A critical review of RAF inhibitors in BRAF-mutated glioma treatment.

BRAF gliomas have garnered significant attention in research due to the lack of effective treatments and their notable incidence, constituting 3% of all gliomas. This underlines the importance of investigating this area and the impact that targeted therapies could hold. This review discusses the development of targeted therapies for these tumors, examining the effectiveness of first-generation BRAF inhibitors such as Vemurafenib, Dabrafenib and Encorafenib, while addressing the challenges posed by paradoxical ERK activation. The advent of pan-RAF inhibitors, notably Tovorafenib, offers a promising advance, demonstrating enhanced efficacy and better penetration of the blood-brain barrier, without the issue of paradoxical activation. Nevertheless, continued research is essential to refine therapeutic strategies for BRAF-mutated gliomas, given the evolving nature of targeted therapy development.

Epidemiology of bone tumors in Lebanon: a retrospective study from 2000 to 2022 at a tertiary center.

Aim: Bone tumors are rare and have an uneven geographic distribution. Methods: 730 patients diagnosed with bone tumors were included in this retrospective analysis. Results: With a 64% rate of malignancy, the most common tumors were metastasis (40%) mostly in the axial skeleton, Osteosarcoma (9%) mostly in the femur, Osteochondroma (8%) mostly in the femur, giant cell tumors (7%) mostly in the knee, and Ewing's sarcoma (6%) mostly in the axial skeleton. Conclusion: Even though a some of the tumors have a predilection for certain localizations in the human body, they may differ in the middle-eastern population. One must also pay attention to the higher rates of malignancies as compared with other cohorts.

With significant morbidity and mortality, bone tumors incidence is low and varies geographically. In our Lebanese population, Seven-hundred-thirty patients with bone tumors were identified with a 64% rate of malignancy with osteosarcoma being the most common primary bone cancer and metastasis being the overall most prevalent bone malignancy. This higher rate of malignancy compared with other populations should be taken into consideration when evaluating Lebanese or Middle eastern patients.

NTRK-rearranged spindle cell neoplasms are ubiquitous tumours of myofibroblastic lineage with a distinct methylation class.

AIMS: NTRK gene fusions have been described in a wide variety of central nervous system (CNS) and soft tissue tumours, including the provisional tumour type 'spindle cell neoplasm, NTRK-rearranged' (SCN-NTRK), added to the 2020 World Health Organisation Classification of Soft Tissue Tumours. Because of histopathological and molecular overlaps with other soft tissue entities, controversy remains concerning the lineage and terminology of SCN-NTRK. METHODS AND RESULTS: This study included 16 mesenchymal tumours displaying kinase gene fusions (NTRK fusions and one MET fusion) initially diagnosed as infantile fibrosarcomas (IFS), SCN-NTRK and adult-type fibrosarcomas from the soft tissue, viscera and CNS. We used immunohistochemistry, DNA methylation profiling, whole RNA-sequencing and ultrastructural analysis to characterise them. Unsupervised t-distributed stochastic neighbour embedding analysis showed that 11 cases (two CNS tumours and nine extra-CNS) formed a unique and new methylation cluster, while all tumours but one, initially diagnosed as IFS, clustered in a distinct methylation class. All the tumours except one formed a single cluster within the hierarchical clustering of whole RNA-sequencing data. Tumours from the novel methylation class co-expressed CD34 and S100, had variable histopathological grades and frequently displayed a CDKN2A deletion. Ultrastructural analyses evidenced a myofibroblastic differentiation. CONCLUSIONS: Our findings confirm that SCN-NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.

Extensive Intratemporal Tumor-An Unusual Diagnosis.

A 21-year-old man presented with left-sided facial paralysis and sensorineural hearing loss; physical examination was otherwise normal. What is your diagnosis?

Molecular profiling of basal cell carcinomas in young patients.

BACKGROUND: Basal cell carcinoma (BCC) represents by far the most common non-melanoma skin cancer (NMSC) in the world with an increasing incidence of 3% to 10% per year, especially in patients under the age of 40. While variants in the sonic Hedgehog and cell cycle regulation pathways account for the majority of BCC cases in adults, the molecular etiology of BCC in young patients is unelucidated yet. This study aims to investigate the molecular profile of BCC in the young population. METHODS: 28 tumors belonging to 25 Lebanese patients under the age of 40, presenting different stages of BCC and diagnosed at Hôtel Dieu de France-Saint Joseph University Medical Center were included in this study. A selected panel of 150 genes involved in cancer was analyzed by Next Generation Sequencing (NGS) in the 28 included tumors. RESULTS: Genetic variants detected in more than 5% of the reads, with a sequencing depth ≥ 50x, were selected. Two hundred and two genetic variants in 48 different genes were detected, with an overall average sequencing depth of 1069x. Among the 28 studied tumors, 18 (64.3%) show variations in the PTCH1 gene, 6 (21.4%) in TP53 and 3 (10.7%) in SMO. CONCLUSIONS: This is the first study reporting NGS-based analysis of BCC in a cohort of young patients. Our results highlight the involvement of the hedgehog and cell cycle regulation pathways in the genesis of BCC in the general population. The inclusion of a larger cohort of young patients is needed to confirm our findings.

PD-L1 expression as a predictive biomarker for immune checkpoint inhibitors: between a dream and a nightmare.

PD-L1 is an important predictive biomarker for treatment by immune checkpoint inhibitors (ICIs). ICIs are now indicated for the treatment of various cancer depending on the level of expression of PD-L1 on tumor cells. PD-L1 testing is done using immunohistochemistry with five different assays approved as companion diagnostic for ICIs. However, these assays have different score reporting methods and do not accurately measure PD-L1 expression. Exosomal PD-L1 testing has recently emerged as an alternative for cell-surface PD-L1 testing however studies are still premature and more extensive knowledge about this new potential biomarker is needed.

Lay abstract Immunotherapy is a new strategy for cancer treatment that aims to reactivate the body's own immune system, originally disabled by the tumor, to fight the malignancy. Immune checkpoint inhibitors are compounds developed for this purpose. However, their efficacy is subject to the abundance of their target, PD-L1, on the surface of cancer cells. Conventional PD-L1 testing through tumor biopsy has multiple technical drawbacks. Another form of PD-L1 secreted by the tumor into the circulation has emerged as a potential target for assessing immune checkpoint inhibitors efficacy but studies are still in their preliminary stages and further testing is required.

[Acrometastasis revealing a pulmonary adenocarcinoma: Report of a case with unusual histopathological findings]. / Acrométastase révélatrice d'un adénocarcinome pulmonaire : à propos d'un cas de présentation histopathologique inhabituelle.

Acrometastasis are rare and can be exceptionally indicative of an occult carcinoma. The prognosis is generally poor. The radiological and immunohistochemical findings can be of great value to determine the primary and to guide treatment. We report a case of a 56-years-old man with acrometastasis at the fourth finger of the left hand revealing a pulmonary adenocarcinoma. Histopathological analysis showed a cribriform adenocarcinoma with an unusual cytoplasmic co-expression of TTF1 and Hepar-1 upon immunohistochemical analysis. There was no nuclear TTF1 immunostaining. Imaging explorations showed a 6-cm mass of the left superior pulmonary lobe. The patient received immunochemotherapy. Upon follow-up, there was evidence of disease progression on chest computed tomography scan.

Epidemiologic and histologic characteristics of CNS lesions: a 20-year experience of a tertiary center in Lebanon.

Aim: Report the epidemiologic and histologic characteristics of CNS lesions in the Lebanese population. Methods: We conducted a retrospective study evaluating 2025 CNS lesions diagnosed between 1998 and 2017 in the pathology laboratory of a Lebanese tertiary center. Results: 52.2% of patients were men with a median age of 50 years. The most frequent symptoms were epilepsy (22.5%), headache (20.6%) and motor impairment (19.9%). 90.7% of tumors were primary. Lung (35.6%) and breast (16.5%) were the most frequent primaries of metastases. 46.2% of primary CNS tumors were glial, predominantly astrocytic (56.4%), and (42.5%) were nonglial, predominantly meningeal tumors (58%). Conclusion: Compared with Western literature, the Lebanese population is characterized by a younger age of onset of brain tumors, a lower rate of meningiomas and a higher rate of gliomas.

Peritoneal Tuberculosis: A Forsaken Yet Misleading Diagnosis.

In women presenting with an abdominal mass and ascites, the first diagnosis to consider is ovarian cancer. However, clinicians should always consider alternative differentials, namely, peritoneal tuberculosis, especially in the presence of respiratory symptoms and with the increasing prevalence of extrapulmonary tuberculosis. Peritoneal tuberculosis can mimic the clinical presentation of ovarian cancer, and on imaging, it can show similar features of peritoneal carcinomatosis and nodules. Tumor markers can also be elevated in the absence of malignancy. We present the case of a 44-year-old woman with abdominal distension and ascites. Imaging with CT scan, MRI, and PET scan were inconclusive, showing peritoneal nodules. Cytology of ascites was negative. Laparoscopy was done showing Koch bacilli followed by pulmonary sampling showing Mycobacterium tuberculosis. The patient was treated with quadritherapy with resolution of symptoms.

Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function.

Membrane type 1-matrix metalloproteinase (MT1-MMP), a membrane-tethered protease, is key for matrix breakdown during cancer invasion and metastasis. Assembly of branched actin networks by the Arp2/3 complex is required for MT1-MMP traffic and formation of matrix-degradative invadopodia. Contrasting with the well-established role of actin filament branching factor cortactin in invadopodia function during cancer cell invasion, the contribution of coronin-family debranching factors to invadopodia-based matrix remodeling is not known. Here, we investigated the contribution of coronin 1C to the invasive potential of breast cancer cells. We report that expression of coronin 1C is elevated in invasive human breast cancers, correlates positively with MT1-MMP expression in relation with increased metastatic risk and is a new independent prognostic factor in breast cancer. We provide evidence that, akin to cortactin, coronin 1C is required for invadopodia formation and matrix degradation by breast cancer cells lines and for 3D collagen invasion by multicellular spheroids. Using intravital imaging of orthotopic human breast tumor xenografts, we find that coronin 1C accumulates in structures forming in association with collagen fibrils in the tumor microenvironment. Moreover, we establish the role of coronin 1C in the regulation of positioning and trafficking of MT1-MMP-positive endolysosomes. These results identify coronin 1C as a novel player of the multi-faceted mechanism responsible for invadopodia formation, MT1-MMP surface exposure and invasiveness in breast cancer cells.

[A peculiar intra-uterine lesion: Inflammatory myofibroblastic tumor (IMT)]. / Une lésion intra-utérine atypique : tumeur myofibroblastique inflammatoire (TMI).

A 25-year-old woman presented with a spontaneous vaginal expulsion of a 4cm well-circumscribed nodule a few weeks after delivery. An inflammatory myofibroblastic tumor diagnosis was made by morphologic, immunohistochemistry and FISH analysis of the nodule.

[A hybrid lesion: Low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF)]. / Une lésion hybride : sarcome fibromyxoïde de bas grade (SFBG) et fibrosarcome épithélioïde sclérosant (FES).

We report the case of a 34-year-old woman presenting a 10cm axillary mass diagnosed as hybrid tumor low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. Microbiopsy for morphological and immunohistochemical analyses was associated with molecular analysis (FISH and PCR) to confirm the diagnosis.

Distribution and Characteristics of Pulmonary Neuroendocrine Tumors: Single Institution Experience in Lebanon.

BACKGROUND: Neuroendocrine tumors represent 20% of primary lung neoplasms in some registries. According to the WHO classification of 2004, reconsidered for 2015, these lung tumors are divided into 4 groups: typical and atypical carcinoid, small cell and large cell neuroendocrine carcinomas. We report in this paper, for the first time in Lebanon, the distribution and the population characteristics of these tumors. MATERIALS AND METHODS: This descriptive retrospective study concerned all the pulmonary neuroendocrine tumors (NET) with their characteristics diagnosed in Hotel Dieu de France in Beirut, Lebanon from 2001 to 2012, with attention to features like age, gender and subgroup. RESULTS: Of 194 patients with pulmonary NET, 12.4% were typical carcinoid tumors, 3.6% atypical carcinoid, 66.5% small cell lung cancer, 7.7% combined small cell carcinomas and 9.8% large cell neuroendocrine tumors. The mean ages of patients were respectively 51.2 years in typical carcinoid, 64 years in atypical carcinoid, 64.2 years in small cell lung cancers, 67.2 in combined small cell lung cancer and 66.9 in large cells neuroendocrine tumors. The M/F sex ratios were respectively 0.3, 1.3, 1.4, 2.7 and 2.2. CONCLUSIONS: The characteristics of lung neuroendocrine tumors in our Lebanese institution are comparable to those reported in the literature.