PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the ...combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts.
Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays.
Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors.
Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of eosinophils in cancer is not yet completely understood, but patients with eosinophilia show a trend towards longer survival in several types of cancer, including melanoma. However, ...eosinophil count at initial diagnosis of metastatic melanoma does not predict survival. Since eosinophil cationic protein (ECP) mediates anticancer effects, such as tissue remodelling and cytotoxic activity, we investigated this marker as an early prognostic marker in metastatic melanoma.
Serum of 56 melanoma patients was collected at the time of diagnosis of metastatic disease. ECP levels as measured by ELISA were correlated with overall survival (OS) in patients before systemic therapy with immunotherapy or chemotherapy. Statistical analyses were performed using the Log-Rank (Mantel-Cox) test.
The median OS for patients with high serum ECP above 12.2 ng/ml was 12 months (n = 39), compared to 28 months for patients with ECP below this threshold (n = 17; p = 0.0642). In patients with cutaneous melanoma, excluding patients with uveal and mucosal melanoma, the survival difference was even more striking (p = 0.0393). ECP's effect size on OS was observed independently of the consecutive therapy. ECP levels were not correlated with LDH levels.
ECP seems to be a novel prognostic serum marker for the outcome of melanoma patients, which is independent of LDH and easy to perform in clinical practice. The striking negative prognostic value of high ECP level is unanticipated and can guide patient management.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and ...describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis.
In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre.
Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43).
ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.
•Presentation of ICI-iE is variable and resembles that of HSV-1 encephalitis.•Abnormal MRI and antineuronal antibodies are less common than previously reported.•Analysis of cerebrospinal fluid has the highest diagnostic value in ICI-iE.•ICI-iE has a mortality of 10% and long-term sequelae occur in 47% of patients.•Early immunosuppressive treatment of ICI-iE is associated with full recovery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
BRAF and MEK inhibitor (BRAFi/MEKi) combinations are currently the standard treatment for patients with BRAF
mutant metastatic melanoma. Since the RAS/RAF/MEK/ERK-pathway is crucial for the function ...of different immune cells, we postulated an effect on their function and thus interference with anti-tumor immunity. Therefore, we examined the influence of BRAFi/MEKi, either as single agent or in combination, on the maturation of monocyte-derived dendritic cells (moDCs) and their interaction with T cells. DCs matured in the presence of vemurafenib or vemurafenib/cobimetinib altered their cytokine secretion and surface marker expression profile. Upon the antigen-specific stimulation of CD8
and CD4
T cells with these DCs or with T2.A1 cells in the presence of BRAFi/MEKi, we detected a lower expression of activation markers on and a lower cytokine secretion by these T cells. However, treatment with any of the inhibitors alone or in combination did not change the avidity of CD8
T cells in peptide titration assays with T2.A1 cells. T-helper cell/DC interaction is a bi-directional process that normally results in DC activation. Vemurafenib and vemurafenib/cobimetinib completely abolished the helper T-cell-mediated upregulation of CD70, CD80, and CD86 but not CD25 on the DCs. The combination of dabrafenib/trametinib affected DC maturation and activation as well as T-cell activation less than combined vemurafenib/cobimetinib did. Hence, for a potential combination with immunotherapy, our data indicate the superiority of dabrafenib/trametinib treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this ...study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.
From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.
These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.
Background
In recent years, monoclonal antibodies such as ipilimumab, nivolumab, and pembrolizumab have made a significant impact on the treatment of advanced melanoma. Combination of immune ...checkpoint inhibitors leads to improved survival and response rates of 58%‐61% as compared to monotherapy (36%‐44%). However, the price for the better response rates is also a higher frequency of severe adverse events (59%) as compared to monotherapy (17%‐21%). This study examines attitudes towards melanoma therapy options of physicians, healthy individuals, melanoma patients, and physicians with oncological disease, their willingness to pay, and preference of quality versus length of life.
Methods
After obtaining ethical approval and informed consent surveys were conducted in 111 participants divided into four groups: melanoma patients (n = 30), healthy individuals as controls (n = 30), physicians (n = 27), and physicians with oncological disease (n = 24). Statistical analyses were conducted using SPSS statistics (version 25, IBM), applying the Pearson´s chi‐squared test, Spearman correlation coefficient, Wilcoxon‐Mann‐Whitney test, and Kruskal‐Wallis test.
Results
Life prolongation is more valued by melanoma patients and physicians with oncological disease compared to healthy controls and healthy physicians. In total, 30% of melanoma patients opt for a life prolonging therapy in all cases, even if this life prolongation is only marginal. Physicians are the strongest proponents of combination immunotherapy.
Conclusion
The valuation of the different treatment options differs in the four study groups with affected people valuing life prolongation much more. The individual value of cancer therapies is high, but differs from the societal standpoint.
Valuation of different melanoma treatment options differs signficantly among different study groups with affected people valuing life prolongation much more. The individual value of cancer therapy is high, but differs from the societal standpoint.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 ...and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for 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 affect skin, gastrointestinal tract, liver, 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 centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. Conclusion Anti-PD1 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
BackgroundMyocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized ...electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.MethodsFrom an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.ResultsBoth the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).ConclusionsThe QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
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