The Pre-Interictal Network State in Idiopathic Generalized Epilepsies.

Generalized spike wave discharges (GSWDs) are the typical electroencephalographic findings of Idiopathic Generalized Epilepsies (IGEs). These discharges are either interictal or ictal and recent evidence suggests differences in their pathogenesis. The aim of this study is to investigate, through functional connectivity analysis, the pre-interictal network state in IGEs, which precedes the formation of the interictal GSWDs. A high-density electroencephalogram (HD-EEG) was recorded in twenty-one patients with IGEs, and cortical connectivity was analyzed based on lagged coherence and individual anatomy. Graph theory analysis was used to estimate network features, assessed using the characteristic path length and clustering coefficient. The functional connectivity analysis identified two distinct networks during the pre-interictal state. These networks exhibited reversed connectivity attributes, reflecting synchronized activity at 3-4 Hz (delta2), and desynchronized activity at 8-10.5 Hz (alpha1). The delta2 network exhibited a statistically significant (p < 0.001) decrease in characteristic path length and an increase in the mean clustering coefficient. In contrast, the alpha1 network showed opposite trends in these features. The nodes influencing this state were primarily localized in the default mode network (DMN), dorsal attention network (DAN), visual network (VIS), and thalami. In conclusion, the coupling of two networks defined the pre-interictal state in IGEs. This state might be considered as a favorable condition for the generation of interictal GSWDs.

EEG Network Analysis in Epilepsy with Generalized Tonic-Clonic Seizures Alone.

Many contradictory theories regarding epileptogenesis in idiopathic generalized epilepsy have been proposed. This study aims to define the network that takes part in the formation of the spike-wave discharges in patients with generalized tonic-clonic seizures alone (GTCSa) and elucidate the network characteristics. Furthermore, we intend to define the most influential brain areas and clarify the connectivity pattern among them. The data were collected from 23 patients with GTCSa utilizing low-density electroencephalogram (EEG). The source localization of generalized spike-wave discharges (GSWDs) was conducted using the Standardized low-resolution brain electromagnetic tomography (sLORETA) methodology. Cortical connectivity was calculated utilizing the imaginary part of coherence. The network characteristics were investigated through small-world propensity and the integrated value of influence (IVI). Source localization analysis estimated that most sources of GSWDs were in the superior frontal gyrus and anterior cingulate. Graph theory analysis revealed that epileptic sources created a network that tended to be regularized during generalized spike-wave activity. The IVI analysis concluded that the most influential nodes were the left insular gyrus and the left inferior parietal gyrus at 3 and 4 Hz, respectively. In conclusion, some nodes acted mainly as generators of GSWDs and others as influential ones across the whole network.

Impact of Bevacizumab Versus Erlotinib on Tumor Metrics in Patients With Previously Untreated Advanced Non-small Cell Lung Cancer: A Study by the Hellenic Cooperative Oncology Group.

BACKGROUND: The mechanism of action of bevacizumab and erlotinib is quite different in the treatment of advanced non-small cell lung cancer (NSCLC). This study sought to compare the two targeted therapies in terms of sequential tumor response metrics. PATIENTS AND METHODS: Parameters of radiological tumor response evaluation were assessed at baseline and periodically in 58 patients receiving either bevacizumab plus platinum-based chemotherapy (N=25) or erlotinib (N=33). RESULTS: Bevacizumab-treated patients had lower longest diameter at best response compared to the erlotinib group (p=0.011). The longest diameter, tumor volume and density significantly decreased from baseline to best response for the entire cohort and bevacizumab-treated patients; no difference was found in the erlotinib group. CONCLUSION: Treatment with bevacizumab substantially improved tumor metrics between baseline and each cycle of treatment, as well as between baseline and best response, in patients with advanced NSCLC.

Reduced expression of L-selectin in T-cells correlates with relative lymphocyte increase in patients with RRMS treated with natalizumab - functional implication towards PML risk.

Objectives: Natalizumab (NTZ), a treatment indicated for patients with highly active Relapsing - Remitting Multiple Sclerosis (RRMS), is known to induce increased relative frequency of lymphocytes. Progressive Multifocal Leukoencephalitis (PML) is a rare but serious adverse event related to NTZ. Moreover, reduced L-selectin (CD62L) expression in T-cells in cryopreserved samples of patients with RRMS under NTZ has been proposed as a biomarker of pre-PML state. We explore the association between L-selectin expression in T-cells and hematological parameters in freshly processed samples of patients with RRMS under NTZ.Methods: We studied L-selectin expression in patients with: RRMS under NTZ (n=34), fingolimod (FTY, n=14), interferon-beta (IFNß, n=22), glatiramer acetate (GA, N=17); in 9 patients with secondary progressive (SP) MS and in 6 healthy controls. Twenty-two patients under NTZ and 6 patients under FTY were followed for 18 months. One NTZ-treated patient developed PML during the study.Results: Patients under NTZ exhibited increased relative frequency of lymphocytes (40.02±1.45) compared to patients under first-line treatment (30.57±1.68, p<0.001) and to patients with SPMS (29±1.56, p=0.02), and a lower mean L-selectin expression in (69.39±1.73) compared to patients under first-line treatment (79.1±1.17, p=0.003). A negative correlation between the relative frequency of CD4+CD62L+ T-cells and the absolute lymphocyte counts (Pearson's r=0.367, p=0.033) was observed.Discussion: We hereby provide mechanistic insight in a possible pathway implicated in NTZ-related PML risk. These results further underline the need for thorough validation of L-selectin expression in T-cells as a potential pre-PML biomarker.

Genetic Variations of VEGFA Gene Are Associated With Infiltration of Adjacent Tissues and the Clinical Outcome of Patients With Nasopharyngeal Carcinoma.

BACKGROUND/AIM: The aim of the present study was to investigate the clinical significance of 7 single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor A (VEGFA), endothelin receptor type A (EDNRA), nibrin (NBS1) and Fas cell surface death receptor (FAS) genes in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Genomic DNA was extracted from the peripheral blood specimens of 60 patients. Genotyping of 4 VEGFA polymorphisms, namely VEGFA -1154 G/A (rs1570360), -2578 A/C (rs699947), -1498 C/T (rs833061) and +936 C/T (rs3025039), as well as EDNRA SNP p.His323 (rs5333), NBS1 p.E185Q (rs1805794) and FAS -671 A/G (rs1800682) was performed by using Sanger sequencing. RESULTS: The VEGFA +936 CC genotype was more frequent in tumors with bilateral infiltration of pterygoid plates compared to those with ipsilateral (76.9% vs. 69.6%, p=0.008) and no infiltration of pterygoid plates (76.9% vs. 68.8%, p=0.023). VEGFA -2578, VEGFA -1154 and VEGFA +936 were significantly associated with infiltration to the pterygoid processes (p=0.011, p=0.041 and p=0.032, respectively). EDNRA H323H TT genotype was marginally associated with infiltration to the ipsilateral medial pterygoid muscles (p=0.045). A trend towards longer overall survival was observed for VEGFA -2578 CC as compared to AC (HR=0.24, p=0.060). CONCLUSION: The studied VEGFA SNPs seem to be associated with the local extension of the NPC and maybe with the clinical outcome of this patient group.

Genotyping KRAS and EGFR Mutations in Greek Patients With Non-small-cell Lung Cancer: Incidence, Significance and Implications for Treatment.

BACKGROUND/AIM: KRAS mutations are reported in 20-25% of non-small cell lung cancer (NSCLC) and their prognostic role is unclear. We studied KRAS and EGFR genotyping in Greek NSCLC patients. PATIENTS AND METHODS: KRAS and EGFR genotypes were centrally evaluated in 421 NSCLC patients (diagnosed September 1998 -June 2013) and associated with clinicopathological parameters. Outcome comparisons were performed in 288 patients receiving first line treatment. RESULTS: Most patients were male (78.6%), >60 years old (63.9%), current smokers (51.1%), with adenocarcinoma histology (63.9%). EGFR and KRAS mutations were found in 10.7% and 16.6% of all histologies, respectively, and in 14.9% and 21.9% of adenocarcinomas. At 4.5 years median follow-up, KRAS status was an independent negative prognostic factor for overall survival (OS, p=0.016). KRAS mutations conferred 80% increased risk of death in patients receiving first-line treatment (p=0.002). CONCLUSION: The presence of KRAS mutations is an independent negative prognosticator among Greek NSCLC patients and an independent response predictor to first line treatment.

Gemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study.

BACKGROUND: The prognosis of patients with advanced pancreatic cancer is dismal, and there is a need for novel and effective treatments. OBJECTIVES: Tο determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a novel gemcitabine (G) and temsirolimus (T) combination (phase I) and estimate the 6-month progression-free survival (PFS) in patients treated with the T + G combination (phase II). PATIENTS AND METHODS: Eligible patients with histologically confirmed inoperable or metastatic pancreatic carcinoma (MPC) were entered into the trial. G was given bi-weekly and T weekly in a 4-week cycle. The first dose level was set at G 800 mg/m2 and T 10 mg. G was escalated in increments of 200 mg/m2 and T in increments of 5 mg until DLT was reached, and the recommended dose was used for the phase II part. RESULTS: Thirty patients were enrolled in the phase I component at the pre-planned six dose levels; one bilirubin DLT of grade III occurred at the first dose level. The MTD was established as the approved doses of both drugs. Fifty-five patients were entered into the phase II component. Median relative dose intensities administered in the first cycle were 0.75 for T and 0.99 for G. Grade 3-4 hematological toxicities were recorded in 87.3% of patients. The most common non-hematological adverse events were metabolic disorders (81.8%) followed by gastrointestinal disorders (63.6%). Median PFS was 2.69 months (95% CI 1.74-4.95) and median OS was 4.95 months (95% CI 3.54-6.85), while the 6-month PFS rate was 30.9%. CONCLUSIONS: Combination of G and T is feasible in patients with locally advanced or MPC with manageable side effects, but lacks clinical efficacy. The study was registered in the Australian New Zealand Clinical Trials Registry (ACTRN12611000643976).

AMALTHEA: Prospective, Single-Arm Study of the Hellenic Cooperative Oncology Group (HeCOG) Evaluating Efficacy and Safety of First-Line FOLFIRI + Aflibercept for 6 Months Followed by Aflibercept Maintenance in Patients With Metastatic Colorectal Cancer.

BACKGROUND: The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity. RESULTS: Seventy-three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of < 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P ≤ .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3]). CONCLUSION: The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology.

Longitudinal Evaluation of Swallowing with Videofluoroscopy in Patients with Locally Advanced Head and Neck Cancer After Chemoradiation.

The aim of this study was to investigate the prevalence, severity, and pattern of evolution of swallowing impairments encountered in head and neck cancer (HNC) patients before and after chemoradiation (CRT) with videofluoroscopy of swallowing study (VFSS), using the modified barium swallow impairment profile (MBSImP) protocol and scoring system, and to determine the appropriate time points in which these patients should undergo VFSS post-CRT. A prospective cohort of 69 patients with locally advanced HNC underwent VFSS with the MBSImP protocol at 5 evaluation points: pre-CRT, and 1, 3, 6, and 12 months post-CRT. VFSS was scored with MBSImP, penetration-aspiration scale (PAS), and swallowing performance status (SPS) scale. Statistical analysis was performed only for the 12-month disease-free subset of patients. MBSImP, PAS, and SPS scale scores reached their peak at 3 months post-CRT and improved at 6-12 months, but without returning at pre-treatment levels. Base of tongue retraction, initiation of pharyngeal swallow, epiglottic movement, laryngeal vestibule closure, and laryngeal elevation were the most frequently observed impaired MBSImP components. Epiglottic movement significantly improved (p = 0.009) and laryngeal vestibule closure significantly deteriorated (p = 0.042) over time (Friedman test). Severe swallowing deficits and high aspiration rates are observed in HNC patients pre-CRT, which further deteriorate post-CRT, peak at 3 months, and despite slight improvement, persist over time. We suggest that these patients, regardless of the presence of subjective dysphagia, should undergo VFSS both before and 3 months post-CRT, and also if possible, 1 month post-CRT, in order to facilitate implementation of early swallowing rehabilitation.

A case report of thrombosed varicosities of pubic collateral veins: Ideal treatment strategy and contribution of era imaging technologies in diagnosis.

Collateral circulation is an alternative path occurring in case of venous or artery obstruction. This path may usually develop after primary recanalization. In our case, a 62-year-old woman presented to our Emergency Department complaining about a suprapubic swelling with a cyanotic discoloration of the overlying skin for the past 10 days for which she had been previously prescribed antibiotics. Investigation with ultrasound and contrast-enhanced computed tomography was performed. An imaging study revealed thrombosed pubic varicose collateral veins due to deep vein obstruction and occlusion of the left external iliac vein. The patient was treated with low-molecular-weight heparin, and swelling subsided gradually. Collateral veins of the abdominal wall and over the pubic tubercle are highly predictive of deep venous obstructive disease proximal to the groin level. These collaterals should never be removed, and the patient should be subjected to a diligent laboratory and imaging investigation.

Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe.

Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1-7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.

Lapatinib with whole brain radiotherapy in patients with brain metastases from breast and non-small cell lung cancer: a phase II study of the Hellenic Cooperative Oncology Group (HeCOG).

Small molecules, mainly tyrosine kinase inhibitors, are currently used in various malignancies. Lapatinib, a dual inhibitor of EGFR/HER2 tyrosine kinases, has demonstrated effectiveness in brain metastases from HER2-overexpressing breast cancer. It also appears to sensitize EGFR-expressing cell lines to radiation. To evaluate the efficacy of lapatinib in combination with whole brain radiotherapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC) and breast cancer, as assessed by volumetric analysis by MRI. 81 patients were treated with WBRT (30 Gy in ten fractions) in combination with lapatinib 1250 mg once daily, followed by lapatinib 1500 mg once daily for a total 6 weeks. 21 patients had primary breast cancer and 60 patients NSCLC. Pre- and post-treatment MRI scans in a compact disk for central volumetric assessment were available for 43 patients. 27 patients (62.8%) achieved partial response, 15 patients (34.9%) had stable disease and only one patient (2.3%) had disease progression. Response was not associated to EGFR protein expression. All 81 patients were assessed for safety. The large majority of the adverse events were mild. Eight deaths occurred, four of which were considered related to the study drugs but there were also other contributing factors. Nine cases of serious infections were observed in eight patients, but they were also receiving dexamethasone. Lapatinib in combination with WBRT in patients with brain metastases from breast cancer and NSCLC is a feasible approach that can be further studied in larger clinical trials.

An Exceptional Case of Intraparotid Plexiform Neurofibroma Originating from Autonomic Fibers of the Auriculotemporal Nerve.

Plexiform neurofibromas are benign tumors that tend to occur in patients suffering from neurofibromatosis type 1 (NF-1). This report addresses a rare case where the tumor affected the parotid gland, deriving almost exclusively from the peripheral portion of the facial nerve. A 6-year-old male was referred to us complaining about a gradually enlarging swelling over the right parotid area. Imaging localized the lesion to the superficial lobe of the parotid gland, suggesting a neurofibroma. Cosmetic disfigurement and a functional deficit led us to perform complete surgical resection. Meticulous surgical dissection as well as auriculotemporal nerve origin made complete extirpation possible with almost zero morbidity and ensured alleviation of both aesthetic impairment and pain. This is the first case of an intraparotid PN in a pediatric NF-1 patient, which originated from branches of the auriculotemporal nerve and particularly from fibers of the autonomic nervous system. Radical surgical excision was decided according to established decision-making algorithms.

Multiple variations of the coeliac axis, hepatic and renal vasculature as incidental findings illustrated by MDCTA.

Vascular anatomical variations are not uncommon and may affect any organ's arterial or venous vasculature. The coexistence of variations in different organic systems is less commonly found, but of great clinical significance in a series of clinical conditions like organ transplantation and surgical preoperative planning. Multidetector computed tomography angiography (MDCTA) has emerged as a valuable alternative to the conventional angiography for accurate evaluation of vascular anatomy and pathology. Radiologists should be familiar with each organ's vascular variations and always report them to the clinician, even if they represent an incidental finding. This case report presents a 52-year-old female patient undergoing abdominal MDCTA for characterization of a renal lesion. This examination revealed the presence of three hilar arteries on the left kidney, a main renal vein in combination with an additional renal vein in both sides along with a replaced right hepatic artery originating from the superior mesenteric artery. Moreover, both inferior phrenic arteries were found originating from the coeliac axis. 3D volume rendering technique images were used in the evaluation of vascular anatomy as illustrated in this case report.

Riedel's lobe of the liver: a case report.

Riedel lobe of the liver is a simple anatomical variation, a downward tongue-like projection of the anterior edge of the right lobe of the liver to the right of the gallbladder with its typical case to be rare.We report the case of a 71-year-old woman with typical feature of a nonpalpable Riedel's lobe of the liver, as an incidental finding who was referred for reported hypergammaglobulinemia (22.7% [9%-19%]). Both features were attributed to a chronic inflammation because of an abscess in the right iliopsoas caused by infection due to bilateral hip replacement which underwent revision surgery. This was confirmed by her medical history, the imaging findings combined with elevated C-reactive protein, and by cross-reaction weak positive autoantibodies.Generally, knowledge or suspicion of Riedel's lobe of the liver is important, as it does not always remain clinically latent, as in our case, and it can be complicated by its torsion or hepatic tumors.

Docetaxel and intermittent erlotinib in patients with metastatic Non-Small Cell Lung Cancer; a phase II study from the Hellenic Cooperative Oncology Group.

AIM: To determine the more effective dosing sequence of intermittent erlotinib and docetaxel for treating chemotherapy-naive patients with advanced Non-Small Cell Lung Cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized to receive daily erlotinib for 12 consecutive days prior to docetaxel (Arm A) or after docetaxel (Arm B). Progression-free survival (PFS) was the primary end-point; secondary end-points were overall survival (OS) and objective response rate (ORR). RESULTS: Fifty eligible patients received a total of 226 treatment cycles (median: 3). Median PFS and OS were 3.6 months and 10.5 months, respectively (differences were not statistically significant between the two arms). Neutropenia grade 3 and 4 occurred in 15 patients, while two patients developed grade 3 diarrhea. There were two treatment-related deaths (pulmonary embolism and non-neutropenic sepsis). CONCLUSION: Intermittent administration of erlotinib does not appear to improve the clinical outcome of single-agent docetaxel chemotherapy in unselected patients with NSCLC in the first-line setting.

STAT-Related Profiles Are Associated with Patient Response to Targeted Treatments in Locally Advanced SCCHN.

The anti-epidermal growth factor receptor antibody cetuximab (Erbitux, CTX) is currently used for the treatment of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), as yet with modest effectiveness, prompting for the identification of response predictors to this treatment and for the targeting of additional pathways implicated in this disease. Within this scope, we investigated the effect of SRC/STAT pathway components on LA-SCCHN patient outcome. SRC, STAT1, STAT3, STAT5A, STAT5B, ANXA1, CAV1, IGFBP2, EPHA2, EPHB2, and MSN relative gene expression, as well as Stat protein activation, were assessed on LA-SCCHN tumor tissues from 35 patients treated with combined radiotherapy (RT) and CTX-based regimens. Stat1, Stat3, and Stat5 proteins were usually found activated in neoplastic nuclei (70.4%, 85.7%, and 70.8%, respectively). Activated Stat3 and Stat5 were associated with each other (P = .017) and with a CAV1(high)/MSN(high)/IGFBP2(low) profile. All patients with tumors expressing high STAT5A/EPHA2 experienced a complete response on RT-CTX-based treatments (12/15 complete responders, P < .0001) and a longer progression-free survival (P = .024). Few tumors expressed high ANXA1/CAV1/EPHA2 and low IGFBP2, a putative dasatinib response-related profile, whereas high ANXA1 was associated with shorter overall survival (P = .003). In conclusion, Stat activation is common in LA-SCCHN, where overexpression of STAT5A and EPHA2 may predict for response to RT-CTX treatments. The STAT5A/EPHA2 profile seems of particular interest for validation in larger cohorts and in multiple tumor types because markers for the positive selection of patients to benefit from CTX-containing treatments are currently lacking.