Summary
CTLA‐4 and PD‐1 play a key role in tumor‐induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer ...types. Anti‐CTLA‐4 and anti‐PD‐1 antibodies affect the interaction between tumor, antigen‐presenting cells and T lymphocytes. Clinical studies of the anti‐CTLA‐4 antibody ipilimumab and the anti‐PD‐1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five‐year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune‐related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy.
The side-effect ...registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised.
Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III–IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.
Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti–programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.
•Neuromuscular side-effects of checkpoint inhibitors are underdetected, which delays proper treatment.•Clinical presentation of immune-related myopathies differs from that of their idiopathic counterparts.•Harmonised approach for detection, diagnostic and treatment is essential.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin. Even though most patients are sufficiently treated by surgical resection, some will eventually metastasize ...and need systemic therapy. Phase I and II studies have shown efficacy for programmed cell death protein 1 (PD-1) inhibitors, but cohort sizes are low and real-world data especially on long-term outcome are pending.
Patients from six German skin cancer centers treated with PD-1 inhibitors (pembrolizumab, nivolumab or cemiplimab) for advanced cSCC were retrospectively studied. Internal patient records were analyzed for clinical outcome including response, progression-free survival (PFS), overall survival (OS) and toxicity.
Of 46 evaluable patients (median age: 76 years), the overall response rate (RR) was 58.7%, including 15.2% with complete response. The disease control rate was 80.4%. Both median PFS and OS were not reached, Kaplan–Meier estimated 1-year PFS was 58.8%. Patients responding to therapy showed durable remission. Response was independent of the PD-1 inhibitor used and also independent of the presence of distant metastases vs. locally advanced disease. Two predictive factors were found: Patients with primaries located on the leg had a poorer therapy outcome and patients with high lactate dehydrogenase serum levels at baseline. Treatment was overall tolerated well, with less than 10% of patients discontinuing therapy due to toxicity.
PD-1 inhibitors fulfill the need for an efficient systemic therapy for advanced cSCC and should be the new standard of care. With high RRs and durable disease control, neoadjuvant and adjuvant regimens should be evaluated.
•Patients treated with programmed cell death protein 1 inhibitorsfor advanced cutaneous squamous cell carcinoma were retrospectively analyzed.•An extraordinary efficacy in routine clinical use was found, comparable to clinical trials.•The response rate was 59%, disease control rate was 80%.•Efficacy was high in both locally advanced and metastasized disease.•The treatment was very well tolerated in the mostly elderly patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
7.
Yellowish nodule with hypertrichosis on the upper lip Hoffmann, Johanna C.; Thoms, Kai‐Martin; Schön, Michael P. ...
Journal der Deutschen Dermatologischen Gesellschaft,
June 2022, Volume:
20, Issue:
6
Journal Article
Peer reviewed
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone ...metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60-70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.
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