Athanasios P. Kyritsis

Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature

Commonly used chemotherapeutic agents in oncology/hematology practice, causing toxic peripheral neuropathy, include taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. This review paper intends to put together and discuss the spectrum of chemotherapy-induced peripheral neuropathy (CIPN) characteristics so as to highlight areas of future research to pursue on the topic. Current knowledge shows that the pathogenesis of CIPN still remains elusive, mostly because there are several sites of involvement in the peripheral nervous system. In any case, it is acknowledged that the dorsal root ganglia of the primary sensory neurons are the most common neural targets of CIPN. Both the incidence and severity of CIPN are clinically under- and misreported, and it has been demonstrated that scoring CIPN with common toxicity scales is associated with significant inter-observer variability. Only a proportion of chemotherapy-treated patients develop treatment-emergent and persistent CIPN, and to date it has been impossible to predict high-and low-risk subjects even within groups who receive the same drug regimen. This issue has recently been investigated in the context of pharmacogenetic analyses, but these studies have not implemented a proper methodological approach and their results are inconsistent and not really clinically relevant. As such, a stringent approach has to be implemented to validate that information. Another open issue is that, at present, there is insufficient evidence to support the use of any of the already tested chemoprotective agents to prevent or limit CIPN. The results of comprehensive interventions, including clinical, neurophysiological, and pharmacogenetic approaches, are expected to produce a consistent advantage for both doctors and patients and thus allow the registration and analysis of reliable data on the true characteristics of CIPN, eventually leading to potential preventive and therapeutic interventions.

Management of meningiomas

The primary treatment of meningiomas is surgery which can be curative if the tumor is completely removed. For parasagittal, lateral sphenoid wing and olfactory groove meningiomas, gross-total resection should be the goal. Tuberculum and diaphragma sella meningiomas can be resected through the subfrontal or the pterional approaches. In meningiomas of the sphenoid wing with osseous involvement or involvement of the cavernous sinus subtotal resection can be achieved via several surgical approaches. Similarly, subtotal resection rather than gross-total resection of meningiomas of the petroclival, parasellar, and posterior fossa regions can preserve neurological function. Prior to surgery, embolization may reduce intraoperative bleeding and prevent postoperative complications. Stereotactic radiosurgery can be used as an alternative treatment to surgery either as a first-line treatment or at recurrence. Various conventional radiotherapy techniques can be employed for residual tumor post surgery or at recurrence. Chemotherapy has modest activity and is reserved for selected cases.

Glioma recurrence versus radiation necrosis: accuracy of current imaging modalities

Treatment for brain gliomas is a combined approach of surgery, radiation therapy and chemotherapy. Nevertheless, high-grade gliomas usually recur despite treatment. Ionizing radiation therapy to the central nervous system may cause post-radiation damage. Differentiation between post-irradiation necrosis and recurrent glioma on the basis of clinical signs and symptomatology has not been possible. Computed tomography (CT) and magnetic resonance imaging (MRI) suffer from significant limitations when applied to differentiate recurrent brain tumor from radiation necrosis. We reviewed the contribution of recent MRI techniques, single-photon emission CT and positron emission tomography to discriminate necrosis for glioma recurrence. We concluded that despite the progress being made, further research is needed to establish reliable imaging modalities that distinguish between true tumour progression and treatment-related necrosis.

Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants for the treatment of depression in patients with Parkinsons Disease (PD) but data on their efficacy are controversial.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials to investigate the efficacy and acceptability of SSRIs in the treatment of depression in PD.ResultsTen studies were included. In the comparison between SSRIs and Placebo (n = 6 studies), the combined risk ratio (random effects) was 1.08 (95% confidence interval: 0.77 - 1.55, p = 0.67). In the comparison between SSRIs and Tricyclic Antidepressants (TCAs) (n = 3 studies) the combined risk ratio was 0.75 (0.39 - 1.42, p = 0.37). An acceptability analysis showed that SSRIs were generally well tolerated.ConclusionsThese results suggest that there is insufficient evidence to reject the null hypothesis of no differences in efficacy between SSRIs and placebo in the treatment of depression in PD. Due to the limited number of studies and the small sample sizes a type II error (false negative) cannot be excluded. The comparison between SSRIs and TCAs is based on only three studies and further trials with more pragmatic design are needed.

Effects of irradiation on tumor cell survival, invasion and angiogenesis.

Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.

Evaluation of meningioma aggressiveness by 99mTc-Tetrofosmin SPECT

OBJECTIVES Although meningiomas usually have a benign clinical course, atypical and malignant types of this brain tumor are associated with high recurrence rates and poor outcome; thus, DNA ploidy and S-phase -- as determined by DNA flow cytometry -- are useful indicators of their biological behavior. Brain single-photon emission computed tomography (SPECT) has been suggested as a potentially useful modality for the metabolic assessment of various brain tumors. This study evaluated whether (99m)Tc-Tetrofosmin ((99m)Tc-TF) uptake correlates with meningioma proliferative activity, as assessed by flow cytometry analysis. PATIENTS AND METHODS Ten consecutive patients (3 males, 7 females, mean age 64.6 years) with a diagnosis of a symptomatic intracranial meningioma, planned to undergo surgery, were studied. Brain SPECT by (99m)Tc-TF was performed within a week prior to surgical excision and flow cytometric analysis was performed in the excised tissue. Tumoral radiotracer accumulation was first assessed visually. Semiquantitative image analysis was also performed, by calculating the lesion-to-normal (L/N) uptake ratio. RESULTS Benign meningiomas were diagnosed in 8/10 cases, the remaining 2/10 patients had anaplastic lesions. DNA aneuploidy was found in 2 lesions, the remaining tumors were diploid. There was a significant correlation between tracer uptake and the percentage of the cell fraction on S-phase (r=0.733, P=0.05). There was also a positive correlation between tracer uptake and the level of aneuploidy and tumor grade. CONCLUSION These results imply that (99m)Tc-TF brain SPECT may have the ability to discriminate benign meningiomas from malignant meningiomas pre-operatively, the tracer uptake being a likely indicator of their proliferative activity.

Body Composition in Ambulatory Patients With Multiple Sclerosis

The aim of this study was to compare between ambulatory patients with multiple sclerosis (MS) and control subjects, bone mineral density (BMD), and body composition, that is, percent of bone minerals (M%), fat (F%), and remaining substances (L%). Total body composition and BMD were measured by dual-energy X-ray absorptiometry in 68 patients with definite MS and Expanded Disability Status Scale (EDSS) score ≤ 6.5 (41 females and 27 males) and 114 control individuals (72 females and 42 males). The amount of F%, L%, M%, and BMD in the whole body, arms, and trunk was not statistically different between MS patients (males and females) and controls, except in the lower extremities of female patients where there was increased F% and reduced L% compared with controls. There were no correlations between F%, L%, M%, and BMD at any anatomic region with EDSS or the cumulative corticosteroid dose. The reduced L% in the lower extremities of female patients suggests a possible increased subsequent risk of osteoporosis in the legs. Brief steroid courses administered during disease exacerbations in ambulatory MS patients did not result in obvious adverse consequences.

Genetic and molecular alterations in meningiomas

Meningiomas are the most common benign intracranial tumors in adults arising from the dura matter. The etiology of meningiomas is mostly unknown, although several risk factors have been described, such as ionizing radiation, head injury, hormones and genetic factors. According to WHO they are classified into 3 grades, grade I, grade II and grade III. Meningiomas express various hormonal and growth factor receptors, such as progesterone, estrogen, somatostatin, transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) receptors, which may be related to their biological behavior and response to treatment. Chromosomal abnormalities linked to meningiomas involve chromosomes 22, 1p, 9p, 10p, 11, 14q, 15, 17, and 18q. In addition, genes that may be involved in the formation of meningiomas include NF2, DAL-1, p14 (ARF), p53, MDM2, Rb, p16 and c-myc. It is likely that detailed molecular information will aid in establishing a molecular grading of these tumors and predict response to treatment and survival.

Evaluation of glioma proliferation by 99mTc-Tetrofosmin

The proliferation potential of gliomas is an indicator of their aggressiveness with significant implications in patient management and prognosis, but its assessment requires tissue sampling.1 We evaluated the relationship between glioma proliferation (as expressed by the Ki-67 index) and the uptake of the tumor-seeking radiotracer technetium-99m Tetrofosmin (99mTc-TF). Fourteen patients with a space-occupying lesion suspicious for glioma on structural brain imaging were prospectively enrolled. Scintitomographic (SPECT) imaging was performed and within a week the lesion was removed surgically; Ki-67 was assessed in the excised specimens by MIB-1 immunostaining. Three patients were excluded from the study because their lesions were proven metastatic. In the 11 patients eligible for analysis (7 males, 4 females; mean age 49.5 ± 7.5 years), the diagnosis was glioblastoma multiforme (6 cases), anaplastic astrocytoma (1), anaplastic oligodendroglioma (2), low-grade oligodendroglioma (1), and low-grade astrocytoma (1). We found a significant positive linear correlation between 99mTc-TF uptake and Ki-67 expression (r = 0.95, p = 0.001 [Spearman rank analysis]; Fig. 1 – 3). No significant correlation was observed between tracer uptake and tumor grade (r = 0.27, p = 0.420). The preliminary results of this pilot study, although deriving from a limited patient sample, propose that this tracer may hold a potential role as a noninvasive marker of glioma proliferative activity. Figure 1 T1-weighted, gadolinium-enchanced MRI (A) in a low-grade oligodendroglioma of the left frontal lobe. Faint 99mTc-Tetrofosmin uptake (B, arrow) correlated with Ki-67 approx. 2% (C; MIB-1 ×100). Figure 3 Correlation between 99mTc-Tetrofosmin uptake (expressed as lesion-to-normal [L/N] uptake ratio) and cellular proliferation rate (MIB-1) in the studied gliomas.

Frequent abnormalities of the immune system in gliomas and correlation with the WHO grading system of malignancy

AIM To investigate the cellular and humoral immunity status of gliomas, and their association with the WHO grading system. MATERIAL AND METHODS We have conducted a case-control study of 49 patients with gliomas and 30 healthy controls. We used ELISA assays, radial immunodiffusion, indirect immunofluorescence, latex test and flow cytometry assays to estimate preoperative in serum the immunological profile. RESULTS Patients with glioma had significantly reduced amounts of IL2 (p=0.000), TNF-a (p=0.033), IgG (p=0.011), IgA (p=0.027),C4 (p=0.026) ,CD3+ (p=0.001), CD4+ (p=0.000), CD8+ (p=0.002), ratio CD4/CD8 (p=0.000), CD19+ (p=0.04) and elevated IL10 (p=0.05) compared with healthy controls. No statistically significant differences were observed concerning viral agents, total NK cells, IgM, IgE, IL16, granzyme-b, RF, ANA, ENA, anti-dsDNA and anti-cardiolipin antibodies. A higher WHO grade, after controlling for age and gender, was associated with decreased number of CD3+ (p=0.011), CD4+ (p=0.015), CD8+ (p=0.048) and ratio CD4/CD8 (p=0.027), as well as with decreased IL2 (p=0.018), C4 (p=0.02), and IgG (p=0.05). IL2 and CD4+ counts were significant predictors of grade. CONCLUSIONS A shift from Th1 to Th2, a CD3+ and CD19+ lymphocytopenia, a diminished fraction CD4/CD8 and a reduced amount of immunoglobulins and complement were observed in the patients with gliomas. A higher WHO grade of the tumor was associated with greater impairments of immunity. Since defects of both humoral and cellular immunity were equally observed and significant predictors of grade were assessed, a preoperative evaluation of the immune system of patients with gliomas is being proposed.