PI3K inhibitor "alpelisib" alleviates methotrexate induced liver injury in mice and potentiates its cytotoxic effect against MDA-MB-231 triple negative breast cancer cell line.

Hepatotoxicity is the main off-target effect of methotrexate (MTX) limiting its effective clinical use. Besides, MDA-MB231 breast cancer cells show chemoresistance, partly via PI3K/AKT pathway. Therefore, we investigated the ameliorative potentials of the PI3K inhibitor, alpelisib (ALP) on MTX-induced hepatotoxicity (in vivo) and the restraining potentials of ALP on MDA-MB231 chemoresistance to MTX (in vitro). Twenty-eight male BALB/c mice were divided into 4 groups. In treatment groups, mice were administered ALP (2.5 and 5 mg/kg) for 5 days and MTX (20 mg/kg) from day 2 till day 5. The results showed that ALP restored hepatic architecture, reduced immune cell infiltration (F4/80, Ly6G and MPO) and repressed the rise in liver enzymes (AST and ALT) induced by MTX. Additionally, ALP rectified the MTX-induced disruption of cellular oxidant status by boosting antioxidant defense systems (HO-1 and GSH) and repressing lipid peroxidation (MDA and 4-HNE). Finally, ALP curbed MTX-induced hepatocyte apoptosis (NF-κB and BAX) and shifted the cytokine milieu away from inflammation (IL-17, IL-22, IL-6 and IL- 10). The results of the in vitro experiments revealed that ALP alone and in combination with MTX, synergistically, reduced cancer cell viability (MTT assay), migration (wound healing assay) and their capacity to establish colonies (colony formation assay) as compared to MTX alone. RT-PCR revealed the antiproliferative (Bcl-2) and proapoptotic (BAX) potentials of ALP and ALP/MTX combination especially after 24 h. In conclusion, targeting PI3K/AKT pathway is a promising strategy in triple negative breast cancer patients by ameliorating hepatotoxicity and restraining chemoresistance to chemotherapy.

Parotid gland masses: outcomes in the pediatric age group.

BACKGROUND: Childhood parotid neoplasms appear to have different characteristics from adults. This point, in addition to the rarity of these tumors, reflects the challenges faced in diagnosing and treating parotid neoplasms in children. PATIENTS AND METHODS: This retrospective study included all children who presented to the Children's Cancer Hospital Egypt (CCHE, 57357) with parotid masses from January 2008 to December 2020. RESULTS: Twenty-one patients were included. Malignant neoplasms were found in 12 (57.1%) of which mucoepidermoid carcinoma was the most common. Benign neoplasms were found in 6 (28.6%) all of them were pleomorphic adenoma, and non-neoplastic lesions were found in 3 (14.3%). Superficial, deep, or total parotidectomy was performed according to the involved lobes. The facial nerve was sacrificed in three cases because of frank invasion by the tumor. Neck dissection was considered in clinically positive lymph nodes and/or T3/4 masses. Complications occurred in 7 (33.3%) all were of the malignant cases. Adjuvant radiotherapy was restricted to high-risk cases (7 cases). Recurrence occurred in two cases, and one patient died of distant metastasis. Fine needle aspiration cytology (FNAC) showed 88.9% sensitivity and 100% specificity for diagnosing malignant neoplasms. The correlation of radiological and pathological staging was fair (66.74% for overall staging). CONCLUSIONS: Parotidectomy is the backbone treatment for benign and malignant pediatric parotid tumors. Neck nodal dissection should be considered after preoperative FNAC of suspicious nodes. Adjuvant radiotherapy is considered only in high-risk tumors. Preoperative FNAC of parotid masses and clinically suspicious lymph nodes is highly recommended.