Inter-rater agreement on identification of electrographic seizures and periodic discharges in ICU EEG recordings.

OBJECTIVE: This study investigated inter-rater agreement (IRA) among EEG experts for the identification of electrographic seizures and periodic discharges (PDs) in continuous ICU EEG recordings. METHODS: Eight board-certified EEG experts independently identified seizures and PDs in thirty 1-h EEG segments which were selected from ICU EEG recordings collected from three medical centers. IRA was compared between seizure and PD identifications, as well as among rater groups that have passed an ICU EEG Certification Test, developed by the Critical Care EEG Monitoring Research Consortium (CCEMRC). RESULTS: Both kappa and event-based IRA statistics showed higher mean values in identification of seizures compared to PDs (k=0.58 vs. 0.38; p<0.001). The group of rater pairs who had both passed the ICU EEG Certification Test had a significantly higher mean IRA in comparison to rater pairs in which neither had passed the test. CONCLUSIONS: IRA among experts is significantly higher for identification of electrographic seizures compared to PDs. Additional instruction, such as the training module and certification test developed by the CCEMRC, could enhance this IRA. SIGNIFICANCE: This study demonstrates more disagreement in the labeling of PDs in comparison to seizures. This may be improved by education about standard EEG nomenclature.

Adherence to outpatient epilepsy quality indicators at a tertiary epilepsy center.

INTRODUCTION: Quality indicators for the treatment of people with epilepsy were published in 2010. This is the first report of adherence to all measures in routine care of people with epilepsy at a level 4 comprehensive epilepsy center in the US. METHODS: Two hundred patients with epilepsy were randomly selected from the clinics of our comprehensive epilepsy center, and all visits during 2011 were abstracted for documentation of adherence to the eight quality indicators. Alternative measures were constructed to evaluate failure of adherence. Detailed descriptions of all equations are provided. RESULTS: Objective measures (EEG, imaging) showed higher adherence than counseling measures (safety). Initial visits showed higher adherence. Variations in the interpretation of the quality measure result in different adherence values. Advanced practice providers and physicians had different adherence patterns. No patient-specific patterns of adherence were seen. DISCUSSION: This is the first report of adherence to all the epilepsy quality indicators for a sample of patients during routine care in a level 4 epilepsy center in the US. Overall adherence was similar to that previously reported on similar measures. Precise definitions of adherence equations are essential for accurate measurement. Complex measures result in lower adherence. Counseling measures showed low adherence, possibly highlighting a difference between practice and documentation. Adherence to the measures as written does not guarantee high quality care. CONCLUSION: The current quality indicators have value in the process of improving quality of care. Future approaches may be refined to eliminate complex measures and incorporate features linked to outcomes.

Display of consistent ictal networks in refractory mesial temporal lobe epilepsy.

OBJECTIVE: Exploration of emergent ictal networks was performed in homogeneous subjects with refractory medial temporal lobe epilepsy. METHODS: Maximal Synchrony Index (SI) values were calculated for all electrode pairs for each second during 25 seizures and displayed as connectivity animations. Consistent temporal patterns of SI value and spatial connectivity were observed across seizures and subjects, and used to define a sequence of network stages. RESULTS: Highest SI values were found in electrodes within the area of surgical resection. Analysis of these electrodes by network stage demonstrated lateral temporal cortex dominance at seizure initiation, giving way to hippocampal synchrony during the major portion of the seizure, with lateral temporal regions re-emerging as the seizure terminated. SI values also corresponded to behavioral severity of seizures, and lower SI values were associated with post-surgical seizure freedom. CONCLUSION: SI based methods of network characterization consistently display the intrinsic MTLE ictal network and may be sensitive to clinical features. SIGNIFICANCE: Consistency of EEG-derived network patterns is an important step as network features are applied towards improvement of clinical management. These data confirm consistency of network patterns within and across subjects and support the potential for these methods to distinguish relevant clinical variables.

Acute changes in maternal thyroid hormone induce rapid and transient changes in gene expression in fetal rat brain.

Despite clinical evidence that thyroid hormone is essential for brain development before birth, effects of thyroid hormone on the fetal brain have been largely unexplored. One mechanism of thyroid hormone action is regulation of gene expression, because thyroid hormone receptors (TRs) are ligand-activated transcription factors. We used differential display to identify genes affected by acute T(4) administration to the dam before the onset of fetal thyroid function. Eight of the 11 genes that we identified were selectively expressed in brain areas known to contain TRs, indicating that these genes were directly regulated by thyroid hormone. Using in situ hybridization, we confirmed that the cortical expression of both neuroendocrine-specific protein (NSP) and Oct-1 was affected by changes in maternal thyroid status. Additionally, we demonstrated that both NSP and Oct-1 were expressed in the adult brain and that their responsiveness to thyroid hormone was retained. These data are the first to identify thyroid hormone-responsive genes in the fetal brain.

Covariation bias in panic-prone individuals.

Covariation estimates between fear-relevant (FR; emergency situations) or fear-irrelevant (FI; mushrooms and nudes) stimuli and an aversive outcome (electrical shock) were examined in 10 high-fear (panic-prone) and 10 low-fear respondents. When the relation between slide category and outcome was random (illusory correlation), only high-fear participants markedly overestimated the contingency between FR slides and shocks. However, when there was a high contingency of shocks following FR stimuli (83%) and a low contingency of shocks following FI stimuli (17%), the group difference vanished. Reversal of contingencies back to random induced a covariation bias for FR slides in high- and low-fear respondents. Results indicate that panic-prone respondents show a covariation bias for FR stimuli and that the experience of a high contingency between FR slides and aversive outcomes may foster such a covariation bias even in low-fear respondents.

[Management by the family physician of patients following cancer surgery]. / Die hausärztliche Betreuung von Patienten nach einem krebschirurgischen Eingriff.

There exist schemas and detailed programs for the follow-up of cancer patients after surgery. Since many of these guidelines in the literature are contradictory and often not up to date, a few rules are given for the benefit of the family doctor responsible for those patients. Over-diagnosis should be avoided since--for some categories of patients--this can lead to unnecessary anxiety without improving the prognosis.

A randomized comparison of doxifluridine and fluorouracil in colorectal carcinoma.

In a randomized study 52 patients with advanced colorectal cancer and measurable lesions were treated with doxifluridine 4000 mg/m2 or fluorouracil 450 mg/m2 i.v. on 5 consecutive days over 3 weeks. None had prior fluoropyrimidines except two who received adjuvant fluorouracil. Partial responses with a duration ranging from 259 to 406 days were observed in five patients treated with doxifluridine and two patients treated with fluorouracil. Toxic reactions were evaluated in 88 doxifluridine courses and 105 fluorouracil courses. The most frequent adverse effects were neurotoxicity (48% of patients) and mucositis (43%) for doxifluridine, leukopenia (48%) and nausea/emesis (37%) for fluorouracil. Mucositis, diarrhea, nausea, emesis and skin reactions were observed in both treatment groups. Fluorouracil produced neurotoxic effects in 26% of patients. Reversible cardiac dysfunctions were observed in four patients treated with doxifluridine, expressed by ectopic ventricular beats (2) precordial pains (1) and ventricular fibrillation (1). This latter toxicity justified the premature interruption of the study. Doxifluridine is an active agent in colorectal cancer. Compared to fluorouracil it produces, when used i.v., a lower myelosuppression and a greater incidence of neurological and cardiac toxicity.

Etoposide, cisplatin and doxorubicin in patients with small cell lung cancer: tumor response and long term survival.

One hundred and fourteen patients with small cell lung cancer received a combination of etoposide 80 mg/m2 IV days 1,2,3,15,16,17, cisplatin 20 mg/m2 IV days 1,2,3 and doxorubicin 40 mg/m2 IV day 1, repeated every 4 weeks. The observation time from the initiation of treatment is longer than 4 years for all patients. An 85% response rate (38% complete response) was obtained after 1-4 cycles in 105 evaluable patients (96 without prior antitumour treatments). The response rate was not influenced by initial performance status and minimally by disease extension, whereas the same prognostic factors correlated significantly with complete responses. For limited disease and WHO performance 0 all responses were complete. For extensive disease and performance 3 no complete response was obtained. Various chemotherapy regimens with or without radiotherapy were used during the maintenance phase. Forty five per cent of first relapses were in the lung or mediastinum and 18% in the nervous system (20% without and 7% with prophylactic cranial irradiation). The median survival was 13.4 months for limited and 8.5 months for extensive disease, and correlated with performance and response. Only 2 patients survived free of disease after 4.8 and 5.5 years. We conclude that the induction treatment as used here produces a high rate of partial and complete responses but a low rate of long survivors.

A clinical trial of aminoglutethimide in advanced postmenopausal breast carcinoma: low response in patients previously treated with medroxyprogesterone.

In an attempt to define the influence of prior hormonal treatments upon aminoglutethimide activity in advanced cancer of the breast, 42 heavily pretreated postmenopausal patients received aminoglutethimide, 4 X 250 mg daily, with hydrocortisone or cortisone. Twenty-six received high doses of medroxyprogesterone before entering this study. There was no significant difference in patients' characteristics with or without medroxyprogesterone pretreatment. A comparison of patients with and without prior medroxyprogesterone shows a significant difference in the response rate to aminoglutethimide-hydrocortisone (4 vs 32%, P = 0.02). In patients pretreated with tamoxifen but not with medroxyprogesterone the response rate to aminoglutethimide was 36%. These results suggest that aminoglutethimide has a low activity in breast cancer patients previously exposed to medroxyprogesterone, an agent with glucocorticoid-like activity inducing adrenal suppression.

[Is the use of adriamycin (doxorubicin) limited by its cardiotoxicity?]. / Wird der Einsatz von Adriamycin (Doxorubicin) durch die Kardiotoxizität limitiert?

Adriamycin (doxorubicin), one of the most active cytotoxic antineoplastic agents, can cause heart failure. This side effect is dose-dependent, the frequency of heart failure being 3% at a cumulative Adriamycin dose of 400 mg/m2 and 18% at 700 mg/m2. It is assumed that Adriamycin, or other anthracycline derivatives, are still active when the cardiotoxic level is reached. In this retrospective study of 171 patients with various metastatic malignant tumors, the total dose of Adriamycin given to the patients and the reasons for withholding the treatment have been analyzed. Overall, among the 171 patients treated by Adriamycin-containing combination chemotherapy, 54 objective remissions (31%) were observed. Remissions were more frequent in untreated patients (52%) than in previously treated patients (20%). In 36 of 54 patients the disease progressed before the cumulative cardiotoxic level was reached. Adriamycin could be discontinued in only 18 patients still in remission. 8 of 171 patients received more than 450 mg/m2 Adriamycin without cardiotoxic side effects being observed. Among the 171 patients, cardiotoxicity probably related to anthracyclines developed in 5 cases (3%), in all cases at a level below 450 mg/m2. These results suggest that in most cases Adriamycin becomes inactive before the dose-limiting cumulative cardiotoxic level is reached.

Drug selection for perioperative chemotherapy.

A wide variety of tumor types can be successfully grown with the clonogenic assay. However, few tumor types perform adequately for routine drug sensitivity testing, e.g., ovarian carcinoma and malignant melanoma. Because of insufficient in vitro growth, the cloning system cannot help substantially in indicating active substances for epidemiologically frequent tumors that usually have a poor prognosis, such as colorectal cancers and non-small cell lung and breast cancers. The degree of in vitro cell kill that would correspond to complete eradication of micrometastases is unknown. The identification of individual patients sensitive to a given antineoplastic agent becomes more difficult as the tumor becomes more refractory to treatment. At this moment, the clonogenic assay appears most promising for trials dealing with the treatment of ovarian adenocarcinoma.

Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer.

In a randomized trial, 210 postmenopausal women with advanced measurable breast cancer were allocated to two different schedules of medroxyprogesterone acetate (MPA). In the induction phase they received either 1,000 mg intramuscular (IM) MPA (high dose) daily or 500 mg IM MPA (low dose) twice weekly for four weeks. The maintenance treatment consisted of 500 mg MPA IM once weekly for all patients. In total, 184 patients were considered evaluable. The response rate was significantly higher (p = 0.004) for patients receiving high-dose MPA (30 [33%] of 91) as compared to the women receiving the low-dose regimen (14 [15%] of 93) and was consistent across all prognostic subgroups. These prognostic subgroups included soft-tissue and osseous metastases, two metastatic sites, patients greater than 60 years, disease-free interval greater than 60 months, no prior chemotherapy, patients with a response to the last hormonal treatment before MPA, unknown estrogen receptors, and positive progestin receptors. The two different schedules of MPA did not influence the time to progression and the survival. Toxicity was similar in both regimens. These results confirm that a higher response rate can be achieved with a more intensive MPA schedule. This treatment may represent an ideal second-line choice in the endocrine therapy of advanced breast cancer; however, its role as a first-line treatment remains to be defined.

Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer.

We report the results of a randomized trial carried out by the Swiss Group for Clinical Cancer Research (SAKK) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment (oophorectomy for pre- and tamoxifen for postmenopausal women) were randomly allocated to three different regimens of combination chemotherapy. The therapeutic results registered with the two more intensive combinations (LMP/FVP and LMFP/ADM) were similar with regard to response rates, time to progression and survival. The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate (32%, P less than 0.001) and a shorter survival (P = 0.03) than the results observed in patients treated with the two other regimens. This difference was particularly pronounced, at least regarding survival, in the following subgroups: postmenopausal women, patients with a poor performance status, dominant visceral lesions, two sites of disease and a disease-free interval longer than 12 months. Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy. This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment. This is, to our knowledge, the first report of a randomized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens.