Janusz Milanowski

Mushroom compost worker's lung (MCWL) is a hypersensitivity pneumonitis (HP) entity occurring in workers employed at preparing compost for the cultivation of white button mushrooms. The aim of the study is to identify the strains of thermophilic actinobacteria as the potential causative agents of MCWL symptoms in workers. Clinical examinations included chest X-ray, high-resolution computed tomography (HRCT), bronchoscopy with bronchoalveolar lavage (BAL), pulmonary function tests comprising spirometric measurements, DLCO measurements, body pletysmography, and arterial - blood gas tests. Identification of thermophilic actinobacteria was performed by microscopy, culture and genetic methods. Allergological tests included the agar gel precipitation test and inhalation challenge with actinomycetal antigens. Among a group of 20 patients, 15 showed in HRCT ground-glass attenuations solely and were diagnosed with acute HP, 3 showed ground-glass attenuations with pulmonary fibrosis and were diagnosed with subacute HP, while 2 patients were diagnosed with Organic Dust Toxic Syndrome (ODTS). Thermobifida fusca and Laceyella sacchari strains were isolated from the symptom-causing mushroom compost. In 3 workers, strong precipitin reactions to Th. fusca were found, whereas there were no reactions to L. sacchari. Four workers showed a positive inhalation response to small doses of Th. fusca antigen. The results of this study indicate that Th. fusca is most probably a major causative agent of MCWL and should be considered in the diagnosis of HP in workers of the mushroom compost facility.

Non-small-cell lung cancer treatment relies greatly on immunotherapy, especially in individuals without targetable mutations enabling the use of molecularly targeted therapies. Negative immune checkpoint inhibitors significantly contribute to improving patients’ survival and quality of life. Both programmed death ligand 1 expression on tumour cells and tumour mutational burden are used to predict the response to such treatment and qualify patients for therapy; however, in some cases, these biomarkers do not perform sufficiently well. Discovering new markers indicating resistance or response to immunotherapy would therefore enable clinicians to tailor the therapy course to the patient’s benefit. This paper aims to describe the genetic and immunological background of immunotherapy courses and identify factors potentially related to clinical benefit or lack of response to immunotherapy, using next-generation sequencing of tumour tissue and flow cytometry analysis of lymphocyte subpopulations in the peripheral blood of non-small cell lung cancer patients in a preliminary study.

The introduction of immune checkpoint inhibitors (ICIs) in the treatment of cancer has significantly improved patient outcomes. Whereas ICIs have a substantially more beneficial risk profile than chemotherapy, immune-related adverse events (irAEs) are currently among the most pressing challenges of clinical oncology. It has been well established that certain variants of HLA genes are associated with increased susceptibility or a decreased risk of certain autoimmune diseases. Considering that irAEs often resemble autoimmune disorders observed in the general population, we conducted the first review summarizing the current knowledge on the link between the HLA system and the development of irAEs during ICIs treatment. We performed a comprehensive search of the US National Library of Medicine (PubMed) database. Based on the research conducted so far, our analysis indicates that certain HLA variants have been described to increase or, conversely, decrease the risk of irAEs. Thus, HLA genotyping may be useful in stratifying the risk of irAEs, allowing for more thorough screening of patients with a higher likelihood of developing ICI-related toxicities and less frequent monitoring of those at lower risk, thereby significantly reducing costs and the overall burden of disease. HLA genotyping may ultimately contribute to the personalization of cancer therapy, significantly improving patient safety and clinical efficacy. Furthermore, identifying an association between certain HLA variants and irAEs may lead to a better understanding of the pathogenesis underlying these adverse effects. Nevertheless, the studies conducted so far have included limited cohorts of patients with a wide variety of malignancies and diverse treatment regimens. Hence, further research that addresses these limitations is needed.

Introduction and objective: Lung cancer remains the leading cause of death from malignant tumours worldwide. Delays in the diagnosis of lung cancer in primary and specialist health care result in a high stage of the disease, lack of possibility of radical treatment, and the shortening of the...

The possibilities of small-cell lung cancer (SCLC) therapy were strictly limited for years, leading to high patient mortality rates. New approaches to SCLC treatment are being proposed, including chemoimmunotherapy. However, biomarkers enabling appropriate personalization of therapy in SCLC patients have not been identified yet. Even though molecular subtyping (ASCL1, NEUROD1, POU2F3, and YAP1) seems pivotal in the management of SCLC, expression of other genes might be potentially valuable during patients’ stratification. Due to their crucial role in tumorigenesis and SCLC invasiveness, benefits arising from MET and SLFN11 gene evaluation are suggested. Our study was designed to evaluate the relationship between the mRNA expression of these genes and chemoimmunotherapy efficacy in SCLC patients. A total of 35 patients with extensive-stage SCLC (ES-SCLC) treated with first-line chemoimmunotherapy were involved in the study. mRNA expression of MET and SLFN11 genes was evaluated using the RT-qPCR technique in FFPE tissue collected from all patients. Molecular results were correlated with clinicopathological features and outcome of disease (OS, PFS). We detected SLFN11 expression in 60% (21 of 35) of the samples. SLFN11 expression was higher in patients with longer PFS (p = 0.05) and with the T4 feature in the TNM scale (p = 0.08). MET mRNA was expressed in all FFPE tissues. We observed that risk of progression and death was higher in patients with higher expression of MET mRNA (p = 0.06 and p = 0.04, respectively). Our study showed that MET and SLFN11 expression might serve as additional biomarkers for prediction of chemoimmunotherapy efficacy in ES-SCLC patients.

Introduction: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients with ALK or ROS1 gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but there is no direct comparison of their efficacy in homogeneous Caucasian populations in real-world practice. In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease. Materials and Methods: One hundred four NSCLC patients with ALK or ROS1 gene rearrangement were enrolled for first-line therapy with ALK inhibitors (crizotinib in 25 patients, brigatinib in 22 patients, and alectinib in 41 patients) or the ROS1 inhibitor (crizotinib in 16 patients) as part of daily clinical practice in two Polish cancer centers. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to treatment methods and clinical data. Results: In ALK-rearranged patients, ORR was insignificantly higher in patients treated with second-generation ALK inhibitors than in patients receiving crizotinib (68.25% vs. 48% of patients, p = 0.0547). Median PFS in the crizotinib group was 8 months, and in the group that received second-generation ALK inhibitors this was not reached (HR = 5.2182, 95% CI: 2.6163–10.4079, p < 0.0001). Similarly, median OS was significantly lower in patients treated with crizotinib than in patients receiving second-generation ALK inhibitors (26 vs. not reached, HR = 3.529, 95% CI: 1.5559–7.2258, p = 0.002). The efficacy of crizotinib in patients with ROS1 and ALK gene rearrangement did not differ significantly (ORR—37.5 vs. 48%, median PFS—6 vs. 7 months, median OS—8 vs. 26 months, respectively). In ALK-rearranged patients, multivariate analysis showed that the only factor significantly increasing the risk of progression was liver metastases (HR = 2.1917, p = 0.0418). The risk of death was significantly higher in patients treated with crizotinib (HR = 2.4823, p = 0.0359) and in patients with liver metastases (HR = 3.1266, p = 0.0104). Conclusions: Second-generation ALK inhibitors are more effective than crizotinib in ALK-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors.

Background: The use of immunotherapy in treatment of non-small cell lung cancer (NSCLC) patients with the BRAF gene mutations is an area of active research and is an item of clinical trials. While BRAF mutations are relatively infrequent in NSCLC patients, comprising approximately 1–3% of cases, the V600E substitution stands out as the most prevalent subtype of BRAF mutations. The presence of this mutation in cancer cells qualifies the patients for first-line therapy with BRAF and MEK inhibitors. This study aims to evaluate the efficacy of immunotherapy in NSCLC patients with BRAF mutations. We presented a series of seven NSCLC cases with BRAF mutations, four of whom received immunotherapy or chemoimmunotherapy. Methods: We observed benefit from immunotherapy in all patients, but its duration depended on comorbidities and the presence of brain metastases. Utilization of the next generation sequencing (NGS) technique causes high detection frequency of BRAF mutations (4.7% of patients), although mutations other than V600E may predominate (4 out of 7 patients). Results: In patients receiving immune checkpoint inhibitors (ICIs)-based therapy, the median progression-free survival (PFS) was 17 months from the start of immunotherapy, the overall objective response rate (ORR) was 50%, and disease control was achieved in all patients. Conclusions: Immunotherapy can benefit NSCLC patients with BRAF mutations, though its efficacy is affected by comorbidities and brain metastases. The use of NGS enhances mutation detection, highlighting the need for personalized treatment approaches in NSCLC management. The varying responses to treatments among the patients emphasize the complexity of NSCLC management and the necessity for a personalized approach.

Endometrial cancer (EC) accounts for 90% of uterine cancer cases. It is considered not only one of the most common gynecological malignancies but also one of the most frequent cancers among women overall. Nowadays, the differentiation of EC subtypes is based on immunohistochemistry and molecular techniques. It is considered that patients’ prognosis and the implementation of the appropriate treatment depend on the cancer subtype. Patients with pathogenic variants in POLE have the most favorable outcome, while those with abnormal p53 protein have the poorest. Therefore, in patients with POLE mutation, the de-escalation of postoperative treatment may be considered, and patients with abnormal p53 protein should be subjected to intensive adjuvant therapy. Patients with a DNA mismatch repair (dMMR) deficiency are classified in the intermediate prognosis group as EC patients without a specific molecular profile. Immunotherapy has been recognized as an effective treatment method in patients with advanced or recurrent EC with a mismatch deficiency. Thus, different adjuvant therapy approaches, including targeted therapy and immunotherapy, are being proposed depending on the EC subtype, and international guidelines, such as those published by ESMO and ESGO/ESTRO/ESP, include recommendations for performing the molecular classification of all EC cases. The decision about adjuvant therapy selection has to be based not only on clinical data and histological type and stage of cancer, but, following international recommendations, has to include EC molecular subtyping. This review describes how molecular classification could support more optimal therapeutic management in endometrial cancer patients.

Lung cancer has become a major public health concern, standing as the leading cause of cancer-related deaths worldwide. Among its subtypes, small-cell lung cancer (SCLC) is characterized by aggressive and rapid growth, poor differentiation, and neuroendocrine features. Typically, SCLC is diagnosed at an advanced stage (extensive disease, ED-SCLC), with distant metastases, and is strongly associated with tobacco smoking and has a poor prognosis. Recent clinical trials, such as CASPIAN and IMpower133, have demonstrated promising outcomes with the incorporation of immune checkpoint inhibitors in first-line chemotherapy, leading to prolonged progression-free survival and overall survival in patients with ED-SCLC compared to standard chemotherapy. Other studies have emphasized the potential for future development of molecularly targeted therapies in SCLC patients, including inhibitors of IGF-1R, DLL3, BCL-2, MYC, or PARP. The molecular subdivision of SCLC based on transcriptomic and immunohistochemical analyses represents a significant advancement in both diagnostic and clinical approaches in SCLC patients. Specific molecular pathways are activated within distinct transcriptome subtypes of SCLC, offering the potential for personalized treatment strategies, such as targeted therapies and immunotherapies. Such tailored approaches hold promise for significantly improving outcomes in SCLC patients.

Mutations in the KRAS gene are among the most common mutations observed in cancer cells, but they have only recently become an achievable goal for targeted therapies. Two KRAS inhibitors, sotorasib and adagrasib, have recently been approved for the treatment of patients with advanced non-small cell lung cancer with the KRAS G12C mutation, while studies on their efficacy are still ongoing. In this work, we comprehensively analyzed RAS gene mutations’ molecular background, mutation testing, KRAS inhibitors’ effectiveness with an emphasis on non-small cell lung cancer, the impact of KRAS mutations on immunotherapy outcomes, and drug resistance problems. We also summarized ongoing trials and analyzed emerging perspectives on targeting KRAS in cancer patients.