Summary
Objective
In one third of patients, seizures remain after epilepsy surgery, meaning that improved preoperative evaluation methods are needed to identify the epileptogenic zone. A potential ...framework for such a method is network theory, as it can be applied to noninvasive recordings, even in the absence of epileptiform activity. Our aim was to identify the epileptogenic zone on the basis of hub status of local brain areas in interictal magnetoencephalography (MEG) networks.
Methods
Preoperative eyes‐closed resting‐state MEG recordings were retrospectively analyzed in 22 patients with refractory epilepsy, of whom 14 were seizure‐free 1 year after surgery. Beamformer‐based time series were reconstructed for 90 cortical and subcortical automated anatomic labeling (AAL) regions of interest (ROIs). Broadband functional connectivity was estimated using the phase lag index in artifact‐free epochs without interictal epileptiform abnormalities. A minimum spanning tree was generated to represent the network, and the hub status of each ROI was calculated using betweenness centrality, which indicates the centrality of a node in a network. The correspondence of resection cavity to hub values was evaluated on four levels: resection cavity, lobar, hemisphere, and temporal versus extratemporal areas.
Results
Hubs were localized within the resection cavity in 8 of 14 seizure‐free patients and in zero of 8 patients who were not seizure‐free (57% sensitivity, 100% specificity, 73% accuracy). Hubs were localized in the lobe of resection in 9 of 14 seizure‐free patients and in zero of 8 patients who were not seizure‐free (64% sensitivity, 100% specificity, 77% accuracy). For the other two levels, the true negatives are unknown; hence, only sensitivity could be determined: hubs coincided with both the resection hemisphere and the resection location (temporal versus extratemporal) in 11 of 14 seizure‐free patients (79% sensitivity).
Significance
Identifying hubs noninvasively before surgery is a valuable approach with the potential of indicating the epileptogenic zone in patients without interictal abnormalities.
We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head ...and neck squamous cell cancers (HNSCC).
Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m2/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy.
Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen.
Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.
We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. ...Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity.
Stages III–IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy.
A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027).
IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.
PURPOSE Death from noncancer causes (competing mortality) is an important event in head and neck cancer, but studies identifying predictors of this event are lacking. We sought to identify predictors ...of competing mortality and develop a risk stratification model for competing events. PATIENTS AND METHODS Cohort study of 479 patients with stage III to IV carcinoma of the head and neck diagnosed between August 1993 and November 2004. Patients were treated on consecutive prospective clinical trials involving organ-preserving chemoradiotherapy and surgery. We used multivariable competing risks regression models to analyze factors associated with the cumulative incidence of competing mortality, locoregional and distant failure, and second malignancies as first events. Results Median follow-up was 52 months median for survivors. The 5-year cumulative incidence of competing mortality was 19.6% (95% CI, 15.8 to 23.4). On multivariable analysis, competing mortality was associated with female sex (hazard ratio HR, 1.72; 95% CI, 1.13 to 2.63), increasing age (HR, 1.30; 95% CI, 1.04 to 1.62), increasing Charlson Comorbidity Index (HR, 1.24; 95% CI, 1.05 to 1.47), decreasing body mass index (HR, 0.33; 95% CI, 0.13 to 0.84), and decreasing distance traveled to the treating center (HR, 0.65; 95% CI, 0.44 to 0.98). Patients with zero, one, two, and > or = three risk factors had 5-year competing mortality of 8.9% (95% CI, 3.0% to 14.8%), 12.4% (95% CI, 7.0% to 17.8%), 22.1% (95% CI, 14.5% to 29.7%), and 39.3% (95% CI, 28.6% to 50.1%), respectively. CONCLUSION Competing mortality in advanced head and neck cancer is associated with several demographic and health status characteristics. Analyses of risk factors for competing mortality may be useful in outcomes reporting and designing clinical trials.
We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil FU, ...hydroxyurea HU, radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients.
Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m(2) (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded.
Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m(2), HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/(2), HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months 95% CI, 5.6 to 13.5; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5).
Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m(2) every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.
The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition ...of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation.
Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%.
110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients.
The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation.
Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial ...treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited.
This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz.
We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups.
In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.
Summary Purpose Current standard therapy for nasopharyngeal carcinoma (NPC) is concurrent chemoradiation based on randomized data. However, limited randomized data exist to support the addition of ...induction chemotherapy (ICT). Methods 58 Patients with NPC were treated from 1990 to 2010. All patients received platinum-based ICT. All 58 patients were treated with chemoradiation, 57 in a week-on/week-off (WOWO) fashion. Concurrent chemotherapy included hydroxyurea/5-fluorouracil for all patients. Median radiation dose was 70 Gy. No patient received adjuvant chemotherapy. Results AJCC 2009 stage was II = 13, III = 21, IVa = 13, and IVb = 11. Median follow-up for surviving patients was 66 months. Response to ICT was complete response (CR) 17% and partial response (PR) 64%. The CR rate after chemoradiation was 96%. Five-year actuarial freedom from local failure (FFLF), freedom from distant failure (FFDF), cause-specific survival (CSS), and overall survival (OS) was 98%, 90%, 90%, and 76%, respectively. Analysis of pediatric patients ( n = 9) demonstrated 5-year actuarial FFLF, FFDF, CSS, and OS of 100%, 88%, 80%, and 80%, respectively. Conclusions ICT followed by concurrent chemoradiation demonstrates excellent FFLF, FFDF, CSS, and OS with tolerable toxicity. Induction chemotherapy followed by concurrent chemoradiation for patients with NPC should be explored further in a randomized setting.
Significant progress has been made in providing guidelines and recommendations for assessing the ecological niche, stage of invasion, and probability of invasive alien plant species (IAPS) potential ...distribution in space and time. We followed these recommendations by developing and comparing ordination and species distribution models (SDMs) of two important woody IAPS in Eastern Africa, Prosopis juliflora and Lantana camara, and interpreting the results to inform IAPS management. The two species differ in their invasion history in Eastern Africa; while L. camara was widely introduced there in the 19th century, P. juliflora was only planted at selected locations in the 1970s and 1980s. For the SDMs, machine learning algorithms were used to generate one ensemble model each for P. juliflora and L. camara. For ordination, we used bioclimatic variables, performed a principal component analysis, and compared the native and global niches of the species with the Eastern African niche. Niches varied substantially depending on the percentage of marginal climates excluded from the models. Additional analysis of the local niches surrounding the original P. juliflora plantations showed that they are complementary, which may have led to an overestimation of regional niche filling. While niche expansion was absent or small depending on the percentage of marginal climates excluded, analysis of the stages of invasion suggested that P. juliflora may have started to adapt to novel climatic conditions and that L. camara is approaching a pseudo‐stable equilibrium in Eastern Africa. The SDMs showed that large areas in Eastern Africa that have not yet been invaded by P. juliflora are suitable or will become suitable with climate change. For L. camara, the global SDM predicted a considerably larger suitable area than the Eastern African one, raising uncertainty about the areas to be included in a regional management strategy. Thus, combining ordination and SDMs and integrating a geographic component into ordination is useful in assessing IAPS invasion stages and potential niche shifts, and the results help inform IAPS policy and management. The combined approach can also serve to guide experimental studies addressing divergences between results generated with the different approaches.
PDF
