Progress in neurological surgery最新文献

Systemic chemotherapy of malignant brain tumors has failed to achieve sufficient drug concentrations at the neoplasm site and frequently results in severe toxicities. Therefore, the local application of several anticancer agents, oncolytic viruses and vectors for gene therapy, immune-modifying preparations, and angiogenesis inhibitors has been investigated widely. Various modes of their administration were introduced, including intratumoral injections, implantation of reservoirs or pumps, convection-enhanced delivery, and use of nanocarriers, thermoreversible gels, microchips, and drug-loaded polymers. Many of these therapeutic approaches have shown promising results in management of high-grade gliomas.

Normal and pathologic cells secrete extracellular vesicles (EV), which are defined as 30-2,000 nm spherical organelles. It has been found that EV mediate various biological functions including cellular remodeling and export of biomolecules, extracellular communication, immune stimulation and suppression, and modulation of the cellular microenvironment. EV secreted by human glioma cells contain a wealth of tumor-specific proteins and nucleic acids that can be isolated from patients with these neoplasms. Thus, EV contribute to the development of biomarkers, and additionally have certain therapeutic potential for possible use in neuro-oncology and neurosurgery.

Malignant gliomas have been historically considered unresponsive to chemotherapy due to their intrinsic resistance to conventional anticancer medications and the role of the blood-brain barrier in preventing access of the cytotoxic agents to the tumor. However, recent studies have demonstrated the efficacy of specific drugs in subsets of patients with high-grade astrocytomas that has revived the enthusiasm for the role of systemic chemotherapy against these neoplasms. Temozolomide, a monofunctional alkylator, was the first chemotherapeutic agent to definitively improve survival in adults with newly diagnosed glioblastoma used in combination with radiation therapy with the most pronounced effect being in a subgroup of tumors with MGMT promoter methylation. Various other cytotoxic drugs and their combinations have been tested in this population with mostly anecdotal reports of benefit. Current efforts are directed towards identifying the subsets of patients most likely to benefit from chemotherapy and to determine the most effective treatment regimens likely to improve outcome. In addition, specific strategies in order to overcome resistance mechanisms to cytotoxic drugs and to disable cellular adaptive pathways are being explored to enhance cell kill and antitumor effects of chemotherapeutic agents.

The effectiveness of chemotherapy or chemoradiotherapy for diffuse astrocytoma (DA) has been largely unknown until recently. However, a randomized controlled study (RTOG 9802) showed that adding of procarbazine, CCNU, and vincristine (PCV) chemotherapy to fractionated radiotherapy (FRT) in patients with "high-risk" WHO grade II gliomas, including DA, has significant positive impact on both progression-free survival and overall survival. Effectiveness of temozolomide (TMZ) in cases of low-grade gliomas was also reported, and a randomized phase III trial comparing FRT alone or in combination with TMZ in cases of unresectable DA (JCOG 1303) is currently ongoing.

For a long time, surgery within the insular lobe, especially in cases of intrinsic tumors, was considered as too dangerous. Even though such interventions are still challenging, resection of insular glioma became more popular during the past decade. First of all, this has happened due to better understanding of the functional anatomy of this complex brain region, combined with an improved knowledge of its connectivity. Furthermore, development of advanced intraoperative techniques, especially functional brain mapping with direct electrical stimulation, resulted in increased safety of procedures. Finally, recent evidence-based data from multiple clinical studies strongly support early maximal safe resection of both low- and high-grade gliomas. These conceptual and methodological advances led neurosurgeons to envision surgical strategy for insular gliomas in a more systematic manner.

Oligodendrogliomas are therapy-responsive tumors, which have better prognosis compared to their astrocytic counterparts. The goal of treatment in such cases is not only prolongation of the patients' survival, but maintaining high neurologic functioning and quality of life. Traditionally, after maximal surgical resection fractionated radiation therapy was given. However, prospective randomized trials comparing irradiation alone and its combination with chemotherapy demonstrated strong impact of the latter on prolongation of overall survival in 1p/19q co-deleted anaplastic and "high-risk" low-grade gliomas. In such cases the median survival of patients is well beyond a decade. The optimal chemotherapy regimen (PCV or temozolomide) remains an active clinical trial question, which may be resolved after completion of the ongoing phase III CODEL study (clinicaltrials.gov identifier NCT00887146). Additional investigations should also refine further the prognostic and predictive role of molecular markers in oligodendroglial tumors.

Patients with brain tumor frequently experience a combination of physical, cognitive, and communication deficits. These may cause severe psycho-emotional stress altering biological and mental conditions and complicating the course of the primary disease, and thus necessiate physical and psychological rehabilitation. While existing data on the effectiveness of such treatment in patients with intracranial glioma are limited and inconsistent, it is possible to suggest that systematic and multidisciplinary rehabilitation plays a very important therapeutic role and leads to improvements in functional independence, mental and emotional state, and quality of life.

Alternating electric fields of intermediate frequencies, also known as Tumor Treating Fields (TTFields or TTF) is a novel anticancer treatment modality that disrupts tumor cell mitosis at the metaphase-anaphase transition, leading to mitotic catastrophe, aberrant mitotic exit, and/or cell death. It is realized through alteration of the cytokinetic cleavage furrow by interference of proteins possessing large dipole moments, like septin heterotrimer complex and α/β-tubulin, and that results in disordered membrane contraction and failed cytokinesis. Aberrant mitotic exit also elicits immunogenic cell death, which may potentiate an immune response against treated tumors. Notably, in patients with recurrent glioblastoma multiforme (GBM) a prospective clinical trial demonstrated comparable overall survival and progression-free survival after TTFields therapy and best physician's choice chemotherapy. Moreover, it was shown that in patients with newly diagnosed GBM initially treated with standard chemoradiotherapy with daily temozolomide (TMZ), adjuvant TTFields combined with TMZ offered better survival than adjuvant TMZ alone. Therefore, TTFields therapy can be appreciated as a standard treatment option in cases of intracranial malignant gliomas, whereas future studies should establish its optimal combination with other existing anticancer modalities, which may offer additional survival benefits for patients.

Given the infiltrative nature of gliomas, controversy has long persisted over the value of their aggressive surgical removal. Nevertheless, in recent decades, the balance of opinion in neurosurgical oncology has shifted from a more nihilistic view that led to many patients' receiving stereotactic biopsy or very limited debulking of lesions for tissue diagnosis only, to more extensive tumor resections which relieve mass effect, lower intracranial pressure, reduce accompanying brain edema, and attenuate dependence on steroids. Achieving a clinically significant cytoreduction makes adjuvant therapy more successful, and ultimately helps to preserve or improve neurological function. Moreover, increased extent of brain tumor removal results in prolongation of progression-free survival and overall survival of patients and improves their quality of life. The beneficial effect of high resection rate may be noted even in selected cases of recurrent neoplasms. However, optimizing an aggressive surgical strategy for intracranial gliomas requires specific skills, availability of advanced intraoperative technological modalities, and the presence of a highly qualified multidisciplinary team of medical professionals for pre-, intra-, and postoperative care of such patients.