatigue (30%) and skin rash (26.7%). Most common G3 TRAE included PPE in 4 patients (13.3%) and oral mucositis in 2 (6.7%). Overall objective response rate was 10% in the whole population and 23.1% among 13 patients with breast cancer; median time-to-treatment failure was 2.7 months. TLD-1 exhibit linear pharmacokinetics, with a median terminal half-life of 95 h. The new liposomal doxorubicin formulation TLD-1 showed a favourable safety profile and antitumor activity, particularly in breast cancer. RP2D was defined at 40 mg/m2 administered every 3 weeks. (NCT03387917) • TLD-1 is a novel liposomal PEGylated doxorubicin. • Liposomes have small diameter, high lipid-to-drug ratio, dense surface PEGylation. • TLD-1 recommended phase 2 dose is 40 mg/m2 iv every 3 weeks • The most common G3 TRAE were palmar-plantar erythrodysesthesia and mucositis. • Activity was observed in patients with advanced breast cancer (ORR 23.1%). [ABSTRACT FROM AUTHOR]

Venous access device-related bloodstream infection (VAD-BSI) with coagulase-negative staphylococci (CoNS) is a common complication after allogeneic hematopoietic cell transplantation (alloHCT). Standard systemic antimicrobial therapy for uncomplicated VAD-BSI with methicillin-resistant CoNS consists of intravenous (IV) vancomycin (vanco). This requires hospitalization, needs new competent venous access, exposes patients to potential toxicity (mainly renal) and increases the risk of commensal flora dysbiosis with selection of vanco-resistant enterococci. Combined with VAD management (removal or antibiotic locks), oral minocycline (mino) has been evaluated as an alternative systemic therapy for the treatment of uncomplicated VAD-BSIs with CoNS at our center, primarily when the reference treatment with IV vanco was not possible (renal failure or allergy) or when hospitalization was refused by patients. Here, we retrospectively report our single center experience with this mino-based approach. From January 2012 to December 2020, 24 uncomplicated VAD-BSIs with CoNS in 23 alloHCT patients were treated with oral mino as systemic antibiotic therapy in combination with VAD management. VAD were implantable ports (n = 17), tunneled catheter (n = 1) or PIC-lines (n = 6). Staphylococci were S. epidermidis (n = 21) or S. haemolyticus (n = 3). Mino was administered with a loading dose of 200 mg followed by 100 mg BID for 7–14 days. For 8 VAD-BSIs, patients were initially treated with IV vanco for the first 1–3 days followed by oral mino, while 16 VAD-BSIs were treated with oral mino as the sole antimicrobial agent for systemic therapy. VAD management consisted of catheter removal (for tunneled catheters and PIC-lines, n = 7) or antibiotic locks with vanco (n = 15) or gentamicin (n = 2) administered at least 3 times a week for 14 days (for ports). Overall, clearance of bacteremia (as assessed by negativity for the same CoNS of surveillance peripheral blood cultures drawn between day+ 3 and +30 after initiation of systemic therapy) was achieved in all but 1 patient (with port) who had persistent bacteremia at day +9. No complication such as suppurative thrombophlebitis, endocarditis, distant foci of infection or BSI-related death was observed in any patient during the 3-month period after initiation of treatment. Regarding the 17 port-BSI cases for which VAD conservative strategy was attempted, failure of 3-month VAD preservation was documented in 7/17 cases and 3-month recurrence of VAD-BSI was observed in 3/17 cases (with 1 patient with cellulitis). Treatment with mino was well tolerated except for a mild skin rash in one patient. Further prospective studies are needed to evaluate efficacy and safety of this approach. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are frequently associated with the development of immunotherapy-related adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season-specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season-specific patterns for early-onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early-onset pneumonitis was more frequent in autumn-winter (p = 0.008) and early-onset nephritis in spring-summer (p = 0.004). Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs. • Cancer immunotherapy is commonly associated with immune-related adverse events. • We analyzed the seasonal variation based on data from centers in both hemispheres. • We propose a methodology to address the complexity of discerning seasonal patterns. • Season-specific patterns were detected for certain toxicities. • Seasonal environmental factors may contribute to the toxicity onset. [ABSTRACT FROM AUTHOR]

Magnusiomyces clavatus is a rare yeast-like fungus that can cause opportunistic infections in immunocompromised patients. Here, we present a 14-year-old patient who was followed up with the diagnosis of acute lymphoblastic leukemia, developed skin rashes, and Magnusiomyces clavatus infection detected. The patient died shortly after the infection was diagnosed. [ABSTRACT FROM AUTHOR]

The introduction of trastuzumab and other subsequent human epidermal growth factor receptor 2 (HER2)–targeted therapies dramatically shifted the treatment landscape of HER2+ breast cancer, changing the natural history of the disease. There is no standard-of-care for patients with HER2+ metastatic breast cancer (MBC) in third and later lines of treatment; however, continued use of anti-HER2 therapies is recommended. Small-molecule tyrosine kinase inhibitors (TKIs) that target HER2 and other HER family receptors play a central role in this setting. TKIs have demonstrated various degrees of efficacy against central nervous system (CNS) metastases, which are a major clinical challenge for patients with HER2+ MBC. The TKIs lapatinib, neratinib, and tucatinib have received regulatory approval for the treatment of HER2+ MBC, while pyrotinib and afatinib have been evaluated in this setting. These TKIs vary by molecular weight, HER protein specificity and reversibility of binding and in turn have unique safety profiles. Toxicities reported in clinical trials of TKIs in HER2+ MBC that may require specific management strategies include diarrhoea, palmar–plantar erythrodysesthesia syndrome and rash. Here, we review the efficacy data, including CNS activity, and the safety profiles of the TKIs, and we provide guidance on adverse event management. Finally, we discuss how to incorporate the TKIs into the HER2+ MBC treatment algorithm. • TKIs that target HER proteins play a central role in the treatment of HER2+ MBC. • HER2-TKIs evaluated include lapatinib, neratinib, tucatinib, pyrotinib and afatinib. • The TKIs vary by molecular weight, HER specificity and reversibility of binding. • We review the efficacy and safety data for the TKIs. • We provide guidance on adverse event in the management of TKIs. [ABSTRACT FROM AUTHOR]

• Dermatomyositis is an autoimmune disease characterized by lesions in skin and inflammatory infiltrates of the muscle. • Its association with ectopic lymphoid structures (ELS) is very rare typical variant. • The role of B-cells in lymphoid follicle is not linked to an unfavorable prognosis. Dermatomyositis (DM) is an immune-mediated inflammatory disease characterized by pathognomic lesions in skin and skeletal muscle including lymphocytic infiltrates. It rarely presents with ectopic lymphoid structures, as other autoimmune and chronic inflammatory diseases. We describe a case of a 47-year-old male, who presented clinically with proximal muscle weakness, skin rash and elevated creatin kinase (CK) levels. The muscle biopsy revealed inflammatory myopathy, with perifascicular pathology, and scattered ectopic lymphoid follicles-like structures harboring reactive B-cells. Clonality analysis of B-cells using polymerase chain reaction ruled out malignant lymphoma. The patient responded favorably to steroid therapy, and his muscle weakness improved. In conclusion, the clinical and histopathologic features of DM can be atypical, and the presence of lymphoid follicles, although rare, is not inevitably linked to an unfavorable prognosis. [ABSTRACT FROM AUTHOR]

• This cross-sectional study included 1592 randomly selected vaccinees • 34.7% reported a reaction on the first telephone call and none had any on the second call • Injection site pain was reported in 30.5%, musculoskeletal symptoms in 27.5% • Males had more fever than females (62.4% vs. 37.6%; P < 0.0001) • The rate of post-vaccine COVID-19 infection was 0.5% with zero hospitalization The Kingdom of Saudi Arabia was one of the first countries to implement a COVID-19 vaccination program. This study estimated the safety and reactogenicity of the ChAdOx1-S vaccine after the first dose administered to adults. This cross-sectional study included 1592 randomly selected vaccinees from April to May 2021. A questionnaire was delivered to the vaccinees via phone calls 7 and 21 days after the first vaccine dose. Of the 1592 vaccinees who had the first dose, the mean age was 37.4 (± 9.6) years and 81% were males. Of all the vaccinees, 553 (34.7%) reported an adverse reaction on the first telephone call. The most common symptoms were: pain at the site of injection (485, 30.5%), musculoskeletal symptoms (438, 27.5%), skin rash (307, 19.2%), gastrointestinal symptoms (379, 23.8%) and fever (498, 31.3%). Men were more likely to report fever (76.9% vs. 23.1%; P = 0.005), skin rash (81.1% vs. 18.9%, P = 0.005) and pain at the injection site (77.3% vs. 22.7%, P < 0.0001). Post-vaccine COVID-19 infection was 0.5% and there were no hospitalizations. This study observed no major side effects of the ChAdOx1-S vaccine and no reported breakthrough infection during the observation period. [ABSTRACT FROM AUTHOR]

This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m2) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model. Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60–93 mg/m2). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m2. The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand–foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m2. Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. NCT02085148. • Regorafenib had acceptable tolerability in paediatric patients. • The recommended phase 2 dose (RP2D) in paediatric patients was 82 mg/m2. • Exposure at the RP2D was comparable with adult exposure at the standard 160 mg/day. • Preliminary antitumour activity supports further studies in paediatric patients. • Regorafenib treatment downregulated circulating target proteins c-KIT and VEGFR2. [ABSTRACT FROM AUTHOR]

Background: No previous studies have validated current clinical practice guidelines for the management of non-blanching rashes in children who have received meningococcal B and C vaccinations. The aim of this study was to evaluate the performance of existing clinical practice guidelines in the diagnosis of invasive meningococcal disease in children presenting with a fever and non-blanching rash in the UK.Methods: The Petechiae in Children (PiC) study was a prospective, multicentre cohort study involving children (aged <18 years) presenting to 37 paediatric emergency departments in the UK with a fever (≥38°C) and a new-onset non-blanching rash or features suggestive of meningococcal infection. Children with pre-existing haematological conditions (ie, haematological malignancy, idiopathic thrombocytopenic purpura, or coagulopathy) or an existing diagnosis of Henoch-Schonlein purpura were excluded. Invasive meningococcal disease was confirmed by positive culture or a quantitative PCR test for Neisseria meningitidis from either blood or cerebrospinal fluid samples. The primary outcome was the performance of six tailored clinical practice guidelines from participating centres (London, Nottingham, Newcastle-Birmingham-Liverpool, Glasgow, Chester, and Bristol) and two clinical practice guidelines from the National Institutes for Health and Care Excellence (NICE; CG102 and NG51) in identifying children with invasive meningococcal disease, assessed by the sensitivity and specificity of each clinical practice guideline. This study is registered with ClinicalTrials.gov, NCT03378258.Findings: Between Nov 9, 2017, and June 30, 2019, 1513 patients were screened, of whom 1329 were eligible and were included in the analysis. The median age of patients was 24 months (IQR 12-48). 1137 (86%) of 1329 patients had a blood test and 596 (45%) received parenteral antibiotics. 19 (1%) patients had confirmed meningococcal disease. All eight clinical practice guidelines had a sensitivity of 1·00 (95% CI 0·82-1·00) for identifying meningococcal disease. The specificities of NICE guidelines CG102 (0·01 [95% CI 0·01-0·02]) and NG51 (0·00 [0·00-0·00]) for identifying meningococcal disease were significantly lower than that of tailored clinical practice guidelines (p<0·0001). The best performing clinical practice guidelines for identifying meningococcal disease were the London (specificity 0·36 [0·34-0·39]) and Nottingham (0·34 [0·32-0·37]) clinical practice guidelines.Interpretation: Invasive meningococcal disease is a rare cause of non-blanching rashes in children presenting to the emergency department in the UK. Current NICE guidelines perform poorly when compared with tailored clinical practice guidelines. These findings suggest that UK national guidance could be improved by shifting towards a tailored approach.Funding: Public Health Agency. [ABSTRACT FROM AUTHOR]

Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non–small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77). • Afatinib with gemcitabine is not superior to gemcitabine alone in the first-line treatment of metastatic pancreatic cancer. • The combination of afatinib with gemcitabine lead to higher toxicity, especially for diarrhoea and skin rash. • The Burden of Therapy/Toxicity©™ methodology offers a more detailed visualisation and understanding of treatment-related adverse events. [ABSTRACT FROM AUTHOR]

Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48–0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30–0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46–0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit. • First-line pertuzumab improves survival in metastatic HER2-positive breast cancer. • Rash and diarrhoea are common side-effects of pertuzumab. • Rash is prognostic independently of docetaxel use. • Diarrhoea is prognostic for PFS only after docetaxel use. • Both rash and diarrhoea are not predictive of PFS and/or OS. [ABSTRACT FROM AUTHOR]

Cutaneous manifestations of drug reactions are common yet vary widely in their appearance and degree of internal organ involvement. Serum sickness-–like reactions, symmetrical drug-related intertriginous and flexural exanthem, granulomatous drug eruption, pseudolymphoma, and drug-induced lupus are medication-induced conditions with dermatologic presentations. Many of the conditions discussed are relatively rare but nonetheless demand our attention and understanding. Some of the conditions presented may be more likely encountered in the hospital setting, as is the case with serum sickness–like reactions and drug-induced lupus, whereas others may present to outpatient clinic for diagnosis. Given the similarities in clinical history of patients presenting with these conditions, an understanding of the clinical presentation, pathophysiology, culprit medications, histologic appearance, and serologic characteristics is warranted to correctly diagnose and manage these uncommon adverse reactions. We also discuss how to differentiate some of these conditions from more serious mimickers, as in the case of pseudolymphoma drug reaction mimicking a true lymphoma and drug-induced lupus mimicking acute systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1–21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1–21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. Twenty-four patients (15 males; median age 14.5 yrs; range 1–22 yr) received a median of 6 courses (range 1–18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6–95.6%) and 54% (95% CI 30.2–78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours. • Bevacizumab, sorafenib and low-dose cyclophosphamide is tolerated in pediatrics. • This regimen had clinical benefit in patients with sarcomas and rhabdoid tumors. • This regimen may be a maintenance therapy for newly-diagnosed sarcoma patients. [ABSTRACT FROM AUTHOR]

We described the epidemiology and healthcare exposures during a measles outbreak in London and identified factors associated with isolation on arrival to healthcare premises. We conducted a cohort study including all confirmed measles cases in London residents from February 1, 2016, to June 30, 2016, and semistructured interviews with two infection prevention and control teams (IPCTs). We described the outbreak and conducted a multilevel mixed-effects analysis to assess the relationship between sociodemographic and clinical factors and isolation on arrival to healthcare premises. We summarised the interviews. There were 182 cases, mostly aged 17–35 years (46%; 84). Excluding cases younger than one year, 76% (92/120) were unvaccinated, including two healthcare workers. The majority presented with rash (97%; 174), and 42% (70/166) required hospitalisation. Of the recorded cases, 93% of cases (164/178) had visited a healthcare setting during their infectious period (median number of visits = 2). In 33% (59/178) of the visits, the case was isolated on arrival; when not isolated, four healthcare exposures resulted in further transmission. Presenting to the hospital as opposed to a general practitioner (GP) was associated with higher odds of isolation (odds ratio = 2.23, 95% confidence interval = 1.1–4.4) when adjusted for age, gender and presenting with a cough. The IPCT identified measles training using standardised risk assessments by triage nurses in accident and emergency and intelligence regarding measles activity in the community as positive measures to prevent healthcare exposures. We recommend opportunistic immunisation of unvaccinated young adults by GPs and that occupational health departments ensure their staff are protected against measles. Raising measles awareness in healthcare settings via training or regular sharing of current measles surveillance activity from public health to the IPCT and GP may improve triage and isolation of cases on arrival to healthcare premises. • Most of the cases were young unvaccinated adults, including healthcare workers. • A third of the infectious cases were isolated on arrival to healthcare settings. • We observed a high number of healthcare exposures. • Cases attending accident and emergency services were more likely to be isolated. Despite high numbers of healthcare exposures, transmission was limited. [ABSTRACT FROM AUTHOR]

• Parvovirus B19 (B19V) causes exanthema in children, similar to rubella and measles virus. • A B19V-qPCR on oral fluid was evaluated as a non-invasive alternative for serum IgM. • On basis of 116 children with exanthema, sensitivity of the qPCR on oral fluid reached 70%. • B19V detection in oral fluid is a suitable public health alternative in the diagnosis of fifth disease. Infections with parvovirus B19 (B19V) have been associated with a wide range of disease manifestations of which erythema infectiosum (fifth disease) in children is most common. Clinical signs following infection of children with B19V can be similar to measles and rubella. Laboratory detection of B19V infections is based on detection of B19V-specific IgM antibodies by enzyme immunoassay (IgM-EIA) and/or B19V DNA by quantitative PCR (qPCR) on blood samples. The need for invasive sampling can be a barrier for public health diagnostics. To evaluate the use of a dual target B19V-qPCR directed against the NS1 and VP2 of B19V on oral fluid samples as a non-invasive alternative for laboratory diagnosis of B19V infections in children below 12 years of age with exanthema. Oral fluid and serum samples were collected from 116 children with exanthema. All serum samples were tested by IgM-EIA/IgG-EIA, while all oral fluid and 56 serum samples were tested by B19V-qPCR. B19V-specific IgM antibodies were detected in 25 of 116 children in the study. B19V DNA was detected in oral fluid in 17 of the 25 children who were IgM positive, as well as two children who were IgM-equivocal or negative. The child with the equivocal IgM had a high quantity of B19V DNA in oral fluid (7 log IU/ml), compatible with an acute B19V infection. The IgM-negative child was IgG-positive and 4 log IU/ml B19V DNA was detected in the oral fluid sample, suggesting an acute infection and a falsely negative IgM. Sample size calculations indicated that oral fluid samples for qPCR should be collected from 2 to 3 children during outbreaks of exanthema to achieve similar sensitivity as IgM-EIA for one child (≥0.9) to confirm or exclude B19V. Results indicate that oral fluid samples are a suitable public health alternative for detection of B19V infections, potentially lowering the barriers for sampling. [ABSTRACT FROM AUTHOR]

Background: Herpes zoster (zoster) also commonly known as "shingles," occurs following re-activation of the varicella zoster virus. It contributes a large cost burden to the U.S. health care system, with an estimated 1 million cases costing $1 billion annually. The current gold standard treatment is acyclovir, which limits viral replication. However, acyclovir has been reported to cause neurotoxicity in patients with acute or chronic kidney disease.Case Report: This case presents an occurrence of acyclovir-induced toxic encephalopathy in a patient with normal renal function. A 63-year-old male presented to the emergency department with ataxia, tremors, fluctuating aphasia, confusion, agitation, and fatigue. Results of imaging, lumbar puncture, and laboratory studies directed clinicians toward acyclovir toxicity, despite a normal creatinine level. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians will likely be the first point of contact in the health care system following the onset of acyclovir toxicity. With an increasing incidence of zoster disease, such atypical toxic manifestations may increase. Early recognition is important to avoid permanent neurologic compromise. [ABSTRACT FROM AUTHOR]

Abstract Background Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role. Methods We established a prospective observational single-centre study and collected data from patients with either metastatic non–small cell lung cancer (NSCLC) or metastatic melanoma, who were treated with anti–PD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyte–associated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing. Results We enrolled 102 patients (median [range] age, 68 [62–74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n = 32 (54%)) and rash (n = 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P >.05). When assessing each irAE individually, we found a significant association between HLA-DRB1*11:01 and pruritus (OR = 4.53, X2 1,95 = 9.45, P <.01) as well as a nominally significant additive association between HLA-DQB1*03:01 and colitis (OR = 3.94, X2 1,95 = 5.67, P =.017). Conclusions The presence of two HLA alleles that are known to predispose to autoimmune diseases were associated with the development of pruritus or colitis during therapy, suggesting a genetic aetiology of irAEs. Larger genome-wide association studies should be performed to confirm our findings. Highlights • Carriers of HLA-DRB1*11:01 likely develop pruritus during immunotherapy. • Carriers of HLA-DQB1*03:01 are predisposed to develop colitis during immunotherapy. • There is a trend between HLA-DRB1*01:01 and skin rash during immunotherapy. • This is the first study showing a link between HLA and immune-related adverse events. [ABSTRACT FROM AUTHOR]

Background In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. Methods Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. Results Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3–4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53 , NOTCH1/2 , KMT2C/D , FAT1 and HER4 were the most frequently mutated genes. BRAF , NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. Conclusions In sSCC, dacomitinib showed activity similar to what was observed with anti–epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio. [ABSTRACT FROM AUTHOR]

Background PQR309 is an orally bioavailable, balanced pan–phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. Patients and methods This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Results Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (T max 1–2 h) and dose proportionality for C max and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed. Conclusion The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation. Clinical trial registration ClinicalTrials.gov # NCT01940133. [ABSTRACT FROM AUTHOR]

Introduction In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. Patients and methods For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1–4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. Results Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8–50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX ( n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7–68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. Conclusions First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17). [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to establish whether the presence of common allergies increases the risk of drug-related hypersensitivity reactions among patients with epilepsy treated with antiepileptic drugs (AEDs). Methods We studied 753 patients with epilepsy seen in tertiary outpatient epilepsy clinic. We obtained data related to epilepsy type, past and ongoing treatment with AEDs, occurrence of maculopapular exanthema or more serious cutaneous adverse reactions (Stevens-Johnson syndrome − SJS) and their characteristics. We noted an occurrence of allergic reactions unrelated to treatment with AED, including rash unrelated to AED, bronchial asthma, persistent or seasonal allergic rhinitis, atopic dermatitis, rash after specific food and other allergic reactions. Results There were 61 cases of AED-related cutaneous hypersensitivity reaction (including 3 cases of SJS) noted in association with 2319 exposures to AEDs (2.63%) among 55 out of 753 patients (7.3%). Cutaneous hypersensitivity reaction to AED was most commonly noted after lamotrigine (12.1%), carbamazepine (5.4%) and oxcarbazepine (4.1%). Prevalence of allergic reactions unrelated to AED was similar between patients with and without AED-related cutaneous hypersensitivity reaction (rash unrelated to AED: 16.4% vs. 10.2%; bronchial asthma: 1.8% vs. 0.1%; persistent allergic rhinitis: 7.3% vs. 10.2%; seasonal allergic rhinitis: 7.3% vs. 11.7%; atopic dermatitis: 0 vs. 0.7%; rash after specific food: 5.4% vs. 6.4%; other allergic reactions: 5.4% vs. 5.2%, respectively; P > 0.1 for each difference). Conclusions Presence of common allergies is not a significant risk factor for AED-related cutaneous hypersensitivity reaction among patients with epilepsy. [ABSTRACT FROM AUTHOR]

Background Preclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab. Methods Temsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150–250 mg/m 2 , until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation. Results Among 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m 2 and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration. Conclusions Combination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development. [ABSTRACT FROM AUTHOR]

Background Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor. Methods This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months. Results Thirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5–23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders. Conclusions Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit. [ABSTRACT FROM AUTHOR]

Background: Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas.Methods: We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088.Findings: Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88-1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6-22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2-22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]).Interpretation: The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting.Funding: Threshold Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) is the most common mosquito-borne disease worldwide. This study aimed to characterize an outbreak of DENV infection in Cajamarca, Peru. Also, to identify the most common serotypes involved and describe the applicability of different diagnostic tests in the diagnosis of primary and secondary cases. The study was performed in the region of Cajamarca, in northern Peru. We included patients attending outpatient health centers with an acute febrile illness (AFI), defined as a temperature of 38°C or higher for up to 7 days, without an identifiable source of infection and presenting at least one of the following symptoms: arthralgia, myalgia, headache, retro-ocular pain, low back pain, cutaneous rash, nausea, vomiting, diarrhea, and conjunctival injection. Serum samples were collected and diagnostic tests were performed including: reverse-transcriptase polymerase chain reaction (RT-PCR), NS1 antigen, IgM and IgG antibodies ELISA-based assays. Primary infection was diagnosed by the detection of NS1 antigen ELISA and/or RT-PCR and/or IgM ELISA in the absence of IgG ELISA. Secondary infection was determined by the presence of IgG ELISA and a positive NS1 antigen ELISA and/or RT-PCR and/or IgM ELISA. A total of 359 serum samples were collected in the study period. Dengue infection was diagnosed in 37.9% (136/359) of the patients, being 107 primary infections and 29 secondary infections. The most common serotype was DENV-3 in 77.5% of the cases. Differences were observed in the diagnostic performance of IgM ELISA (17.6% vs 55.2%, p≤0.01) and RT-PCR (74.8% and 31.0%, p≤0.01) in primary and secondary infections respectively. The combination of NS1 and IgM performed better than the other assays in detecting primary (91.9%) and secondary infections (96.6%). The most frequent symptoms associated with DENV infection were headaches, myalgias, and arthralgias. We report an important outbreak of dengue infection caused by DENV-3 in Cajamarca, Peru. Our findings encourage the use of NS1 antigen and IgM co-detection. These findings demonstrate an increasing expansion of DENV-3 in Peru and highlight the importance of molecular diagnosis and serotype characterization among febrile patients to strengthen the Peruvian epidemiological surveillance. [ABSTRACT FROM AUTHOR]

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.Methods: The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.Findings: Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred.Interpretation: The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination.Funding: Novartis Pharmaceuticals Corporation. [ABSTRACT FROM AUTHOR]

Background The drug-induced lymphocyte stimulation test (DLST), also referred to as lymphocyte transformation test (LTT), is used to identify the culprit drug in cases of cutaneous adverse drug reactions (cADR). Although DLST is a widely used in vitro test, its sensitivity and specificity are unsatisfactory. Recent reports suggest that the detection of drug-induced interferon (IFN)-γ production using enzyme-linked immunoSpot (ELISpot) assay (conventional IFN-γ ELISpot) is useful for identifying culprit drugs in cADR cases. Objective The aim of this study was to establish a novel method for identifying culprit drugs in patients with cADR by efficiently detecting drug-specific IFN-γ production using activated cells. Methods Sixteen patients with cADR, including drug-induced hypersensitivity syndrome, erythema multiforme-like eruption, maculopapular exanthema, Stevens-Johnson syndrome, and toxic epidermal necrolysis, caused by clinically convincing culprit drugs were enrolled in this study. In some cases, the blood samples were obtained at two or three different time points. Peripheral blood mononuclear cells (PBMCs) from total 20 samples were analyzed using both the DLST and drug-induced conventional IFN-γ ELISpot. In addition, drug-induced IFN-γ ELISpot was performed using PBMCs, which were stimulated with anti-cluster of differentiation (CD)-3/CD28 antibody-coated microbeads and interleukin (IL)-2 for 7 days before exposure to the culprit drugs (modified IFN-γ ELISpot). Results Among the culprit drugs tested in each patient, the modified IFN-γ ELISpot was positive in 17 samples (13 patients) while DLST and conventional IFN-γ ELISpot were positive in eight and four samples (six and three patients), respectively. Conclusion The modified IFN-γ ELISpot using activated PBMCs was more sensitive than the conventional IFN-γ ELISpot was for detecting drug-induced IFN-γ production, which could be a useful in vitro tool for identifying culprit drugs in cADR cases. [ABSTRACT FROM AUTHOR]