Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload.

Antibody-drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components-an antibody, a linker molecule, and a cytotoxic agent ("payload"), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs' effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review.

Hereditary cancer predisposition syndromes (HCS) become more recognizable as the knowledge about them expands, and genetic testing becomes more affordable. In this review, we discussed the known HCS that predispose to central and peripheral nervous system tumors. Different genetic phenomena were highlighted, and the important cellular biological alterations were summarized. Genetic mosaicism and germline mutations are features of HCS, and recently, they were described in normal population and as modifiers for the genetic landscape of sporadic tumors. Description of the tumors arising in these conditions was augmented by representative cases explaining the main pathological findings. Clinical spectrum of the syndromes and diagnostic criteria were tabled to outline their role in defining these disorders. Interestingly, precision medicine has found its way to help these groups of patients by offering targeted preventive measures. Understanding the signaling pathway alteration of mammalian target of rapamycin (mTOR) in tuberous sclerosis helped introducing mTOR inhibitors as a prophylactic treatment in these patients. More research to define the germline genetic alterations and resulting cellular signaling perturbations is needed for effective risk-reducing interventions beyond prophylactic surgeries.

Learning Curve and Early Results of Interlaminar and Transforaminal Full-Endoscopic Resection of Lumbar Disc Herniations.

Background Full-endoscopic spinal surgery is an evolving technique. A laborious learning phase is inevitable due to the complexity of the orientation and instrumentation. The goal of the present study is to evaluate a single surgeon's learning curve and early outcomes in full-endoscopic resection of lumbar disc herniations. Methods This was a prospective non-controlled single-surgeon cohort study. In 54 patients with 57 herniations, 41 interlaminar and 16 transforaminal resections were performed. Surgery time, severity of adhesive process in the spinal canal, complication rates and clinical outcomes (VAS, ODI, custom questionnaire, recurrence and re-operation rate) were assessed. Results In the interlaminar group, operative time has decreased from 60 ± 20 min in the first 20 operations to 45 ± 14 min in the following 17 (p=0.023). In the transforaminal group, operative time has decreased from 60 ± 16 min in the first 7 operations to 41 ± 12 min in following 9 (p=0.023). Severe adhesive process in spinal canal was associated with duration of symptoms greater than 2 years, longer surgery and higher risk of surgical complications. Four recurrent disc herniations were re-operated using full-endoscopic technique. VAS, ODI and pain medications significantly decreased in both groups and in re-operated patients. Conclusion The plateau of the learning curve and good short-term clinical results of full-endoscopic interlaminar and transforaminal surgery may be achieved after twenty operations, given extensive previous experience in microsurgery. Risk of complications at the learning phase may be decreased by excluding the patients with symptoms lasting over two years.