BackgroundUveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic ...UM is currently unclear.MethodsPatients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.ResultsThe best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0–65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0–65.0). The median PFS was 3.0 months (95% CI 2.4–3.6). The median OS was estimated to 16.1 months (95% CI 12.9–19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).ConclusionsThe tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. ...steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking.
The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies.
From a total of 1330 cases, 217 patients (16.3%) received 249 second‐line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only.
Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.
•Steroid-refractory immune-related adverse events pose a clinical challenge.•Analysis of the SERIO-registry: 19 different second-line therapies were used.•Therapy choice was determined by the type of immune-related adverse event.•Similar onset of steroid-responsive and steroid-refractory irAEs.•Similar tumor responses in second-line treated and steroid-only treated patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. ...However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence.
Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS.
The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 95% confidence interval {CI} 9.3–15.1; 9.8 95% CI 6.9–12.6 versus 5.1 95% CI 2.7–7.5; P = .03).
SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies.
•Two hundred eight patients with melanoma brain metastases are reported.•Patients were treated with radiotherapy (RT) and systemic therapy (ST).•Stereotactic radiosurgery and immunotherapy achieved highest overall survival (OS) rates.•For RT and targeted therapy, treatment sequencing is critical.•Whole brain RT and ST achieved unprecedentedly high OS rates.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Vertical transmission of maternal cancer cells to the child is extremely rare, but melanoma represents the most common culprit. The aim of this study is to determine individual risks for ...materno-fetal transmission of melanoma cells and to establish standardized procedures for pregnant melanoma patients and their offspring.
In this retrospective multicenter study, data on women with stage III or IV melanoma that had been diagnosed before, during or up to 12 months after pregnancy, were analyzed for the occurrence of metastases in the placenta or the infant. In addition, a literature search for previously described materno-fetal transmission in case of maternal melanoma was conducted. A historical patient group was established from these cases and a statistical analysis was performed (SAS, p < 0.05 significant).
In total, 67 children born to women with stage III or IV melanoma were included. No placental or infant metastases were detected in any of the cases. The additional literature search revealed 37 cases with placental metastases and 14 cases with infant metastases (6 of them overlapping). Of the affected children, 10 (71.43%) died from their disease. Maternal death shortly after birth seems to be an unfavorable factor for transmission to the infant.
The risk of materno-fetal transmission of maternal melanoma metastases seems to be much lower than anticipated based on former studies. However, thorough placental screening and systematic follow-up of the children resulting from pregnancies of high-risk melanoma patients should be performed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Measurements of the ratios of charged kaon decay rates for Ke3/K2 π, Kμ3/K2π and Kμ3/Ke3 are presented. These measurements are based on charged kaon decays collected in a dedicated run in 2003 by the ...NA48/2 experiment at CERN. The results obtained are Ke3/K2π = 0.2470 ± 0.0009 (stat) ± 0.0004 (syst ) and Kμ3/K2π = 0.1637 ± 0.0006 (stat) ± 0.0003 (syst). Using the PDG average for the K2pi normalization mode, both values are found to be larger than the current values given by the Particle Data Book and lead to a larger magnitude of the Vus parameter in the Cabibbo-Kobayashi-Maskawa (CKM) matrix than previously accepted. When combined with the latest Particle Data Book value of |Vud|, |Vus| is in agreement with unitarity of the CKM matrix. A new measured value of the ratio of the semileptonic decay rates, Kμ3/Ke3 = 0.663 ± 0.003(stat) ± 0.001(syst) is compared to semi-empirical predictions based on the latest form factor measurements.
•First multicenter study on HIV-1 drug resistance testing by 454 ultra-deep pyrosequencing to evaluate reproducibility and concordance of this new protocol.•All HIV-1 drug resistance mutations ...identified by population sequencing were also identified by 454 ultra-deep pyrosequencing.•Minority HIV-1 drug resistance mutations were only detected by 454 ultra-deep pyrosequencing.•454 ultra-deep pyrosequencing provided highly concordant results together with excellent cross-site correlation.
The detection of mutant spectra within the viral quasispecies is critical for therapeutic management of HIV-1 infections. Routine clinical application of ultrasensitive genotyping requires reproducibility and concordance within and between laboratories. The goal of the study was to evaluate a new protocol on HIV-1 drug resistance testing by 454 ultra-deep pyrosequencing (454-UDS) in an international multicenter study. Sixteen blinded HIV-1 subtype B samples were provided for 454-UDS as both RNA and cDNA with viral titers of 88,600–573,000 HIV-1 RNA copies/ml. Eight overlapping amplicons spanning protease (PR) codons 10–99 and reverse transcriptase (RT) codons 1–251 were generated using molecular barcoded primers. 454-UDS was performed using the 454 Life Sciences/Roche GS FLX platform. PR and RT sequences were analyzed using 454 Life Sciences Amplicon Variant Analyzer (AVA) software. Quantified variation data were analyzed for intra-laboratory reproducibility and inter-laboratory concordance. Routine population sequencing was performed using the ViroSeq HIV-1 genotyping system. Eleven laboratories and the reference laboratory 454 Life Sciences sequenced the HIV-1 sample set. Data presented are derived from seven laboratories and the reference laboratory since severe study protocol execution errors occurred in four laboratories leading to exclusion. The median sequencing depth across all sites was 1364 reads per position (IQR=809–2065). 100% of the ViroSeq-reported mutations were also detected by 454-UDS. Minority HIV-1 drug resistance mutations, defined as HIV-1 drug resistance mutations identified at frequencies of 1–25%, were only detected by 454-UDS. Analysis of 10 preselected majority and minority mutations were consistently found across sites. The analysis of drug-resistance mutations detected between 1 and 10% demonstrated high intra- and inter-laboratory consistency in frequency estimates for both RNA and prepared cDNA samples, indicating robustness of the method. HIV-1 drug resistance testing using 454 ultra-deep pyrosequencing results in an accurate and highly reproducible, albeit complex, approach to the analysis of HIV-1 mutant spectra, even at frequencies well below those detected by routine population sequencing.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
