Adoptive transfer of chimeric antigen receptor (CAR)-expressing natural killer (NK) cells has demonstrated success against hematological malignancies. Efficacy against solid tumors has been limited by poor NK cell survival and function in the suppressive tumor microenvironment (TME). To enhance efficacy against solid tumors, stimulatory cytokines have been incorporated into CAR-NK cell therapeutic approaches. However, current cytokine strategies have limitations, including systemic toxicities, exogenous dependencies, and unwanted TME bystander effects. Here, we aimed to overcome these limitations by modifying CAR-NK cells to express a constitutively active interleukin (IL)-7 receptor, termed C7R, capable of providing intrinsic CAR-NK cell activation that does not rely on or produce exogenous signals nor activate bystander cells.

We examined persistence, antitumor function, and transcriptional profiles of CAR-NK cells coexpressing C7R in a novel tumor immune microenvironment (TiME) co-culture system and against hematologic and solid tumor xenografts in vivo.

Peripheral blood NK cells expressing a CAR directed against the solid tumor antigen GD2 and modified with C7R demonstrated enhanced tumor killing and persistence in vitro compared with CAR-NK cells without cytokine support and similar functions to CAR-NK cells supplemented with recombinant IL-15. C7R.CAR-NK cells exhibited enhanced survival and proliferation within neuroblastoma TiME xenografts in vivo but produced poor long-term tumor control compared with CAR-NK cells supplemented with IL-15. Similar results were seen using C7R-expressing CD19.CAR-NK cells against CD19+leukemia xenografts. Gene expression analysis revealed that chronic signaling via C7R induced a transcriptional signature consistent with intratumor stressed NK cells with blunted effector function. We identified gene candidates associated with chronic cytokine-stressed NK cells that could be targeted to reduce CAR-NK cell stress within the solid TME.

C7R promoted CAR-NK cell survival in hostile TMEs independent of exogenous signals but resulted in poor antitumor function in vivo. Our data reveals the detrimental role of continuous IL-7 signaling in CAR-NK cells and provides insights into proper application of cytokine signals when attempting to enhance CAR-NK cell antitumor activity.

The induction of telomere dysfunction-related chromosomal aberrations by the radiomimetic antibiotic bleomycin (BLM) was studied in human lymphoblastoid cells immortalized with the Epstein-Barr virus (EBV). To this end, an EBV-induced lymphoblastoid cell line (T-37) was exposed to increased concentrations of BLM (10-100 µg/mL) for 2 h at 37ºC, and telomere aberrations were analyzed 24 h (first mitosis) after treatment using PNA-FISH with pan-telomeric plus pan-centromeric probes. Telomere signal duplications (TSD) increased significantly in BLM-exposed cells (p < 0.01), although the concentration-response relationship was non-linear. Most of the induced TSD (95-99 %) were of chromatid-type. No induction of telomere signal loss, telomere fusions or telomere associations by BLM was observed in T-37 cells. These findings show that BLM induces short-term telomere dysfunction in EBV-transformed human lymphoblastoid cells in the form of TSD (which implies telomere fragility) and suggest that these effects mainly occur during the G2 stage of the cell cycle. The persistence of this type of aberrations in the long-term in EBV-induced lymphoblastoid cells and other human cells exposed to BLM may be of medical relevance. Telomere fragility induced by BLM could promote genomic instability, which might contribute to the development of secondary tumors in patients undergoing chemotherapy based on this compound. Consequently, our study raises concerns about the potential long-term genomic effects of BLM in treated patients and suggests that the analysis of TSD could be a useful biomarker for detecting BLM-induced telomere dysfunction in human cells.

Cancer, marked by uncontrolled cell growth, is a leading global cause of death. Conventional cancer treatments such as chemotherapy and radiation, for all their use, often come with severe side effects. This has really pushed the development of immunotherapies and cancer vaccines, which try to leverage the body's immune system to fight tumors. Effective delivery of therapeutic agents to immune cells or tumors is critical, and natural carriers such as exosomes, archaeosomes, virosomes, and dendritic cells offer promising solutions. These systems excel in biocompatibility, low toxicity, and immune activation compared to synthetic alternatives. This review examines their role in cancer vaccines and immunotherapy, highlighting challenges like production consistency and tumor heterogeneity. Future directions include personalized vaccines and combination therapies, advancing these natural carriers in the fight against cancer.

Oligometastatic head and neck squamous cell carcinoma is a distinct clinical state inadequately addressed in current metastatic disease trials. This narrative review is based on historical literature and recently published data of the Omet trial. The Gortec 2014-04 Omet phase II randomized trial investigated whether genuine metachronous oligometastases in head and neck squamous cell carcinoma, characterized by a limited number (up to three) of lesions not induced by prior systemic therapy, may benefit from a "de-escalation strategy" using curative-intent stereotactic ablative radiotherapy alone rather than strategies relying on systemic treatments upfront. Randomized phase II-III trials are scarce on head and neck squamous cell carcinoma. In the Omet trial, survival at 1 year exceeded 85 % in both arms. Progression-free survival was, as anticipated, slightly longer in the group chemotherapy and stereotactic ablative radiotherapy (10 months versus 7.5 months) but without deleterious impact upon metastatic relapse. Stereotactic ablative radiotherapy alone showed significantly lower grade 3-4 toxicity (8.8 % versus 60 %). Quality of life declined less with stereotactic ablative radiotherapy alone. Poor prognostic factors included male sex and multiple metastases. Major protocol deviations correlated with worse outcomes. Stereotactic ablative radiotherapy offers a viable, less toxic alternative to systemic therapy for genuine oligometastatic head and neck squamous cell carcinoma, warranting refined patient selection and further research. Despite its role as a new standard-of-care, the role of immunotherapy remains uncertain in the oligometastatic setting and requires specific studies in oligometastatic head and neck squamous cell carcinoma to challenge this new option.

Increasing numbers of adolescent and young adult (AYA) patients are diagnosed with myeloproliferative neoplasms (MPNs). Management strategies are often extrapolated from older MPN cohorts and frequently fail to address specific needs. Through retrospective description of 107 AYA patients registered at a UK specialist centre, we identify unique clinicopathological features compared with older patients, including lower incidence of JAK2 V617F and additional non-driver mutations, and a reduced rate of transformation. Despite these favourable disease characteristics, we demonstrate significant rates of venous thrombosis (>14 %). This data highlights areas of unmet clinical need and calls for tailored management approaches for AYA MPN patients.

Immunotherapy is a promising therapeutic strategy for cutaneous carcinoma in locally advanced and advanced stages. This study aims to compare the survival outcomes between patients treated with surgery and those treated with cemiplimab. Secondly, we evaluated how adjuvant treatment, tumor stage, and margins status may influence the oncological outcomes in the surgical group.

The study included 77 patients with locally advanced cutaneous carcinoma of the external ear treated between 2015 and 2023 with surgery, either followed or not by adjuvant therapy, or treated with cemiplimab.

Immunotherapy demonstrated a benefit in the disease-specific survival both at 24 months (HR = 0.09, p = 0.02) and at 60 months (HR = 0.11, p = 0.04) when compared to patients treated by surgery, with an estimated 5-year survival of 80 % and 55.9 %, respectively (log-rank = 0.03). Conversely, surgery showed a more favorable trend for disease-free survival than cemiplimab (HR 0.58, p = 0.08), with a median survival of 25.6 and 14.2 months. Stage IV, compared to stage III, tended to have a worse survival rate when stratified by treatment strategy. The addition of adjuvant therapy improved median disease-specific survival from 12 to 40 months for stage IV. On the other hand, adjuvant radiotherapy did not significantly affect outcomes when stratified by margin status, especially when resection margins were clear (p = 0.36).

Cutaneous carcinoma of the external ear represents a rare entity, affecting elderly patients and still associated with high complication rates. Emerging therapeutic strategies, which may serve as alternatives to surgery, offer a basis for future adjustments of treatment algorithms for these neoplasms.

Melanomas represent a small percentage of skin malignancies, but they represent the majority of deaths from skin cancer. The etiology of vulvar melanomas may differ from other melanomas, where the most important risk factor is exposure to ultraviolet light. Compared to adults, pediatric melanomas have an atypical clinical presentation, posing as low-suspicion lesions, thus leading to a diagnostic delay and increased mortality in this patient population.

A 10-year-old female with a painful hyperpigmented lesion localized in the left vulvar region, with no other associated symptoms. Dermatology assessment described a palpable neoformation of 5 × 6 mm, black color, with irregular borders. Dermoscopy shown asymmetrical pattern, peripheral globules, irregular projections, and blue-white veil. Subsequently, an excisional biopsy of the lesion was performed, with a histopathological report of melanoma HMB45 positive, p-53 positive and focal Ki-67, negative margins. Further studies revealed no evidence of metastatic activity; therefore, it was decided to continue medical surveillance by the pediatric oncology service.

Vulvar melanoma is a malignant entity with a low incidence rate. There are no case reports published in Mexico that describe its location in the pediatric population. Given the high mortality, early diagnosis and treatment would improve life expectancy in our patients.

Glutathione S-transferase P1-1 (GST P1) is an important drug target as it is implicated in drug resistance. GST P1-1 inhibitors are typically non-productive analogues of glutathione which covers broad chemical space; hence it is likely that several clinically used drugs may unknowingly act as GST P1-1 inhibitors. We developed a high-throughput screening assay for GST P1-1 and screened 5830 compounds. From the screening, 24 potent GST P1-1 inhibitors were identified and assessed for cytotoxicity in MCF-7 and MDA-MB-231 breast cancer cell lines. Ethacrynic acid (a known GST P1-1 inhibitor), ZM 39923, PRT 4165, 10058-F4, and cryptotanshinone were shown to be the most active. A competitive GST P1-1 assay was performed to identify the inhibition type of these five compounds. Another in vitro cytotoxicity experiment was conducted to explore the differences in the cytotoxicity profiles of the combinations tested. Western blot analysis was used to identify the presence of GST P1-1 in the breast cancer cell lines tested. The implications of these results concerning alternative treatment options for breast cancers are discussed.

Cancer treatments often fall short of durable cures, yet most therapeutic strategies neglect the tumor stroma. A concerted effort is needed to understand, model, target and reprogram the tumor 'soil', recognizing its profound influence on cancer from tumorigenesis to therapy resistance.

Elastic laminal invasion (ELI), defined as tumor invasion beyond the peritoneal elastic lamina, may affect gastric cancer (GC) prognosis, though limited data exist on this relationship.

We retrospectively reviewed representative pathological slides from 396 patients with pT3 or pT4a GC who underwent curative resection to assess the association between ELI and relapse-free survival (RFS) and overall survival (OS).

The 5-year RFS of pT3 GC with negative ELI was 85.9%, which was better than the 55.9% of that of ELI-positive pT3 (P < 0.001) or pT4a (51.3%) GC (P < 0.001). Similarly, the 5-year OS of ELI-negative pT3 GC was 90.4%, while the corresponding values for ELI-positive pT3 and pT4a were 67.0% (P < 0.001) and 63.6% (P < 0.001), respectively. Multivariate analysis revealed that the most significant prognostic factors for RFS were pT factors (i.e., pT3 with ELI/pT4), tumor size (≥ 80 mm), and nodal metastasis. We subdivided our cohort of patients with pathological stage II (pT3N0, pT3N1) GC into ELI-negative and ELI-positive subgroups, and found that the ELI-negative ones had better RFS percentages than those who were ELI-positive or stage III (P = 0.002 and P < 0.001, respectively).

ELI-positive pT3 GC has a worse prognosis than its ELI-negative counterpart, comparable to that of pT4a. These findings suggest a need to revisit the pT grading system in GC.