Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.
The authors sought to understand the ...presentation and clinical course of ICI-associated myocarditis.
After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.
The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.
Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The prognostic role of eosinophils in cancer has been controversial. Some entities such as gastrointestinal cancers show a better survival, while others such as Hodgkin's lymphoma a worse survival in ...patients with eosinophilia. Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or pembrolizumab were shown to survive longer. We wanted to investigate whether eosinophilia is a prognostic marker in metastatic melanoma.
In total, 173 patients with metastatic melanoma from our data base (median age 60 years; n = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for eosinophil counts and survival over the course of 12 years. Eosinophilic count was detected by peripheral blood smear. The ethical committee had approved this retrospective study.
Melanoma patients with eosinophilia at any point in their course of disease show a trend toward longer survival independently of their therapy. There is a statistically significant difference for the patients who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor therapy, survival was significantly prolonged in every patient with eosinophilia (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy experienced at least once an eosinophilia of 5% or greater compared with 46% in the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%, respectively. Interestingly, in patients with more than 20% eosinophils (n = 7) survival was prolonged with a median of 35 months (range 19-60 months) as compared with 16 months (range 1-117 months).
Eosinophilia is a prognostic marker in patients with metastatic melanoma.
Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted ...therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 ...receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. Methods and findings In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. Conclusion Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Purpose
Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be ...life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized.
Methods
This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA).
Results
During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml;
p
= 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l;
p
= 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml;
p
= 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems.
Conclusion
Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Immune checkpoint inhibitors (ICIs) are effective against a wide variety of cancers. However, they also induce a plethora of unique immune-related adverse events (irAEs). Since for many organ ...systems symptoms can be unspecific, differential diagnosis with progression of disease or infection may be difficult. C-reactive protein (CRP) has been suggested as a marker for infection. The purpose of this study was to evaluate the diagnostic value of CRP in differentiating infectious causes from autoimmune side effects induced by ICIs.
Methods
In order to investigate the role of CRP in irAEs, we screened our patient data base. Only events with full infectious workup were included. In total 88 events of irAEs in 37 melanoma patients were analyzed. CRP levels before and during irAEs were evaluated. Statistical analyses were conducted using the Chi-square test for categorical variables.
Results
At the onset of irAE, CRP rose in 93% of cases to a mean of 52.7 mg/L (CI 35.1–70.3) from 8.4 mg/L at baseline (normal < 5 mg/L) (
P
< 0.0001). Other causes of CRP elevation including infectious diseases were excluded, and procalcitonin (PCT) levels were normal in 92% of events. Importantly, in 42% of cases CRP elevations preceded clinical symptoms.
Conclusion
CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
New melanoma therapies, like e.g. ipilimumab, improve survival. However, only a small subset of patients benefits while 60% encounter side effects. Furthermore, these marginal benefits come at a very ...high price of €110'000 per treatment. This study examines attitudes towards melanoma therapy options of physicians, healthy individuals and patients, their willingness to pay and preference of quality versus length of life.
Based on findings from a focus group questionnaires were developed and pretested. After obtaining ethical approval and informed consent surveys were conducted in a total of 90 participants (n = 30 for each group). Statistical analyses were conducted using R.
Attitudes vastly differed between healthy participants, physicians and melanoma patients. Whereas melanoma patients show a high willingness to endure side effects despite very small survival gains (down to 1 extra week) or even only hope with no survival benefit, healthy controls are more critical, while physicians are the most therapy adverse. Consequently, if given €100'000 and the free decision what to spend the money on the willingness to pay for therapy was much higher in the patient group (68%) compared to 28% of healthy controls and only 43% of the physicians, respectively. When lowering the amount of cash that could be received instead of ipilimumab to €50'000 or €10'000 to test price sensitivity 69% (+1%) and 76% (+8%) of melanoma patients, respectively, preferred ipilimumab over cash. When judging on societal spending even melanoma patients opted for spending on ipilimumab in only 21%.
The judgment about the benefits of new treatment options largely differs between groups, physicians being the most critical against therapy. Price elasticity was low.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker ...of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.
This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.
This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.
Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).
GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The skin prick test – European standards Heinzerling, Lucie; Mari, Adriano; Bergmann, Karl‐Christian ...
Clinical and translational allergy,
02/2013, Volume:
3, Issue:
1
Journal Article
Peer reviewed
Open access
Skin prick testing is an essential test procedure to confirm sensitization in IgE‐mediated allergic disease in subjects with rhinoconjunctivitis, asthma, urticaria, anapylaxis, atopic eczema and food ...and drug allergy. This manuscript reviews the available evidence including Medline and Embase searches, s of international allergy meetings and position papers from the world allergy literature. The recommended method of prick testing includes the appropriate use of specific allergen extracts, positive and negative controls, interpretation of the tests after 15 – 20 minutes of application, with a positive result defined as a wheal ≥3 mm diameter. A standard prick test panel for Europe for inhalants is proposed and includes hazel (Corylus avellana), alder (Alnus incana), birch (Betula alba), plane (Platanus vulgaris), cypress (Cupressus sempervirens), grass mix (Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense), Olive (Olea europaea), mugwort (Artemisia vulgaris), ragweed (Ambrosia artemisiifolia), Alternaria alternata (tenuis), Cladosporium herbarum, Aspergillus fumigatus, Parietaria, cat, dog, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and cockroach (Blatella germanica). Standardization of the skin test procedures and standard panels for different geographic locations are encouraged worldwide to permit better comparisons for diagnostic, clinical and research purposes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look ...at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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