BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.

• Klíčová slova
• Antitumor immunity, Immune checkpoint inhibitors, Peripheral blood circulating immune subsets, Predictive biomarker,
• MeSH
• antigeny CD278 metabolismus   MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• antigeny CD28 MeSH
• CD8-pozitivní T-lymfocyty imunologie   účinky léků   metabolismus   MeSH
• dospělí MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom * farmakoterapie   imunologie   krev   patologie   MeSH
• nádory plic * farmakoterapie   imunologie   krev   patologie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   imunologie   krev   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD278 MeSH
• antigeny CD279 MeSH
• antigeny CD28 MeSH
• ICOS protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů * MeSH

BACKGROUND: Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. METHODS: This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. RESULTS: Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. CONCLUSIONS: Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.

• Klíčová slova
• BRAF mutation, immunotherapy, real-world data, targeted therapy,
• MeSH
• lidé MeSH
• melanom * farmakoterapie   genetika   patologie   MeSH
• nádory kůže * farmakoterapie   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• receptory domény smrti MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH
• receptory domény smrti MeSH

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

• Klíčová slova
• TNM, immune checkpoint blockade, immune checkpoint inhibitors ipilimumab, immunotherapy, sinonasal mucosal melanoma,
• Publikační typ
• časopisecké články MeSH

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors associated with poor prognosis and limited therapeutic options. Recent advances in oncology-related immunotherapy, specifically in targeting of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathways, have identified a new treatment potential in a variety of tumors, including advanced and rare tumors. Only a fraction of patients being treated by immune checkpoint inhibitors have shown to benefit from it, displaying a need for strategies which identify patients who may most likely show a favorable response. Building on recent, promising outcomes in a clinical study of metastatic PPGL using pembrolizumab, a humanized IgG4κ monoclonal antibody targeting the PD-1/PD-L1 pathway, we examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in our PPGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy. We evaluated RNA expression in the NIH cohort of 48 patients with known genetic predisposition (sporadic; pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: RET, NF1) and 6 normal medulla samples (NAM). For comparison, 72 PPGL samples from The Cancer Genome Atlas (TCGA) were used for analysis of gene expression based on the variant status (pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: NF1, RET). Expression of PD-L1 was elevated in the PPGL cohort compared to normal adrenal medulla, aligning with the TCGA analysis, whereas PD-L2 was not elevated. However, expression of PD-L1 was lower in the pseudohypoxia cluster compared to the sporadic and the kinase signaling subtype cluster, suggesting that sporadic and kinase signaling cluster PPGLs could benefit from PD-1/PD-L1 therapy more than the pseudohypoxia cluster. Within the pseudohypoxia cluster, expression of PD-L1 was significantly lower in both SDHB- and non-SDHB-mutated tumors compared to sporadic tumors. PD-L1 and PD-L2 expression was not affected by the metastatic status. We conclude that PD-L1 and PD-L2 expression in our cohort of PPGL tumors was not linked to metastatic behavior, however, the presence of PPGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with PPGL.

• Klíčová slova
• immunotherapy, neuroendocrine tumors, paraganglioma, pheochromocytoma, programmed death ligand 1,
• Publikační typ
• časopisecké články MeSH

PURPOSE: Insomnia in cancer patients is a common symptom contributing to poor quality of life and poor functioning. Sleep disturbances have been associated with inflammatory activity, and systemic cancer therapies chemotherapy, hormonal therapy, and immunotherapy may cause insomnia. We have carried out a meta-analysis to estimate the occurrence of insomnia in patients with solid cancer treated with immunotherapy using checkpoint inhibitors (CPI). METHODS: PubMed and ClinicalTrials.gov were searched for phase 3 studies in solid tumours where treatment included a checkpoint inhibitor in the experimental arm. Data on the incidence of insomnia were acquired from the adverse events tables available from clinicaltrials.gov and/or from the full texts. Random effect logistic model was used to compare pooled data. Heterogeneity between studies was assessed using Cochrane Q statistics and I2 statistics. RESULTS: A total of 54 studies (including six three-arm studies) involving 37,352 patients were included in the analysis. Insomnia was reported in 8.3% of subjects (95% confidence interval [CI] 8.0%-8.7%) treated with immunotherapy. Insomnia was significantly more common in patients receiving immunotherapy compared to those enrolled in study arms with inactive treatment (odds ratio [OR] 1.49, 95% CI 1.13-1.96). The odds for insomnia were similar between the arms for studies comparing CPI versus chemotherapy and CPI versus non-immunologic targeted therapies (OR 1.07, 95% CI 0.94-1.22 and OR 1.40, 95% CI 0.90-2.18, respectively). The OR for insomnia was higher for cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor inhibitors compared to the inhibitors of programmed death-1 (PD-1) receptor (OR 1.36, 95% CI 1.06 - 1.74). CONCLUSION: Cancer immunotherapy using CPI is associated with insomnia but the odds of developing the symptom are not greater with immunotherapy than with other systemic modalities including chemotherapy and non-immunologic targeted therapies.

• Klíčová slova
• cancer, checkpoint inhibitors, immunotherapy, insomnia, systematic analysis,
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH

Colorectal cancer (CRC) is one of the most common cancers worldwide. The patient's prognosis largely depends on the tumor stage at diagnosis. The pathological TNM Classification of Malignant Tumors (pTNM) staging of surgically resected cancers represents the main prognostic factor and guidance for decision-making in CRC patients. However, this approach alone is insufficient as a prognostic predictor because clinical outcomes in patients at the same histological tumor stage can still differ. Recently, significant progress in the treatment of CRC has been made due to improvements in both chemotherapy and surgical management. Immunotherapy-based approaches are one of the most rapidly developing areas of tumor therapy. This review summarizes the current knowledge about the tumor microenvironment (TME), immune response and its interactions with CRC development, immunotherapy and prognosis.

• Klíčová slova
• colorectal cancer, consensus molecular subtypes, immune cells, immunoscore, tumor microenvironment, tumorigenesis,
• MeSH
• imunita MeSH
• imunoterapie MeSH
• kolorektální nádory * patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí * MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Fatigue is one of the most common adverse effects associated with cancer immunotherapy using checkpoint inhibitors (CPIs). Because treatment-related fatigue also frequently occurs in patients treated with non-immunological therapies, our study aimed to compare the incidence of fatigue in CPI-treated patients with that associated with non-immune therapies in randomised trials. METHODS: PubMed and ClinicalTrials.gov were searched for phase III studies using a CPI alone or in combination with chemotherapy or non-immunologic targeted therapy in the experimental arm and control arm using inactive therapies such as placebo or observation, chemotherapy, or non-immunologic targeted therapy. Adverse events listed in the full texts as well as those available from clinicaltrials.gov were reviewed for all identified studies. RESULTS: A total of 60 studies involving 41 435 patients were included in the analysis. All-grade fatigue was reported in 30.4% of patients [95% confidence interval (CI) 29.9% to 31.0%] in the immunotherapy arms of the analysed studies. Using anti-programmed cell death protein 1 agents as reference, the odds ratio (OR) for fatigue was significantly higher both for anti-cytotoxic T lymphocyte-associated antigen 4 agents (OR 1.46, 95% CI 1.04-2.04) and the combination of anti-cytotoxic T lymphocyte-associated antigen 4 and anti-programmed cell death protein agents (OR 1.43, 95% CI 1.12-1.83). Fatigue was significantly less likely to occur in patients treated with CPI compared with patients receiving chemotherapy (OR 0.79, 95% CI 0.73-0.85), but significantly was more common in patients receiving the combination of CPI/chemotherapy compared with patients receiving chemotherapy alone (OR 1.12, 95% CI 1.03-1.22). CONCLUSIONS: Although immunotherapy using CPIs was associated with treatment-related fatigue, the occurrence of all-grade fatigue was significantly higher in patients treated with chemotherapy compared with patients receiving CPIs. The risk of fatigue was higher for CPI/chemotherapy combinations than for chemotherapy alone. These results suggest that although the effects of CPIs and chemotherapy are additive, chemotherapy was the dominant cause of treatment-related fatigue in the analysed trials.

• Klíčová slova
• checkpoint inhibitors, chemotherapy, fatigue, immunotherapy, meta-analysis, targeted therapy,
• MeSH
• imunoterapie škodlivé účinky   metody   MeSH
• incidence MeSH
• inhibitory kontrolních bodů * škodlivé účinky   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• únava chemicky indukované   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory kontrolních bodů * MeSH

BACKGROUND: Implementation of adjuvant therapies in non-metastatic melanoma improved treatment outcomes in some patients; however, adjuvant therapy can be associated with significant cost and risk of toxicity. Therefore, there is an unmet need to better identify patients at high risk of recurrence. PATIENTS AND METHODS: We carried out an ultrasensitive droplet digital PCR (ddPCR)-based detection of BRAFV600E-mutated circulating tumor DNA (ctDNA) from blood samples prospectively collected before surgery, 1 hour after surgery, and then serially during follow-up. RESULTS: In 80 patients (stages ≤III), BRAFV600E mutations were detected in 47.2% of tissue, in 37.7% of ctDNA samples collected before surgery, and in 25.9% of ctDNA samples collected 1 hour after surgery. Patients with detected ctDNA in blood collected 1 hour after surgery compared to patients without detected ctDNA had higher likelihood of melanoma recurrence (P < 0.001) and shorter median disease-free survival (P = 0.001) and overall survival (P = 0.003). CONCLUSIONS: Ultrasensitive ddPCR can detect ctDNA in pre- and post-surgical blood samples from patients with resectable melanoma. Detection of ctDNA in post-surgical samples is associated with inferior treatment outcomes.

• Klíčová slova
• circulating tumor DNA, liquid biopsy, melanoma,
• MeSH
• cirkulující nádorová DNA * genetika   MeSH
• lidé MeSH
• melanom * genetika   MeSH
• mutace * MeSH
• polymerázová řetězová reakce MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• cirkulující nádorová DNA * MeSH
• protoonkogenní proteiny B-Raf * MeSH

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.

• Klíčová slova
• abscopal effect, anti-CTLA-4, cryotherapy, melanoma, tumor neoantigens, wound healing,
• MeSH
• antigen prezentující buňky imunologie   MeSH
• antigeny nádorové metabolismus   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• ipilimumab terapeutické užití   MeSH
• kryoterapie MeSH
• lidé MeSH
• melanom imunologie   sekundární   terapie   MeSH
• modely imunologické MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory kůže imunologie   patologie   terapie   MeSH
• paliativní péče MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH
• Názvy látek
• antigeny nádorové MeSH
• inhibitory kontrolních bodů MeSH
• ipilimumab MeSH

Non-Hodgkin lymphomas (NHLs) are lymphoid malignancies of B- or T-cell origin. Despite great advances in treatment options and significant improvement of survival parameters, a large part of NHL patients either present with a chemotherapy-refractory disease or experience lymphoma relapse. Chemotherapy-based salvage therapy of relapsed/refractory NHL is, however, capable of re-inducing long-term remissions only in a minority of patients. Immunotherapy-based approaches, including bispecific antibodies, immune checkpoint inhibitors and genetically engineered T-cells carrying chimeric antigen receptors, single-agent or in combination with therapeutic monoclonal antibodies, immunomodulatory agents, chemotherapy or targeted agents demonstrated unprecedented clinical activity in heavily-pretreated patients with NHL, including chemotherapy-refractory cases with complex karyotype changes and other adverse prognostic factors. In this review, we recapitulate currently used immunotherapy modalities in NHL and discuss future perspectives of combinatorial immunotherapy strategies, including patient-tailored approaches.

• Klíčová slova
• CAR T-cells, bispecific antibodies, immune checkpoint inhibitors, immunomodulatory agents, non-Hodgkin lymphomas,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH