Alleviative effect of melatonin against the nephrotoxicity induced by cadmium exposure through regulating renal oxidative stress, inflammatory reaction, and fibrosis in a mouse model.

Chronic cadmium (Cd) exposure causes severe adverse health effects on the human body, especially the kidney tissue. Studies have demonstrated oxidative stress to be involved in renal pathological variations after exposure to Cd, but few effective treatments are available for the disease yet. Therefore, the present study was carried out to investigate the potential therapeutic intervention and its underlying molecular mechanisms of melatonin (MT), a natural antioxidant with multiple biological activities, against renal injury caused by Cd exposure in mice. C57BL/6 male mice (eight-week-old) were intragastrically administered with CdCl2, MT, or both for 30 days. Biochemical analysis showed that MT intervention significantly improved the SOD, GSH, and CAT activities while markedly decreasing the kidney MDA content of the mice exposed to Cd. Histological examination indicated that Cd exposure resulted in the atrophy of the renal glomerular, the degeneration and dilation of tubules, and the accumulation of fibrocytes. By contrast, MT administration effectively ameliorated the histological outcome of the injured kidney tissue. Moreover, administrating MT significantly inhibited proinflammatory cytokines TNF-α and iNOS expression in Cd-treated mice. Further, MT treatment markedly suppressed the expressions of renal fibrosis-related factors TGF-ß1, α-SMA, and collagen Ⅰ in the injured renal tissue and the accumulation and development of renal fibrosis. In addition, the administration of MT significantly reduced the expression of caspase-3 and cell apoptotic death in the kidney tissue of Cd-exposed mice. In all, the data showed that MT has a compelling therapeutic potential in alleviating the pathological variations of renal injury caused by Cd exposure.

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

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

Estimating the Effectiveness of DPYD Genotyping in Italian Individuals Suffering from Cancer Based on the Cost of Chemotherapy-Induced Toxicity.

Fluoropyrimidines (FLs) have been widely used for more than 60 years against a range of solid tumors and still remains the cornerstone for the treatment of colorectal, gastric, and breast cancer. Here, we performed an economic analysis to estimate the cost of DPYD-guided toxicity management and the clinical benefit expressed as quality adjusted life years (QALYs) in a large group of 571 individuals of Italian origin suffering from cancer and treated with a fluoropyrimidines-based chemotherapy. Individuals suffering from cancer with a histologically confirmed diagnosis of cancer, who received a fluoropyrimidines-based treatment, were retrospectively genotyped in the DPYD gene. Effectiveness was measured as survival of individuals from chemotherapy, while study data on safety and efficacy as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. DPYD extensive metabolizers (528 individuals) had greater effectiveness and lesser cost, representing a cost-saving option over DPYD intermediate and poor metabolizers (43 individuals) with mean QALYs of 4.18 (95%CI: 3.16-5.55) versus 3.02 (95%CI: 1.94-4.25), respectively. Our economic analysis showed that there are some indications for differences in survival between the two groups (p > 0.05), while the cost of DPYD extensive metabolizers was significantly lower (p < 0.01) compared with those belonging to the group of intermediate/poor metabolizers. These findings suggest that DPYD-guided fluoropyrimidines treatment represent a cost-saving choice for individuals suffering from cancer in the Italian healthcare setting.

Clinical and histopathological spectrum of delayed adverse cutaneous reactions following COVID-19 vaccination.

BACKGROUND: As more people become vaccinated against the SARS-CoV-2 virus, reports of delayed cutaneous hypersensitivity reactions are beginning to emerge. METHODS: In this IRB-approved retrospective case series, biopsy specimens of potential cutaneous adverse reactions from the Pfizer-BioNTech or Moderna mRNA vaccine were identified and reviewed. Clinical information was obtained through the requisition form, referring clinician, or medical chart review. RESULTS: Twelve cases were included. Histopathological features from two injection-site reactions showed a mixed-cell infiltrate with eosinophils and a spongiotic dermatitis with eosinophils. Three biopsy specimens came from generalized eruptions that showed interface changes consistent with an exanthematous drug reaction. Three biopsy specimens revealed a predominantly spongiotic pattern, consistent with eczematous dermatitis. Small-vessel vascular injury was seen in two specimens, which were diagnosed as urticarial vasculitis and leukocytoclastic vasculitis, respectively. There were two cases of new-onset bullous pemphigoid supported by histopathological examination and direct immunofluorescence studies. Eosinophils were seen in 10 cases. CONCLUSIONS: Dermatopathologists should be aware of potential cutaneous adverse reactions to mRNA-based COVID-19 vaccines. Histopathological patterns include mixed-cell infiltrates, epidermal spongiosis, and interface changes. Eosinophils are a common finding but are not always present. Direct immunofluorescence studies may be helpful for immune-mediated cutaneous presentations such as vasculitis or bullous pemphigoid.

Role of silymarin (Silybum marianum) in the prevention of colistin-induced acute nephrotoxicity in rats.

Silymarin (Silybum marianum) has some protective effects against drug toxicity (cisplatin, acetaminophen, adriamycin, gentamicin etc.). Colistin is a strong antimicrobial, which is frequently used in the treatment of resistant gram-negative bacterial infections in recent years although it has nephrotoxic potential. This study was aimed to determine the role of silymarin against colistin-induced acute nephrotoxicity (CIN). Rats were randomly divided into four groups. The control group was treated with tap water whereas groups 2 and 3 received silymarin (orally, 100 mg/kg/day) and colistin (intraperitoneally, 750.000 IU/kg/day) for seven days, respectively. Group 4 received both 750,000 IU/kg/day colistin and 100 mg/kg/day silymarin for seven days. After euthanasia, histopathological and biochemical examinations were completed for the kidney tissue specimens and blood samples. All parameters of the control and silymarin groups were similar. Severe weight loss was seen in the groups receiving colistin (groups 3 and 4). Silymarin significantly increased glutathione peroxidase and superoxide dismutase levels when administered with colistin in group 4 only. Acute tubular injury, tubular necrosis, meduller congestion, interstitial inflammation and apoptotic indices of colistin group were significantly higher than the control group. The administration of colistin with silymarin (group 4) was able to make some improvements in tubular necrosis and significant increase in antioxidant capacity. Silymarin increased antioxidant enzyme activity only when used in combination with colistin. The effects of silymarin may become more pronounced when used at higher doses or with a longer duration of treatment and may prevent nephrotoxicity.

Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis.

BACKGROUND: Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies. METHODS: We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I2 statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617). FINDINGS: We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I2=75%) for all-grade adverse events and 68·3% (60·7-75·0; I2=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I2=86%) for all-grade adverse events and 47·3% (37·3-57·5; I2=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I2=94%) for all-grade adverse events and 35·9% (29·5-42·9; I2=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I2=74%) for all-grade adverse events and 12·4% (4·4-30·6; I2=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias. INTERPRETATION: Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care. FUNDING: National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund.

Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not respond to or who have progressive disease after salvage therapies have a poor prognosis. Loncastuximab tesirine is a CD19-directed antibody-drug conjugate with encouraging phase 1 single-agent antitumour activity and acceptable safety in non-Hodgkin lymphoma. We aimed to evaluate the antitumour activity and safety of loncastuximab tesirine in patients with relapsed or refractory DLBCL. METHODS: We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with relapsed or refractory DLBCL after two or more multiagent systemic treatments, who had measurable disease and Eastern Cooperative Oncology Group performance status 0-2. Eligible patients received loncastuximab tesirine intravenously on day 1 of each 21-day cycle, at 150 µg/kg for two cycles, then 75 µg/kg thereafter, for up to 1 year or until disease relapse or progression, unacceptable toxicity, death, major protocol deviation, pregnancy, or patient, investigator, or sponsor decision. The primary endpoint was overall response rate assessed by central review. Primary antitumour activity and safety analyses were done in the as-treated population (patients who received at least one dose of loncastuximab tesirine), when all responding patients had at least 6 months of follow-up after initial documented response. Enrolment is complete. This trial is registered with ClinicalTrials.gov, NCT03589469. FINDINGS: Between Aug 1, 2018, and Sept 24, 2019, 184 patients were assessed for eligibility and 145 (79%) were enrolled and received at least one dose of loncastuximab tesirine, including patients with high-risk characteristics for poor prognosis, such as double-hit, triple-hit, transformed, or primary refractory DLBCL. 70 of 145 patients had complete or partial response (overall response rate 48·3% [95% CI 39·9-56·7]); 35 had complete response and 35 had partial response. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Serious adverse events were reported in 57 (39%) of 145 patients. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. INTERPRETATION: Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. FUNDING: ADC Therapeutics.

Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues.

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. Direct effects of these drugs on the human heart remain very poorly defined. To better understand the mechanisms of action of HCQ +/- AZM, we employed bioengineered human ventricular cardiac tissue strip (hvCTS) and anisotropic sheet (hvCAS) assays, made with human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCMs), which have been designed for measuring cardiac contractility and electrophysiology, respectively. Our hvCTS experiments showed that AZM induced a dose-dependent negative inotropic effect which could be aggravated by HCQ; electrophysiologically, as revealed by the hvCAS platform, AZM prolonged action potentials and induced spiral wave formations. Collectively, our data were consistent with reported clinical risks of HCQ and AZM on QTc prolongation/ventricular arrhythmias and development of heart failure. In conclusion, our study exposed the risks of HCQ/AZM administration while providing mechanistic insights for their toxicity. Our bioengineered human cardiac tissue constructs therefore provide a useful platform for screening cardiac safety and efficacy when developing therapeutics against COVID-19.

Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis.

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines.

Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience.

BACKGROUND: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. METHODS: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death. RESULTS: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). CONCLUSIONS: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. LAY SUMMARY: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.

The effects of targeted immune-regulatory strategies on tumor-specific T-cell responses in vitro.

BACKGROUND: Immune-related adverse events (IrAEs) are auto-immune reactions associated with immune checkpoint inhibitor-based therapy (ICI). Steroids are currently the first-line option for irAE management; however, recent studies have raised concerns regarding their potential impairment of tumor-specific immune responses. In this study, we investigated the in vitro effects of commonly used irAE treatment drugs on the anti-tumor activity of tumor-infiltrating lymphocytes (TILs). METHODS: Impairment of anti-tumor immune responses by four drugs (antibodies: vedolizumab and tocilizumab; small molecules: mycophenolate mofetil and tacrolimus) reported to be effective in treating irAEs was tested at clinically relevant doses in vitro and compared to a standard moderate dose of corticosteroids (small molecules) or infliximab (antibodies). TIL responses against autologous tumor cell lines, in the presence or absence of irAE drugs, were determined by flow cytometry (short-term tumor-specific T-cell activation) or xCELLigence (T-cell-mediated tumor killing). RESULTS: None of the tested antibodies influenced T-cell activation or T-cell-mediated tumor killing. Low-dose mycophenolate and tacrolimus did not influence T-cell activation, whereas higher doses of tacrolimus (> 1 ng/ml) impaired T-cell activation comparably to dexamethasone. All tested small molecules impaired T-cell-mediated tumor killing, with high-dose tacrolimus reducing killing at levels comparable to dexamethasone-mediated inhibition. In addition, mycophenolate and tacrolimus alone also demonstrated anti-proliferative effects on tumor cells. CONCLUSIONS: These data support clinical testing of targeted immune-regulatory strategies in the initial phase of irAE management, as a potential replacement for corticosteroids.

Antibiotics and steroids, the double enemies of anticancer immunotherapy: a review of the literature.

The advent of immunotherapy in onco-haematology has represented a kind of revolution that has been able to modify the prognosis of numerous tumours that until recently would have been rapidly lethal. While much is known about the mechanism of action of these drugs, relatively little is known about the factors that represent potential predictors of response and toxicity. Among these factors, the simultaneous administration of antibiotics and/or steroids seems to have a negative impact. Furthermore, several retrospective studies have highlighted the strong link between cancer and gut microbiota, regardless of the tumour site, and how microbiota, playing a key role in the prevention of systemic inflammation at various levels and in the intestinal homeostasis, can be negatively influenced by the dysbiosis caused by antibiotic therapy administered during or in the weeks immediately preceding the start of immunotherapy. Moreover, we assume that the concurrent administration of steroids, which is often necessary in cancer patients, likely results in a deleterious effect on the therapeutic outcomes of immunotherapy. In this review, we will try to clarify the evidence on the possible detrimental effects of antibiotics and steroids, which are currently considered the double enemies of anticancer immunotherapy.

The Role of Immune-Related Adverse Events in Prognosis and Efficacy Prediction for Patients with Non-Small Cell Lung Cancer Treated with Immunotherapy: A Retrospective Clinical Analysis.

PURPOSE: The development of immune-related adverse events (irAEs) in patients undergoing immunotherapy has been reported to be a favorable prognostic factor in several studies. We aimed to examine the correlation between irAEs and prognosis in patients with non-small cell lung cancer (NSCLC) and further reveal the patient characteristics associated with response to immunotherapy among treatment responders who developed irAEs. METHODS: We retrospectively enrolled 80 patients with NSCLC who received immunotherapy at Shinshu University Hospital between February 2016 and February 2020. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and those without irAEs. We examined the prognostic factors associated with PFS and OS using univariate and multivariate Cox proportional-hazards models. We further analyzed the patients who developed irAEs by classifying them into responders and non-responders. RESULTS: Twenty-five patients developed irAEs. The median PFS and OS of the patients with irAEs were significantly longer than those of the patients without irAEs (6.8 vs. 1.9 months, p < 0.001, and 37.8 vs. 8.1 months, p < 0.001, respectively). Multivariate analysis associated with PFS and OS indicated that the development of irAEs was an independent favorable prognostic factor. Among the patients developing irAEs, the responder group had a significantly higher incidence of multiple irAEs than the non-responder group (41.7 vs. 0.0%, p = 0.009). CONCLUSION: Our findings revealed that the development of irAEs was associated with clinical benefits in NSCLC patients who received immunotherapy. In particular, patients with multiple irAEs might have good prognoses.

Aerodigestive adverse effects during intravenous pentamidine infusion for Pneumocystis jirovecii pneumonia prophylaxis.

Aerodigestive adverse effects (AD-AE) during intravenous pentamidine (IV-P) infusion for Pneumocystis jiroveci pneumonia prophylaxis are uncommon in retrospective chart review studies. We conducted a survey in patients on IV-P, which included 31 specific questions. Twenty-five patients were included in the analysis; AD-AE were observed in 22 (88%) with recurrence of symptoms in 88% participants with subsequent infusions. Five leading symptoms were congestion (48%), lip tingling (32%), nausea (28%), tongue tingling (24%), vomiting, and throat swelling (17%); multiple symptoms were reported in 72% of the patients. In conclusion, AD-AE of IV-P infusion are common, self-limited, and tend to be recurrent.

Histopathologic reaction patterns to differentially cross-linked hyaluronic acid fillers: A retrospective case series.

BACKGROUND: Hyaluronic acid filler reactions have been increasingly observed in recent years. Our study investigates whether the increased number of filler reactions observed since 2014 is associated with a specific histopathologic inflammatory pattern and type of filler. METHODS: The institution's dermatopathology electronic database was retrospectively searched for histopathologic reactions to hyaluronic acid from January 2014 to December 2019. The age, sex, type of filler, procedure, location, and histopathologic patterns were recorded. RESULTS: From 2014 to 2019, there were 15 cases of granulomatous reactions to hyaluronic acid filler. In 10 of these cases, there was a characteristic inflammatory pattern characterized by tightly cuffed palisades of histiocytes with varying numbers of eosinophils. Of the 11 cases in which the type of filler was known, all used Vycross technology, a novel manufacturing process in the production of hyaluronic acid filler. CONCLUSION: A characteristic histopathologic pattern of discrete foci of tightly cuffed palisaded granulomas with eosinophils is associated with fillers manufactured using Vycross technology.

Drug-induced psoriasiform alopecia associated with interleukin-17 inhibitor therapy.

Drug-induced psoriasiform alopecia is an increasingly recognized form of alopecia mostly reported in association with TNF-alpha inhibitors. However, drug-induced psoriasiform alopecia in association with IL-17A inhibitors has not been described. We present a 62-year-old woman with severe psoriasis who developed new psoriatic plaques on the scalp with alopecia after initiating ixekizumab (anti-IL-17A). Scalp biopsy specimens revealed a non-cicatricial alopecia with increased telogen/catagen follicles, atrophy of the sebaceous glands, peribulbar and perifollicular inflammation with frequent lymphocytes, plasma cells, eosinophils, psoriasiform dermatitis, and lack of intra-corneal or intra-epidermal neutrophils. Overall, the clinical and histopathologic findings were most compatible with a drug-induced psoriasiform alopecia in association with IL-17A inhibitor therapy. Our case shows that drug-induced psoriasiform alopecia can paradoxically occur in patients on IL-17A inhibitor therapy and contributes to the growing list of cutaneous eruptions associated with biologic agents.

Cutaneous sarcoid-like drug reaction caused by an anaplastic lymphoma kinase inhibitor.

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

A Retrospective Review of Mercaptopurine Metabolism Reveals High Rate of Patients With Suboptimal Metabolites Successfully Corrected With Allopurinol.

Skewed drug metabolism of 6-mercaptopurine (6-MP) can jeopardize antileukemic effects and result in toxicities during the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Allopurinol can alter 6-MP metabolism to maximize therapeutic effects while reducing toxicities. Over 75% of our patients with acute lymphoblastic leukemia or lymphoblastic lymphoma experienced a 6-MP-related toxicity. Review of metabolite date a showed 6-methylmercaptopurine nucleotide levels were >10,000 in 55% of the cohort, suggesting 6-MP shunting. Allopurinol was initiated in 12 of 23 shunters with resolution of toxicities. We propose an algorithm to incorporate allopurinol into chemotherapy regimens for patients with inappropriate 6-MP metabolism.

Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review. The experience of a single large specialist institution.

Checkpoint inhibitor (CPI) therapy has significantly improved overall survival for metastatic melanoma, and is now approved for use in the adjuvant setting. Modulating the immune system is recognized to cause cutaneous immune-related adverse events (irAEs). We conducted a retrospective observational cohort study of adult patients with melanoma at our tertiary referral centre, who received CPI therapy from 2006 to March 2018. This is the single largest study of cutaneous irAEs occurring on CPI therapy in patients with melanoma to date and encompasses 12 years. The results showed that cutaneous toxicity occurs in 24% of patients but is generally manageable, with < 5% patients discontinuing treatment.

A cross-industry survey on photosafety evaluation of pharmaceuticals after implementation of ICH S10.

A cross-industry survey was conducted by EFPIA/IQ DruSafe in 2018 to provide information on photosafety evaluation of pharmaceuticals after implementation of ICH S10. This survey focused on the strategy utilized for photosafety risk assessment, the design of nonclinical (in vitro and in vivo) and clinical evaluations, the use of exposure margins in risk assessment, and regulatory interactions. The survey results indicated that a staged approach for phototoxicity assessment has been widely accepted by regulatory authorities globally. The OECD-based 3T3 NRU Phototoxicity Test is the most frequently used in vitro approach. Modifications to this assay suggested by ICH S10 are commonly applied. For in-vitro-positives, substantial margins from in vitro IC50 values under irradiation to Cmax (clinical) have enabled further development without the need for additional photosafety data. In vivo phototoxicity studies typically involve dosing rodents and exposing skin and eyes to simulated sunlight, and subsequently evaluating at least the skin for erythema and edema. However, no formal guidelines exist and protocols are less standardized across companies. A margin-of-safety approach (based on Cmax at NOAEL) has been successfully applied to support clinical development. Experience with dedicated clinical phototoxicity studies was limited, perhaps due to effective de-risking approaches employed based on ICH S10.