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Neuropathology Of Neuro-Ophthalmic Disorders
Published in Vivek Lal, A Clinical Approach to Neuro-Ophthalmic Disorders, 2023
Retinoblastoma is a common childhood intraocular tumor which accounts for 3% of all childhood cancers.31 It is commonly diagnosed at an average age of 18 months but generally before the age of 5. The highest disease burden is reported from Asia and Africa, being the most populous countries with higher birth rates.32 Retinoblastoma is caused by mutational inactivation of both alleles of the RB1 gene which maps to chromosome 13q14. The gene encodes retinoblastoma protein which acts as a tumor suppressor.33 The retinoblastoma may occur as a bilateral tumor due to germline mutations in RB1 gene, and 15% of unilateral cases have a heritable mutation. The most common manifestation in retinoblastoma is leukocoria followed by strabismus, painful blind eye and visual loss.32 In Southeast Asian countries, most retinoblastoma patients present late and at advanced stage of the disease. Fortunately, with current advancement in treatment protocols, the eye can be salvaged with chemotherapy particularly when the tumor is intraocular. Following chemotherapy, if there is a residual tumor, the eye is enucleated. On subsequent evaluation, when spread to extraocular compartment or to the optic nerve is demonstrated, the patient needs adjuvant radiotherapy. The pathology specimens should be evaluated in detail since all histology information is important for further treatment.32
Ocular Tumors
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Vishal Raval, Alexander Melendez, Hansell Soto, Alléxya Affonso, Rubens Belfort Neto, Arun D. Singh
A mother’s use of insect or garden sprays during pregnancy, diagnostic X-ray with direct fetal exposure, and father’s employment as a welder, machinist, or related metal worker are associated with increased risk of sporadic retinoblastoma.20,21,23–25 In a case–control study in central Mexico, lower intake of vegetables and fruits during pregnancy was associated with increased risk of retinoblastoma in the child.26 A study in the Netherlands estimated that children born after in vitro fertilization had a five- to sevenfold increased risk of retinoblastoma.27 Some viral proteins bind to and inactivate the retinoblastoma protein that is coded by RB1, and thus, it is hypothesized that viruses may contribute to the development of retinoblastoma. One such viral protein is the human papillomavirus (HPV) protein, E7. In support of the viral hypothesis, DNA sequences from oncogenic HPV subtypes were detected in approximately one-third of retinoblastoma tumor samples studied in central Mexico.28
Germ Cell Tumors of the Central Nervous System
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Matthew J. Murray, Ute Bartels, James C. Nicholson
CNS teratoma may occur in isolation or as part of a mixed tumor, either combined with germinoma or non-germinomatous malignant components, or rarely with non-GCT malignant components. The main challenge in the management of teratoma is to achieve a complete surgical resection, as there is very little evidence to support the use of adjuvant chemotherapy or radiotherapy in their management. When they are combined with germinoma, there will inevitably be a residual tumor on imaging following chemotherapy and/or radiotherapy for the malignant component. Similarly, in a mixed malignant tumor treated on an NGGCT strategy with a substantial teratoma component, there will also inevitably be a residual tumor following chemotherapy, which is likely to warrant surgical removal. In some cases, “growing teratoma syndrome”99 follows chemotherapy for NGGCT (Figure 16.7), where the tumor enlarges on chemotherapy, but in the face of normalization of tumor markers, which were initially raised at diagnosis. Such cases warrant surgery prior to continuation of treatment (Figure 16.7). Where resection is not deemed feasible and the tumor continues to grow, in the absence of treatable malignant components as indicated by markers, the use of cell cycle inhibitors shows early promise; teratomas expressing the retinoblastoma protein may respond to inhibition of cyclin-dependent kinases (CDK) 4 and 6.100–102
Predictive biomarkers for systemic therapy of hepatocellular carcinoma
Published in Expert Review of Molecular Diagnostics, 2021
Nurbubu T. Moldogazieva, Sergey P. Zavadskiy, Susanna S. Sologova, Innokenty M. Mokhosoev, Alexander A. Terentiev
Cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6)-retinoblastoma protein (Rb) pathway has a key role in cancer initiation and progression. CDK4/6 are serine/threonine kinases, which phosphorylate and inactivate tumor suppressor Rb that is able to suppress E2F transcription factors [117]. In turn, Rb phosphorylation/inactivation leads to CDK4/6-mediated G1/S cell cycle progression followed by DNA replication and cell proliferation associated with tumor growth and poor prognosis in cancer. Rb inhibits PKB/Akt and blocks the access of Akt to mTORC2, and this sensitizes cancer cells to chemotherapeutic drugs, while Rb phosphorylation causes the release of mTORC2 suppression and PKB/Akt activation leading to drug resistance [118]. Thus, CDK4/6 inhibitor-based cancer therapy depends on the presence of Rb within cancer cells and is based on G1 cell cycle arrest due to the inhibition of Rb phosphorylation.
Prognostic models to help predict patient responses to intravesical immunotherapy
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ekaterina Laukhtina, David D’Andrea, Benjamin Pradere, Dmitry Enikeev, Mohammad Abufaraj, Shahrokh F. Shariat
Retinoblastoma protein (pRB), a tumor suppressor protein, which plays an essential role in the regulation of cell cycle and apoptosis, has also been extensively investigated as a candidate biomarker. Bladder tumors lacking pRB expression show a more aggressive behavior [39]. In a retrospective series of 27 patients treated with TURB and adjuvant intravesical instillations of BCG for T1G3 NMIBC, altered pRB expression was associated with RFS (p = 0.037) and PFS (p = 0.018) [40]. In a subsequent study conducted by the same research group, authors added the expression of p53 to the prognostic model and found a statistically significant improvement regarding the association with PFS [41]. However, limitations inherent to the study design do not allow clinical applicability of these biomarker, alone or in combination.
Budget impact of including ribociclib in combination with letrozole on US payer formulary: first-line treatment of post-menopausal women with HR+/HER2− advanced or metastatic breast cancer
Published in Current Medical Research and Opinion, 2018
Rohit Mistry, Gaurav Suri, Kate Young, Robert Hettle, Jessica R. May, Diana Brixner, Gary Oderda, Joseph Biskupiak, Derek Tang, Devarshi Bhattacharyya, Subrata Bhattacharyya, Dinesh Mishra, Anand A. Dalal
Significant recent additions to the breast cancer treatment armamentarium are the orally bioavailable cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors ribociclib (KISQALI®, Novartis), palbociclib (IBRANCE®, Pfizer Inc.), and abemaciclib (VERSENIO®, Eli Lilly)1. The antitumor activity of these agents results from the inhibition of the retinoblastoma protein, which regulates cell proliferation2. The MONALEESA-2 clinical trial has demonstrated that the combination of ribociclib with letrozole is a safe alternative to letrozole monotherapy as a first-line treatment for postmenopausal women with HR+/HER2− advanced breast cancer, achieving substantially longer progression-free survival (PFS)3. Specifically, in the MONALEESA-2 study, the combination of ribociclib and letrozole increased PFS by 7.1 months compared with letrozole monotherapy, corresponding to a 44% reduction in the rate of disease progression or death (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.43–0.72, p < .0001)3.