Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy.

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent histology. While immunotherapy with checkpoint inhibitors has shown outstanding results in NSCLC, the precise identification of responders remains a major challenge. Most studies attempting to overcome this handicap have focused on adenocarcinomas or squamous cell carcinomas. Among NSCLC subtypes, the molecular and immune characteristics of lung large cell carcinoma (LCC), which represents 10% of NSCLC cases, are not well defined. We hypothesized that specific molecular aberrations may impact the immune microenvironment in LCC and, consequently, the response to immunotherapy. To that end, it is particularly relevant to thoroughly describe the molecular genotype-immunophenotype association in LCC-to identify robust predictive biomarkers and improve potential benefits from immunotherapy. We established a cohort of 18 early-stage, clinically annotated, LCC cases. Their molecular and immune features were comprehensively characterized by genomic and immune-targeted sequencing panels along with immunohistochemistry of immune cell populations. Unbiased clustering defined two novel subgroups of LCC. Pro-immunogenic tumors accumulated certain molecular alterations, showed higher immune infiltration and upregulated genes involved in potentiating immune responses when compared to pro-tumorigenic samples, which favored tumoral progression. This classification identified a set of biomarkers that could potentially predict response to immunotherapy. These results could improve patient selection and expand potential benefits from immunotherapy.

An Fc-free EGFR-specific 4-1BB-agonistic Trimerbody Displays Broad Antitumor Activity in Humanized Murine Cancer Models without Toxicity.

PURPOSE: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell-mediated antitumor response. Systemic administration of anti-4-1BB-agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity. EXPERIMENTAL DESIGN: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo. RESULTS: In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non-small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer. CONCLUSIONS: These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.

Blood mRNA expression of REV3L and TYMS as potential predictive biomarkers from platinum-based chemotherapy plus pemetrexed in non-small cell lung cancer patients.

PURPOSE: Therapeutic options for cancer patients have increased in the last years, although drugs resistance problem remains unresolved. Genetic background in individual susceptibility to cancer treatment could influence the therapy responses. The aim of this study was to explore the feasibility of using blood 4 genes (AEG-1, BRCA-1, REV3L and TYMS) expression levels as a predictor of the efficacy of pemetrexed therapy in patients with advanced non-small cell lung cancer. METHODS: Sixteen patients from the Medical Oncology Department at "12 de Octubre" Hospital, were included in the study. Total mRNA was isolated from blood samples, and gene expression was analyzed by RT-qPCR. A panel of lung tumor cell lines were used in cell proliferation tests and siRNA-mediated silencing assays. RESULTS: Similarity between blood gene expression levels and protein expression in matched tumor tissue was observed in 54.54% (REV3L) and 81.81% (TYMS) of cases. Gene expression of REV3L and TYMS in blood correlated directly and inversely, respectively, with progression-free survival and overall survival in the patients from our cohort. In tumor cell lines, the knockdown of REV3L conferred resistance to pemetrexed treatment, and the TYMS silencing increased the pemetrexed sensitivity of tumor cells. CONCLUSIONS: The use of peripheral blood samples for expression quantification of interest genes is an affordable method with promising results in the evaluation of response to pemetrexed treatment. Therefore, expression levels of REV3L and TYMS genes might be used as predictive biomarkers in advanced NSCLC patients.

Primary cutaneous leiomyosarcoma: clinicopathological analysis of 36 cases.

AIMS: Cutaneous leiomyosarcomas (LMS) are rare in comparison with their deep-seated soft tissue and uterine counterparts, and have been poorly characterized. The aim was to verify whether the clinical behaviour of purely dermal LMS is different from that of LMS with minimal subcutis invasion. METHODS AND RESULTS: Twenty-one purely dermal LMS and 15 dermal LMS with minimal subcutis extension were analysed. Tumours developed in 27 men and nine women (age range 29-91 years); most tumours showed a fasciculated (n = 23), pilar-type (n = 12) and pleomorphic (n = 1) pattern. During the follow-up period (range 2-192, mean 41 months) recurrences occurred in 1/16 (6.2%) of tumours confined to the dermis and in 2/11 (18.1%) tumours with minimal subcutis extension. The three recurrent tumours were high-grade LMS, two of which exhibited myxoid areas. One patient with a pleomorphic dermal LMS with minimal extension into fat developed distant metastases 15 years after diagnosis. CONCLUSIONS: For LMS involving the skin, it is advisable to recognize and indicate in the histopathology report the depth of dermal and/or subcutaneous extension, since even minimal subcutaneous involvement may be associated with late local recurrences and/or distant metastases, and therefore appropriate and long-term follow-up is needed.

Subcutaneous atypical fibrous histiocytoma.

Benign fibrous histiocytoma is one of the most frequent benign neoplasms mainly composed of a mixture of fibroblastic and histiocytic cells, especially found in the skin (dermatofibroma), particularly in the limbs. The diagnosis of cutaneous benign fibrous histiocytoma is generally easy; however, rare variants may be difficult to identify, and the diagnosis only confirmed after exhaustive histopathological examination. Thus, deep subcutaneous dermatofibroma may be difficult to distinguish from dermatofibrosarcoma protuberans and dermatofibroma with monster giant cells from malignant fibrous histiocytoma and atypical fibroxanthoma. We report a case of a 38-year-old woman with a painless swelling on the abdominal wall, which was totally excised and histopathologically diagnosed as subcutaneous atypical fibrous histiocytoma. The lesion was deeply located within the subcutaneous tissue and consisted of interlacing fascicles of predominant histiocyte-like spindle cells intermingled with pleomorphic giant cells with bizarre large nuclei (bilobed and multilobed) and prominent eosinophilic nucleoli. Only 1 mitotic figure was found in the whole lesion. Prominent hyaline collagen bundles surrounded by tumor cells were observed, predominantly at the periphery of the lesion. Immunohistochemical study showed positivity only for vimentin and factor XIIIa, whereas pan-keratins, actin, desmin, CD34, CD10, and S-100 protein were negative. Recognition of dermatofibroma is important, allowing sequential excision and optimal results. Definitive diagnosis, although especially difficult in our case, is established by characteristic histological and immunohistochemical criteria. To the best of our knowledge, we report the first case of subcutaneous fibrous histiocytoma with monster cells.

Eruptive syringoma developed over a waxing skin area.

Syringomas are benign, eccrine, sweat gland tumors that clinically appear as small skin-colored or yellow papules. Eruptive syringomas are rare variants that typically develop on the body's cutaneous anterior surface. Syringomas on the genital area have rarely been reported, although several authors maintain that syringoma should be considered in the differential diagnosis of pubic pruritic papular dermatitis. We present a case of a 31-year-old man with multiple, eruptive, asymptomatic papules involving the pubic area developed after waxing of the zone. Histological examination revealed disseminated syringomata. We postulate that the lesions were induced by depilation with a subsequently reactive inflammatory process resulting in a hyperplastic reaction of the eccrine ducts. This case supports the previous hypothesis suggesting that some of the so-called "eruptive syringomas" may start as a primary inflammatory eccrine reaction.