Immunotherapies revolutionized cancer treatment, yet their efficacy remains constrained by the tumor's immunosuppressive microenvironment. Here, we evaluated whether combining CD39 blockade with other modalities of immunotherapy such as IL-2/anti-IL-2 complexes (IL-2cx) administration could further enhance T cell-mediated antitumor responses and improve tumor control. We demonstrated that CD39 deficiency in MC38 tumor-bearing CD39KO (Entpd1 null) mice decreases tumor growth. This better tumor growth control was associated with increased infiltration of PD-1^High CD8⁺ T cells, expressing elevated levels of exhaustion markers and transcription factors such as TOX. This PD-1^High CD8⁺ T cell subset also exhibited a higher frequency of IFN-γ-producing and cytotoxic (Granzyme B⁺, Perforin⁺) cells. In contrast, the less immunogenic B16F10-OVA model did not show significant differences in tumor growth; however, CD39KO mice displayed an increased frequency of antigen-specific, pre-exhausted (PD-1^Int) CD8⁺ T cells, a population recognized as a key target of immunotherapy. Pharmacological CD39 blockade with POM-1, when combined with IL-2cx treatment to redirect IL-2 activity, enhanced the accumulation of pre-exhausted CD8⁺ T cells with cytotoxic potential, thereby improving tumor control. This combinatorial strategy also reshaped the tumor immune landscape by increasing activated NK cells, elevating Granzyme B expression in CD4⁺ T cells, and decreasing immunosuppressive M-MDSCs expressing CD39, CD38, and CD73. Collectively, our findings demonstrate that integrating purinergic pathway inhibition with IL-2-based immunotherapies can coordinately reprogram lymphoid and myeloid compartments, attenuate immunosuppressive mechanisms within the tumor microenvironment, and amplify antitumor immunity, providing a strong rationale for advancing this strategy toward clinical translation.

ROS1 rearrangement is a rare mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), with an incidence of less than 1% in non-small cell lung cancer (NSCLC). However, the clinical characteristics and therapeutic strategies for patients who develop ROS1 rearrangement after resistance to EGFR-TKIs remain undefined. Here, we describe the first case of EGFR-TKIs resistance caused by the EZR exon 10-ROS1 exon 34 rearrangement. This case highlights ROS1 rearrangement as a rare but targetable mechanism of acquired resistance to EGFR-TKIs. Additionally, we conducted a comprehensive review of previously reported cases of other ROS1 rearrangements occurring after EGFR-TKIs resistance in NSCLC. Our analysis reveals that this rare mutation shares notable clinical similarities with primary ROS1 rearrangement in certain characteristics. However, it exhibits significant differences in fusion partner distribution and co-mutation frequency compared to the primary ROS1 rearrangement. The efficacy of crizotinib in this molecular subset demonstrates favorable clinical outcomes. Furthermore, considering the relatively high prevalence of ROS1 co-mutations with other genetic alterations in these cases, multi-targeted combination therapy may represent a promising therapeutic strategy for this distinct patient population.

Toll-like receptors (TLRs) are a group of pathogen recognition receptors expressed not only on immune cells but also cancer cells, where TLR activation may lead to tumour progression or suppression. At present, little is known about the role of TLRs and their connection with immune responses in precancerous lesions, such as oral leukoplakia (OL). In the present study, we have explored the immune activation and the expression of the intracellular TLRs - TLR3, TLR7, TLR8, and TLR9 in OL without and with dysplasia, and in oral squamous cell carcinoma (OSCC).

Immunohistochemistry was performed on 19 OL patients without dysplasia (OL-no) and 13 patients with dysplasia (OL-dys) and 10 OSCC patients. On digitalised images, TLR3-, TLR7-, TLR8- and TLR9-expressing cells were semi-quantitatively assessed, while the number of CD3- and CD8-expressing cells/mm2 was registered.

Nuclear TLR7 appeared in 31% of OL-dys but was absent in OL-no (p = 0.03). Cytoplasmic TLR8 was higher in OL-no than OL-dys (32% vs. 8%, p = 0.02). Similarly, cytoplasmic TLR9 was also higher OL-no than OL-dys (42% vs. 23%, p = 0.01).

TLR3, TLR7, TLR8, and TLR9 are all expressed in OL-no, OL-dys, and OSCC. Also, the study provides evidence for possible nucleocytoplasmic shuttling of TLRs.

Polatuzumab vedotin, an antibody-drug conjugate (ADC) targeting the B cell receptor (BCR) signaling subunit CD79B, has recently entered frontline therapy for diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBCL), achieving encouraging clinical results. However, MYC-driven B cell lymphomas, particularly HGBCL with MYC and BCL2 rearrangements, frequently silence surface BCR/CD79B expression, limiting the therapeutic reach of CD79B-directed ADCs and underscoring the need for complementary treatment strategies. To uncover drug vulnerabilities associated with BCR extinction in aggressive B cell lymphomas, we conditionally ablated surface BCR expression in the λ-MYC mouse B cell lymphoma model and screened 1475 small-molecule compounds, including clinically approved agents, on syngenic BCR-positive and BCR-negative tumor cells. This screening revealed compounds with comparable activity across both states as well as compounds with improved efficacy against BCR-deficient lymphomas. Notably, inhibitors of mTORC1/2 and CDK4/6 displayed robust and reproducible potency in BCR-negative lymphoma cells. Mechanistically, BCR loss impaired mTOR-dependent anabolic control, reducing protein synthesis, while diminished Cyclin D3 abundance sensitized tumor cells to pharmacological CDK4/6 blockade. Human BCR-negative HGBCL with MYC and BCL2 rearrangements similarly exhibited sub-micromolar sensitivity to mTORC1/2 and CDK4/6 inhibitors. Overall, our results uncover targetable vulnerabilities in MYC-driven B cell lymphomas, possibly extending to other aggressive B cell tumors silencing BCR expression. The data provide a rational basis for integrating CD79B-directed ADCs with mTOR or CDK4/6 inhibitors to prevent or overcome treatment resistance of aggressive B cell lymphomas.

T-follicular helper cell lymphomas (TFHLs) are frequently associated with epigenetic mutations and clonal haematopoiesis (CH), but the clinical and prognostic implications of CH in TFHL remains unclear. We performed next-generation sequencing on paired peripheral blood (PB) and tumour tissue samples from 30 patients with TFHL. CH was defined by the detection of CH-associated mutations in PB at variant allele frequency ≥2%. Patients were stratified into CH-positive, CH-suspected or CH-negative based on genotyping and bone marrow involvement. CH-associated mutations were detected in PB in 12 of 30 patients (40.0%) and were suspected in four additional cases (13.3%), with no cases progressed to overt myeloid neoplasms. Ten-eleven translocation 2 and DNA methyltransferase 3A were the most frequently shared mutations between tumour and PB. CH-positive patients were significantly older, exhibited poorer performance status (Eastern Cooperative Oncology Group [ECOG] ≥2: 50.0% vs. 0.0%, p = 0.004), elevated systemic inflammation (high-sensitivity C-reactive protein [hs-CRP]: 66.9 vs. 20.3 mg/L, p = 0.010) and inferior treatment response (complete response [CR] rate: 9.1% vs. 50.0%, p = 0.042). In multivariate analysis adjusting for age and ECOG performance status, CH positivity remained independently associated with inferior progression-free survival (PFS) (hazard ratio [HR] = 4.41, 95% confidence interval [CI]: 1.46-13.35, p = 0.009), even after adjustment for age and ECOG performance status. In conclusions, CH is common in TFHL which represents early events in lymphomagenesis and is associated with elevated systemic inflammation, poor performance status, worse treatment response and inferior PFS.

Frontal lobes are essential in making complex decisions and ensuring subtle social interactions. Importantly, patients with low-grade glial tumors often have no deficiency detected by standard neurological examination, but they may be completely unable to live a normal life in real world. The key principle in choosing surgical tactics for frontal lobe tumors is analysis of pathway with appropriate functional system adjacent to neoplasm and assessment of its functional safety before surgery. Research data on surgery for glioma near motor centers indicate that transient motor deficiency occurs in 30-90%, persistent deficiency - in 4-47% of cases. Intraoperative monitoring reduces the incidence of persistent deficiency (from 8.2% to 3.4%) and increases extent of resection (from 58% to 75%). To identify corticospinal tract, some studies demonstrate superiority of subcortical stimulation with monopolar probe and multipulse technique over bipolar stimulation. Importantly, complete disappearance of evoked motor potentials during transcranial stimulation is associated with high (up to 85%) risk of persistent motor deficit. New methods for «passive» mapping of speech function (corticocortical evoked potentials) reduce postoperative speech deficit. They are indicated in patients with contraindications for awake craniotomy.

Cavernous malformations of the corpus callosum are rare accounting for less than 1% of all subtentorial cavernous malformations. Clinical manifestations are usually caused by hemorrhage into adjacent parenchyma. Epileptic seizures are the most common. Multiple hemorrhages with progressive neurological impairment require surgical intervention.

To present giant cavernoma of the genu of the corpus callosum extending to the fornix, basal frontal lobes and bottom of the third ventricle, as well as review of available literature.

A patient with giant cavernous malformation of the genu of the corpus callosum extending to the fornix, basal frontal lobes and bottom of the third ventricle underwent total resection of malformation. Symptoms included headaches, epileptic seizures, and hydrocephalus. Korsakoff syndrome developed after surgery and partially regressed at discharge. After 3 months, hydrocephalus completely regressed. Elements of Korsakoff syndrome persisted with improvements under rehabilitation sessions with neuropsychologist.

Despite difficult anatomical location and giant size, total resection of cavernous malformation provided satisfactory outcome with minimal neurological complications.

β-Carboline alkaloids, such as harmine (1), have demonstrated notable anticancer properties, making them attractive candidates for anticancer drug development. This study evaluated the antiproliferative activity of compound 1 and thirty-three N⁹-substituted derivatives across a panel of cancer cell lines representing various histotypes. Among these, derivative 6, a harmine analog bearing a 3,5-dimethylbenzyl substituent, was the most potent, showing enhanced cytotoxicity and selectivity toward cancer cells. Compound 6 exhibited IC₅₀ values below 10 µM in all tested cancer cell lines, while its IC₅₀ in non-cancerous cells exceeded 100 µM. Viability assays and xCELLigence real-time monitoring confirmed a concentration-dependent inhibition of cancer cell growth with minimal effects on non-malignant cells. Flow cytometry demonstrated G1 phase arrest in MOLT-4 cells, supported by Western blot data showing reduced phosphorylated Rb and increased p27 protein levels. Apoptosis induction was confirmed through Annexin V/PI staining, TUNEL assays, and caspase activation studies. These revealed the involvement of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways, along with activation of caspases 3/7. Western blot analysis also showed a concentration-dependent increase in the Bax/Bcl-2 ratio. Immunofluorescence microscopy visualization indicated DNA damage through elevated levels of PAR and γH2AX, consistent with single- and double-strand DNA breaks. Importantly, compound 6 exhibited low inhibitory activity against monoamine oxidase A (MAO-A) and did not promote reactive oxygen species (ROS) generation, minimizing potential off-target effects. Together, these findings support the potential of compound 6 as a selective and effective candidate for antileukemia therapy.

BACKGROUND Esophagopleural fistula (EPF) is a rare but life-threatening complication following pneumonectomy, with a reported incidence of up to 1% and a mortality rate ranging from 49% to 63%. Management strategies vary depending on the fistula's characteristics and the patient's clinical status, encompassing conservative, endoscopic, and surgical approaches. CASE REPORT We report the case of a 65-year-old woman diagnosed with lung adenocarcinoma and N2 nodal involvement who received neoadjuvant chemo-immunotherapy, followed by surgical treatment with left pneumonectomy. In the early postoperative course, she developed fever and pleural contamination with food particles, leading to the diagnosis of EPF via methylene blue test and esophagogastroduodenoscopy (EGD). Initial endoscopic treatment with stent placement was attempted multiple times but its failure prompted the need for surgical intervention. After addressing the infectious and nutritional issues associated with the condition and optimization of the patient's clinical status, a complex 3-stage procedure was performed involving esophageal exclusion and reconstruction of the gastrointestinal tract using a retrosternally transposed gastric conduit. This was achieved through 3 surgical approaches: laparoscopy, left cervicotomy, and minilaparotomy. The postoperative course was uneventful, with successful reintroduction of oral intake. The esophagogram performed 3 months postoperatively showed a good caliber of the esophagogastric anastomosis and no leakage of contrast from the esophageal lumen. CONCLUSIONS Surgical treatment of large esophagopleural fistulas is indicated when endoscopic treatment fails. Furthermore, esophageal exclusion and bypass is the best course of action when the extent of the fistulous tract presents a problem for direct repair and the chest cavity presents difficulties.

Human papillomavirus is the dominant etiological factor underlying atypical cervical squamous epithelial cell abnormalities and cervical carcinoma. Currently, only a limited number of drugs targeting specific biomarkers in cervical cancer are available. This study aimed to assess the expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and the Ki-67 proliferative index (Ki-67) in p16-positive cervical squamous premalignant and malignant lesions, which may help clarify the potential role of targeted therapies in cervical cancer.

In p16-positive, histologically proven premalignant and malignant cervical lesions, ER, HER2, and Ki-67 expression were evaluated according to predefined criteria.

p16 showed strong nuclear and cytoplasmic positivity in 54 of 56 cases. Patchy nuclear positivity was mainly observed in low-grade squamous intraepithelial lesion (LSIL) cases (2/56). Ki-67 demonstrated a variable proliferative index ranging from 5% to 95% across all cases, with higher indices predominantly observed in squamous cell carcinomas (SCC). ER positivity in LSIL, high-grade squamous intraepithelial lesion, and SCC was 100% (2/2), 66.7% (10/15), and 46.15% (18/39), respectively. HER2 expression was predominantly negative, observed in 78.6% (44/56) of cases, equivocal in 17.8% (10/56), and positive in 3.6% (2/56). Both HER2-positive cases were SCC. ER and HER2 interpretations were analyzed and were not significantly correlated with clinical or pathological parameters.

ER positivity decreased with progression of cervical squamous lesions, and HER2 expression was rare in cervical squamous neoplasia. No statistically significant correlation was identified between ER or HER2 expression and clinicopathological parameters. The findings of the current study may help fill gaps in the existing literature and provide essential foundational knowledge for optimizing emerging therapeutic strategies, including ER- and HER2-related therapies.