Identification of protein-protein interaction bridges for multiple sclerosis.

MOTIVATION: Identifying and prioritizing disease-related proteins is an important scientific problem to develop proper treatments. Network science has become an important discipline to prioritize such proteins. Multiple sclerosis, an autoimmune disease for which there is still no cure, is characterized by a damaging process called demyelination. Demyelination is the destruction of myelin, a structure facilitating fast transmission of neuron impulses, and oligodendrocytes, the cells producing myelin, by immune cells. Identifying the proteins that have special features on the network formed by the proteins of oligodendrocyte and immune cells can reveal useful information about the disease. RESULTS: We investigated the most significant protein pairs that we define as bridges among the proteins providing the interaction between the two cells in demyelination, in the networks formed by the oligodendrocyte and each type of two immune cells (i.e. macrophage and T-cell) using network analysis techniques and integer programming. The reason, we investigated these specialized hubs was that a problem related to these proteins might impose a bigger damage in the system. We showed that 61%-100% of the proteins our model detected, depending on parameterization, have already been associated with multiple sclerosis. We further observed the mRNA expression levels of several proteins we prioritized significantly decreased in human peripheral blood mononuclear cells of multiple sclerosis patients. We therefore present a model, BriFin, which can be used for analyzing processes where interactions of two cell types play an important role. AVAILABILITY AND IMPLEMENTATION: BriFin is available at https://github.com/BilkentCompGen/brifin.

Radiotherapy for benign diseases in Turkey: a patterns of care survey of the Turkish Society for Radiation Oncology (TROD 05-002).

PURPOSE: We aimed to investigate the patterns of radiotherapy (RT) care in cases of benign diseases in Turkey. METHODS: A questionnaire survey was sent to all radiation oncology (RO) departments in Turkey. The number of patients treated for benign disease between 2015 and 2020 was requested. A list of benign conditions was given, and information on the number of patients per disease, single and total doses prescribed, weekly fractions, radiation type, energy, and device was requested. RESULTS: Of the 138 RO departments, 29 (21%) responded. The data received concerned 15 (52%) university, 10 (34%) public, and four (14%) private hospitals. A total of 130,846 patients were treated with RT in these departments. Of these patients, 6346 (4.85%) were treated for benign conditions. The most common benign diseases treated with RT were meningioma (35%), plantar fasciitis (19%), schwannoma (16%), arteriovenous malformation (11%), and pituitary adenoma (7%). Most centers performed RT for paraganglioma, heterotopic ossification, vertebral hemangioma, and Graves' ophthalmopathy, but none treated arthrosis. Wide variations were observed across the departments. Radiosurgery for intracranial pathologies was performed intensively in four centers. By contrast, RT for plantar fasciitis was predominantly treated in five centers, one of which had more than 1000 patients. CONCLUSION: The ratio of patients who underwent RT for benign diseases in Turkey among all patients who underwent RT was 4.85%. The common pattern of RT in 72% of patients was radiosurgery for intracranial benign diseases, followed by low-dose RT for plantar fasciitis in 19%.

Hypofractionated stereotactic re-irradiation for progressive glioblastoma: twelve years' experience of a single center.

PURPOSE: We aimed to evaluate the prognostic factors and the role of stereotactic radiotherapy (SRT) as a re-irradiation technique in the management of progressive glioblastoma. METHODS: The records of 77 previously irradiated glioblastoma patients who progressed and received second course hypofractionated SRT (1-5 fractions) between 2009 and 2022 in our department were evaluated retrospectively. Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM, Armonk, NY, USA) was utilized for all statistical analyses. RESULTS: The median time to progression from the end of initial radiotherapy was 14 months (range, 6-68 months). The most common SRT schedule was 30 Gy (range, 18-50 Gy) in 5 fractions (range, 1-5 fractions). The median follow-up after SRT was 9 months (range, 3-80 months). One-year overall (OS) and progression-free survival (PFS) rates after SRT were 46% and 35%, respectively. Re-irradiation dose and the presence of pseudoprogression were both significant independent positive prognostic factors for both OS (p = 0.009 and p = 0.04, respectively) and PFS (p = 0.008 and p = 0.04, respectively). For PFS, progression-free interval > 14 months was also a prognostic factor (p = 0.04). The treatment was well tolerated without significant acute toxicity. During follow-up, radiation necrosis was observed in 17 patients (22%), and 14 (82%) of them were asymptomatic. CONCLUSION: Hypofractionated SRT is an effective treatment approach for patients with progressive glioblastoma. Younger patients who progressed later than 14 months, received higher SRT doses, and experienced pseudoprogression following SRT had improved survival rates.

External Beam Radiotherapy in the Management of Uveal Melanoma.

OPINION STATEMENT: Uveal melanoma is the most common primary ocular tumor in adults. With the evidence demonstrating that episcleral plaque brachytherapy (EPB) has similar survival rates as enucleation in the Collaborative Ocular Melanoma Study (COMS), eye-sparing treatments have come to the fore today. External radiotherapy techniques (proton beam radiotherapy and stereotactic radiosurgery/fractionated stereotactic radiosurgery) are an important treatment option for globe-sparing treatments. There are no prospective randomized trials comparing these techniques; however, retrospective series, meta-analyses, and reviews indicate that these EPB and external radiotherapy techniques are equal. With this review, we aimed to examine the external radiotherapy techniques used in the treatment of uveal melanoma in detail with reference to the current literature.

Intracerebral de novo arterio-venous malformations as a side effect of bevacizumab.

INTRODUCTION: Bevacizumab is a monoclonal antibody for the vascular endothelial growth factor receptor and is utilized in the treatment of various tumors. Gastrointestinal perforation/fistula, heart failure, hemorrhage, hypertension, proteinuria/nephrotic syndrome, thromboembolism, posterior reversible encephalopathy syndrome, and necrotizing fasciitis are serious side effects of bevacizumab. Bevacizumab associated de novo brain arterio-venous malformation formation has not been documented in the literature. CASE REPORT: Here, we presented a 35-year-old female patient with recurrent high-grade glial tumor who developed multiple supra- and infratentorial de novo arterio-venous malformations after receiving the last dose of bevacizumab. MANAGEMENT & OUTCOME: Intervention options for the adverse effect were limited. In fact, there was no chance of intervention because the patient died for another reason. DISCUSSION: Based on this experience, it can be hypothesized that bevacizumab may induce de novo arterio-venous malformations in the brain as a result of arterial and venous thrombotic effects. Additional studies should be done to clarify the causal relationship between bevacizumab and arterio-venous malformations in primary brain tumors.

Role of sarcopenia on survival and treatment-related toxicity in head and neck cancer: a narrative review of current evidence and future perspectives.

PURPOSE: The purpose of this article is to provide an up-to-date summary of sarcopenia and its clinical implications for patients with head and neck cancer (HNC). METHODS: We conducted a literature review of recent studies investigating the prevalence of sarcopenia in HNC patients, its detection using MRI or CT scans, and its association with clinical outcomes such as disease-free and overall survival time, radiotherapy-related side effects, cisplatin toxicity, and surgical complications. RESULTS: Sarcopenia, characterized by low skeletal muscle mass (SMM), is a prevalent condition in HNC patients and can be effectively detected using routine MRI or CT scans. Low SMM in HNC patients is associated with increased risks of shorter disease-free and overall survival times, as well as radiotherapy-related side effects such as mucositis, dysphagia, and xerostomia. In addition, cisplatin toxicity is more severe in HNC patients with low SMM, leading to higher dose-limiting toxicity and treatment interruptions. Low SMM may also predict higher risks of surgical complications in head and neck surgery. Identifying sarcopenic patients can aid physicians in better riskstratifying HNC patients for therapeutic or nutritional interventions to improve clinical outcomes. CONCLUSIONS: Sarcopenia is a significant concern for HNC patients and can impact their clinical outcomes. Routine MRI or CT scans can effectively detect low SMM in HNC patients. Identifying sarcopenic patients can aid physicians in better risk-stratifying HNC patients for therapeutic or nutritional interventions to improve clinical outcomes. Further research is needed to explore the potential of interventions to mitigate the negative effects of sarcopenia in HNC patients.

The association between pan-immune-inflammation value and survival in head and neck squamous cell carcinoma.

PURPOSE: A significant portion of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) relapse despite multimodality treatment denoting the need for biomarkers. The pan-immune-inflammation value (PIV) is a recently developed blood count-based prognostic biomarker. We evaluated the relationship between PIV and survival in locally advanced HNSCC patients treated with chemoradiotherapy (CRT). METHODS: A total of 199 patients who underwent CRT at Hacettepe University Oncology Hospital were included. The relationship between clinical and laboratory parameters with overall survival (OS) and disease-free survival (DFS) was analyzed by multivariate analyses. RESULTS: The median age was 59 years and 90.5% of the patients were male. 66.8% of the patients had laryngeal primaries, and 78.9% had T3-T4 disease. 84.9% of the patients received CRT with cisplatin. The optimal PIV threshold value was calculated as 404 in ROC analyses. This PIV value had 75.8% sensitivity and 70.4% specificity for OS prediction (AUC 0.781; 95% CI 0.715-0.846; p < 0.001). In multivariate analyses, high PIV levels (≤ 404 vs. > 404, HR 2.862; 95% CI 1.553-5.276; p = 0.001), higher NLR (≤ 2.5 vs. > 2.5, HR 1.827; 95% CI 1.017-3.281; p = 0.044) levels and ECOG performance score of 2 (HR 2.267; 95% CI 1.385-3.711; p = 0.001) were associated with shorter OS. These factors were associated with shorter DFS also (HR for PIV 2.485, 95% CI 1.383-4.467, p = 0.002). CONCLUSIONS: We observed shorter OS and DFS in locally advanced HNSCC patients with high PIV levels. If prospective studies support our findings, the PIV score could be a prognostic biomarker in HNSCC.

The Effect of Video-Based Education on Anxiety of Patients Receiving Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy.

Patients receiving stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) may have an anxiety due to unknown aspects of the treatment. We aimed to reduce patient anxiety by using video-based education. Forty patients were divided into 2 groups, with one-to-one information session (n = 20) and one-to-one information session plus video-based education (n = 20). The patients completed the State-Trait Anxiety Inventory (STAI) and visual facial anxiety scale before and after information sessions and after treatment. The setup time and disruptions during treatment sessions were recorded for patients receiving treatment with Novalis® and Cyberknife®, respectively. The patient characteristics and STAI scores before education were similar between groups. The anxiety level was significantly lower in group 1 after treatment (median 38, interquartile range (IQR) 27-45) compared to before (median 43, IQR 36-47) (p = 0.003) and after information sessions (median 42, IQR 36-47) (p = 0.004); however, any difference was not observed in anxiety levels between before and after information sessions (p = 0.317). The anxiety level was significantly lower in group 2 after video-based education (median 25, IQR 22-33) and after treatment (median 25, IQR 20-30) compared to before video-based education (median 35, IQR 31-42) (p < 0.001 for both), while there was no significant difference in anxiety levels between after video-based education and after the treatment (p = 0.407). The interruptions during treatment were observed in 9 (60%) patients in group 1 and 6 (40%) patients in group 2 (p = 0.038). Video-based educations significantly reduce patient anxiety before SRS/SBRT and increase their compliance with the treatment.

Do grape and black mulberry molasses have an effect on oral mucositis and quality of life in patients with head and neck cancer?

OBJECTIVE: We aimed to investigate the effect of black mulberry and grape molasses on the prevention and treatment of oral mucositis and quality of life (QoL) in patients with head and neck cancer (HNC). METHODS: Patients treated for HNC between 2010 and 2018 in our department were divided into three groups (group 1 = control (n = 14), group 2 = grape molasses (n = 40), and group 3 = black mulberry molasses (n = 40)). Oral mucositis, pain scoring, and weight loss were evaluated weekly. The European Organization for Research and Treatment of Cancer (EORTC) General QoL Questionnaire (QLQ-C30) and EORTC Head and Neck Cancer QoL Module (QLQ-HN35) were used to evaluate QoL. RESULTS: The mean body weight, scores of oral mucositis, and pain were similar among the groups throughout the treatment. Both groups 2 and 3 were associated with improved outcomes for swallowing, opening mouth, and weight loss in the EORTC HN35, and these parameters were not significantly different between groups 2 and 3. Global health score was higher in group 3 at the 6th week of RT compared to that of group 2. Both groups 2 and 3 had improved scores for role functioning, emotional and social functioning, fatigue, appetite loss, and pain throughout the treatment compared to group 1. CONCLUSIONS: Both grape and black mulberry molasses improved the QoL in HNC patients. No significant difference between black mulberry and grape molasses was found with regard to the healing of oral mucositis.

Investigation of the Effect of Radiotherapy Dose on Chewing and Swallowing Structures in Head and Neck Cancer Patients Treated with Concomitant Chemoradiotherapy.

Intensity-modulated radiotherapy (IMRT) is a treatment method that is used in the treatment of head and neck cancers. Impairment of chewing and swallowing functions in the early and late periods of radiotherapy is frequent. Therefore, revealing the dose-effect relationship is important. The main purpose of this study is to investigate the dose-effect relationship between chewing and swallowing structures objectively via a standardized videofluoroscopy protocol. The study included 35 participants treated with chemo-IMRT. A videofluoroscopic swallowing study (VFSS) was performed before IMRT, and 3 and 6 months after IMRT. VFSS results were scored according to the Modified Barium Swallow Impairment Profile (MBSImP) and the Penetration-Aspiration Scale (PAS). Maximum interincisor mouth opening, body mass index (BMI), and Functional Oral Intake Scale levels were determined in these cases. The quality of life of participants was evaluated. There was a significant increase in PAS and MBSImP scores and a significant decrease in BMI scores of the patients after treatment. Xerotomy and sticky saliva complaints increased after treatment. The dose to the mastication muscles (> 40 Gy) and the temporomandibular joint (> 46 Gy) were found to be associated with a decrease in BMI; the dose to the superior pharyngeal constructor muscle (> 58 Gy) was found to be associated with pharyngeal stripping wave. The presence of aspiration was associated with the inferior pharyngeal constructor muscle, glottic larynx, supraglottic larynx, and upper esophageal sphincter. Important findings to emerge from this study include detected toxic dose limits. These findings may guide physicians to minimize the side effects of IMRT.

Stereotactic body radiotherapy optimization to reduce the risk of carotid blowout syndrome using normal tissue complication probability objectives.

PURPOSE: To determine the possibility of further improving clinical stereotactic body radiotherapy (SBRT) plans using normal tissue complication probability (NTCP) objectives in order to minimize the risk for carotid blowout syndrome (CBOS). METHODS: 10 patients with inoperable locally recurrent head and neck cancer, who underwent SBRT using CyberKnife were analyzed. For each patient, three treatment plans were examined: (1) cone-based without delineation of the ipsilateral internal carotid (clinical plan used to treat the patients); (2) cone-based with the carotid retrospectively delineated and spared; and (3) Iris-based with carotid sparing. The dose-volume histograms of the target and primary organs at risk were calculated. The three sets of plans were compared based on dosimetric and TCP/NTCP (tumor control and normal tissue complication probabilities) metrics. For the NTCP values of carotid, the relative seriality model was used with the following parameters: D50 = 40 Gy, γ = 0.75, and s = 1.0. RESULTS: Across the 10 patient plans, the average TCP did not significantly change when the plans were re-optimized to spare the carotid. The estimated risk of CBOS was significantly decreased in the re-optimized plans, by 14.9% ± 7.4% for the cone-based plans and 17.7% ± 7.1% for the iris-based plans (p = 0.002 for both). The iris-based plans had significant (p = 0.02) reduced CBOS risk and delivery time (20.1% ± 7.4% time reduction, p = 0.002) compared to the cone-based plans. CONCLUSION: A significant improvement in the quality of the clinical plans could be achieved through the delineation of the internal carotids and the use of more modern treatment delivery modalities. In this way, for the same target coverage, a significant reduction in the risk of CBOS could be achieved. The range of risk reduction varied depending on the proximity of carotid artery to the target.

A hesitated approach: primary radiotherapy for keloids-a case series.

PURPOSE: To assess the efficacy and toxicity of hypofractionated radiotherapy (RT) alone in treatment-resistant symptomatic keloids. METHODS: Six patients with a total of 13 inoperable large keloid lesions and no response to previous treatments were admitted to our department between 2017 and 2019. All patients were examined for detailed wound localization, size, contour, and color assessment, and for objective and subjective symptoms. Response to treatment was graded as "complete remission" in case of full symptomatic relief and >75% decrease in lesion size, as "partial remission" in case of partial symptomatic relief and 25-75% decrease in lesion size, and as "stable disease" in case of no symptomatic relief or <25% decrease in lesion size. Patients were followed up monthly for the first 3 months and every 3 months thereafter by physical examination. RESULTS: A total dose of 37.5 Gy external RT in five fractions was prescribed by 6­MeV electrons in 4 patients and 6­MV photons in 2 patients. Complete response was obtained in all patients at the 6­month control. All patients were satisfied with cosmetic results at their last control. Grade 2 dermatitis developed in all patients during the second week of RT but resolved completely in all after 6 months following the end of RT. CONCLUSION: In keloids that are unresponsive to standard treatment, hypofractionated RT using a total dose of 37.5 Gy in five fractions is feasible.

Radiotherapy-induced alterations in vitreous humor: A new potential critical structure.

Vitreous humor (VH) is not considered as a critical structure in the radiotherapy planning process. In the present study, an experimental animal model was performed to examine the effects of radiotherapy on VH. The right eyes of twelve New Zealand rabbits were irradiated to 60 Gy in 3 fractions in accordance with the scheme used in the treatment of uveal melanoma in our clinic, and contralateral (left) eyes were considered as control. Weekly ophthalmologic examination was performed after irradiation, for three months. At the end of the third month, enucleation and vitreous collection were conducted. The vitreous samples were subjected to metabolomic analyses, ELISA analyses, viscosity measurements, and electron microscopic examination. In control and experimental vitreous samples, 275 different metabolites were identified, and 34 were found to differ significantly between groups. In multivariate analyzes, a clear distinction was observed between control and irradiated vitreous samples. Pathway analysis revealed that nine pathways were affected, and these pathways were mainly related to amino acid metabolism. A significant decrease was observed in the expressions of type II, V, and XI collagens in protein level in the ELISA. There was a non-significant decrease in type IX collagen and viscosity. Electron microscopic examination revealed disrupted collagen fibrillar ultra-structure and dispersed collagen fragments in the experimental vitreous. An intact vitreous is essential for a healthy eye. In this study, we observed that radiation causes changes in the vitreous that may have long-term consequences.

The evolution of bone marrow signal changes at the skull base in nasopharyngeal carcinoma patients treated with radiation therapy.

BACKGROUND: Clival infiltration is frequently seen in nasopharyngeal carcinoma (NPC) and the resultant bone marrow signal changes (BMSC) can persist even after complete tumor response to the radiation therapy (RT). The differentiation of those residual BMSC from recurrent/persistent disease may be challenging. We performed serial analysis of the clival BMSC after RT, to define an expected temporal evolution of those signal changes during the follow-up. MATERIALS AND METHODS: Serial MRI studies of 50 NPC patients (with or without initial clival infiltration) who had undergone RT were retrospectively examined. Abnormal clival BMSC and contrast enhancement (CE) were evaluated on each follow-up scan. Duration of BMSC/CE was correlated with the degree of baseline clival involvement (BCID), RT dose, and primary mass volume (PMV). RESULTS: Clival BMSC persisted without any evidence of recurrence, for a mean of 66.5 (max. 137) months (with accompanying CE for up to 125 months) in 26 patients with clival infiltration at diagnosis. Duration of BMSC and CE showed statistical correlations with PMW (p < 0.05), but not with RT dose or BCID. The rate of recurrence in clivus was 14%. New clival lesions that occurred within the first 12 months after RT (in six patients) did not develop recurrence suggesting radiation osteitis (12%). CONCLUSION: After RT, residual clival medullary signal change/enhancement is seen in most NPC patients and can persist even years without recurrence.

A Novel Missense LIG4 Mutation in a Patient With a Phenotype Mimicking Behçet's Disease.

DNA ligase IV (LIG4) syndrome is a rare autosomal recessive disorder, manifesting with variable immune deficiency, growth failure, predisposition to malignancy, and cellular sensitivity to ionizing radiation. The facial features are subtle and variable, as well. Herein, we described an 18-year-old boy, the first child of consanguineous parents who presented with Behçet's disease (BD)-like phenotype, developmental delay, and dysembryoplastic neuroepithelial tumor (DNET). Whole-exome sequencing revealed a homozygous p.Arg871His (c.2612G > A) mutation in LIG4. To date, 35 cases have been reported with LIG4 syndrome. Peripheral blood mononuclear cells of the patient displayed notable sensitivity to ionizing radiation. Flow cytometric annexin V-propidium iodide (PI) and eFluor670 proliferation assays showed accelerated radiation-induced apoptosis and diminished proliferation, respectively. To our knowledge, this is the first case presenting with a BD-like phenotype. This case provides further evidence that rare monogenic defects could be the underlying cause of atypical presentations of some well-described disorders. Moreover, this clinical report further expands the phenotypical spectrum of LIG4 deficiency.

The role of ABO blood groups in glial neoplasms.

INTRODUCTION: There are numerous diseases that are claimed to have a correlation with AB0 blood groups. Analysis on distribution of blood groups in primary brain tumors and clinical value has revealed conflicting results. The purpose of this study is to evaluate the association between AB0 blood groups and glial neoplasms (GN) and their effects on prognosis. METHODS: A retrospective cross sectional study was performed. Patients admitted between 2000-2014 and had a diagnosis of GN were evaluated. Blood groups of patients were analyzed and compared with the National blood group data obtained from Turkish Red Crescent Society. The prognostic significance of AB0 blood groups was analyzed within glioblastoma multiforme (GBM), anaplastic astrocytoma and grade 1-2 astrocytoma. RESULTS: 759 patients with a diagnosis of glial neoplasia were evaluated. Distribution of AB0 blood groups in the different grades of Glial neoplasia was similar with the national blood group frequencies. There was not a statistically significant difference between grades of glial neoplasia and healthy control patients. Median overall survival (mOS) of GBM patients were 12.9 months in A (95% CI, 10.2-15.5), 13.4 months in B (95% CI, 7.3-19.5), 5.7 months in AB (95% CI, 0.8-10.6), 12.8 months in 0 blood groups (95% CI, 8.6-16.8) (p = .46). mOS of anaplastic astrocytoma patients were 24.4 months in A (95% CI, 15.2-33.6), 47.2 months in B (95% CI, 9.9-84.5), 37.8 months in AB (95% CI, 10.2-80.3), 29.2 months in 0 blood groups (95% CI, 21.2-33.4) (p = .96). mOS in grade 1-2 were 84.2, 90.6 and 144 months for A, AB and 0 blood groups respectively. CONCLUSIONS: In our patient group, when compared with general population, there seems to be no association between frequencies of AB0 blood groups and Glial Neoplasia. In addition, the AB0 blood groups have no prognostic impact on glial neoplasms.

High-grade glioma in children and adolescents: a single-center experience.

PURPOSE: The aim of this study was to report the outcome in children with high-grade astrocytoma outside the brain stem and spinal cord that were treated at a single center. MATERIALS AND METHODS: The study included 26 patients with anaplastic astrocytoma and 37 patients with glioblastoma; all patients were aged ≤18 years. At initial diagnosis, 18 of the patients with glioblastoma received only temozolomide (TMZ), 14 received other chemotherapies, and 5 did not receive any chemotherapy. Among the patients with anaplastic astrocytoma, 9 received TMZ, 9 received other chemotherapy regimens, and 8 patients did not receive any chemotherapy. The median radiotherapy dose in all patients was 60 Gy. RESULTS: Median age of the patients was 12.5 years. Median overall survival was 20 months and mean progression-free survival was 4.7-11.3 months (median: 8 months) in all patients. Patients with a Karnofsky performance score (KPS) ≥70 had median overall survival of 32 months, versus 7 months in those with a KPS < 70. Patients aged <15 years had median survival of 38 months, versus 16 months in those aged 15-18 years. Patients with anaplastic astrocytoma that received TMZ, other chemotherapy regimens, and no chemotherapy had median survival of 21 months, 132 months, and 11 months, respectively. Patients with glioblastoma that received TMZ, other chemotherapy regimens, and no chemotherapy had median survival of 32 months, 12 months, and 8 months, respectively. CONCLUSION: In the present study, patients with anaplastic astrocytoma treated with chemotherapy protocols other than TMZ had the longest OS; however, in the glioblastoma group, OS was 32 months in those treated with standard TMZ and 12 months in those treated with other protocols (P = 0.493). Although TMZ is less toxic than PCV, it was not shown to be superior.