Third order spectral analysis robust to mixing artifacts for mapping cross-frequency interactions in EEG/MEG.

We present a novel approach to the third order spectral analysis, commonly called bispectral analysis, of electroencephalographic (EEG) and magnetoencephalographic (MEG) data for studying cross-frequency functional brain connectivity. The main obstacle in estimating functional connectivity from EEG and MEG measurements lies in the signals being a largely unknown mixture of the activities of the underlying brain sources. This often constitutes a severe confounder and heavily affects the detection of brain source interactions. To overcome this problem, we previously developed metrics based on the properties of the imaginary part of coherency. Here, we generalize these properties from the linear to the nonlinear case. Specifically, we propose a metric based on an antisymmetric combination of cross-bispectra, which we demonstrate to be robust to mixing artifacts. Moreover, our metric provides complex-valued quantities that give the opportunity to study phase relationships between brain sources. The effectiveness of the method is first demonstrated on simulated EEG data. The proposed approach shows a reduced sensitivity to mixing artifacts when compared with a traditional bispectral metric. It also exhibits a better performance in extracting phase relationships between sources than the imaginary part of the cross-spectrum for delayed interactions. The method is then applied to real EEG data recorded during resting state. A cross-frequency interaction is observed between brain sources at 10Hz and 20Hz, i.e., for alpha and beta rhythms. This interaction is then projected from signal to source level by using a fit-based procedure. This approach highlights a 10-20Hz dominant interaction localized in an occipito-parieto-central network.

Frequency specific interactions of MEG resting state activity within and across brain networks as revealed by the multivariate interaction measure.

Resting state networks (RSNs) are sets of brain regions exhibiting temporally coherent activity fluctuations in the absence of imposed task structure. RSNs have been extensively studied with fMRI in the infra-slow frequency range (nominally <10(-1)Hz). The topography of fMRI RSNs reflects stationary temporal correlation over minutes. However, neuronal communication occurs on a much faster time scale, at frequencies nominally in the range of 10(0)-10(2)Hz. We examined phase-shifted interactions in the delta (2-3.5 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (13-30 Hz) frequency bands of resting-state source space MEG signals. These analyses were conducted between nodes of the dorsal attention network (DAN), one of the most robust RSNs, and between the DAN and other networks. Phase shifted interactions were mapped by the multivariate interaction measure (MIM), a measure of true interaction constructed from the maximization of imaginary coherency in the virtual channels comprised of voxel signals in source space. Non-zero-phase interactions occurred between homologous left and right hemisphere regions of the DAN in the delta and alpha frequency bands. Even stronger non-zero-phase interactions were detected between networks. Visual regions bilaterally showed phase-shifted interactions in the alpha band with regions of the DAN. Bilateral somatomotor regions interacted with DAN nodes in the beta band. These results demonstrate the existence of consistent, frequency specific phase-shifted interactions on a millisecond time scale between cortical regions within RSN as well as across RSNs.

Adding dynamics to the Human Connectome Project with MEG.

The Human Connectome Project (HCP) seeks to map the structural and functional connections between network elements in the human brain. Magnetoencephalography (MEG) provides a temporally rich source of information on brain network dynamics and represents one source of functional connectivity data to be provided by the HCP. High quality MEG data will be collected from 50 twin pairs both in the resting state and during performance of motor, working memory and language tasks. These data will be available to the general community. Additionally, using the cortical parcellation scheme common to all imaging modalities, the HCP will provide processing pipelines for calculating connection matrices as a function of time and frequency. Together with structural and functional data generated using magnetic resonance imaging methods, these data represent a unique opportunity to investigate brain network connectivity in a large cohort of normal adult human subjects. The analysis pipeline software and the dynamic connectivity matrices that it generates will all be made freely available to the research community.

Multimodal integration of fMRI and EEG data for high spatial and temporal resolution analysis of brain networks.

Two major non-invasive brain mapping techniques, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have complementary advantages with regard to their spatial and temporal resolution. We propose an approach based on the integration of EEG and fMRI, enabling the EEG temporal dynamics of information processing to be characterized within spatially well-defined fMRI large-scale networks. First, the fMRI data are decomposed into networks by means of spatial independent component analysis (sICA), and those associated with intrinsic activity and/or responding to task performance are selected using information from the related time-courses. Next, the EEG data over all sensors are averaged with respect to event timing, thus calculating event-related potentials (ERPs). The ERPs are subjected to temporal ICA (tICA), and the resulting components are localized with the weighted minimum norm (WMNLS) algorithm using the task-related fMRI networks as priors. Finally, the temporal contribution of each ERP component in the areas belonging to the fMRI large-scale networks is estimated. The proposed approach has been evaluated on visual target detection data. Our results confirm that two different components, commonly observed in EEG when presenting novel and salient stimuli, respectively, are related to the neuronal activation in large-scale networks, operating at different latencies and associated with different functional processes.

Open magnetic and electric graphic analysis.

The OMEGA software provides an analysis platform for user-independent, fast, and reproducible multimodal data analysis in one single software environment. Synergetic interactions pursued between the two functional imaging techniques fMRI and MEG use the morphological MRI recording as a basis for a common coordinate frame. In this way, direct interchange, comparison, and integration among the results of the different modalities have become feasible. The fMRI data analysis provides information about the localization of functional activity with low temporal resolution, whereas the MEG recording complements the corresponding time evolution with a high temporal resolution. The implementation of OMEGA allows the analyst to receive comprehensive MEG/fMRI results in a matter of minutes after the measurements have been completed. With OMEGA, the clinical researcher gets comprehensive information in a quick and standardized approach about the sites and the time course of neurological activation, which is useful for clinical applications and diagnostics.

nm23 and p53 expression.

Breast cancer is a common malignancy and the modalities and the aggressiveness of treatment strategies are variable and depend on information regarding the biological characteristics and behavior of an individual tumor. Therefore, to improve overall survival it is important to identify and select lymph node negative patients at high risk who would benefit from adjuvant therapy. Besides prognostic factors such as lymph node status, hormone receptor status and histopathologic parameters, nm23 antimetastatic gene and the p53 protein were studied in 32 breast cancer patients. Positive staining for nm23 was inversely associated with lymph node involvement in 82.4% of the cases. Most of the non-diploid lesions (70.8%) showed a high protein expression. Positive immunostaining for p53 was present in 28.1% of the cases and was strongly correlated with prognostic indicators such as necrosis and histologic grading. Tumor grade, DNA ploidy and lymph node metastasis were not significantly correlated with p53 protein expression. In this study, all the prognostic indicators studied, satisfactorily explain the important characteristics of the biologic behaviour of breast cancer, but the detection of lymph node metastasis is still the most accurate prognostic factor utilized for a predictive role in disease recurrence.

99mTc-MIBI prone scintimammography in patients with high and intermediate risk mammography.

Mammographic lesions can be classified into categories of high (HR), intermediate (IR) and low risk of breast cancer. We have performed 99mTc MIBI scintimammography on 85 patients with high or intermediate risk lesions in order to verify its ability to diagnose cancer before biopsy. The scintimammography was performed in prone lateral view; all the patients were submitted to excisional biopsy. HR lesions showed 86% of cancers and scintigraphic accuracy of 0.81. The accuracy of scintimammography was 0.97 in lesions larger than 1 cm. IR lesions showed 47% of cancer with scintigraphic accuracy of 0.95. The scintigraphic sensitivity was 0.97 lesions larger than and 0.50 in lesion smaller than 1 cm, whereas the specificity was always about 90%. Our results suggest that scintimammography can substantially decrease the need of biopsy for breast cancer diagnosis.

Docetaxel and epirubicin plus G-CSF as mobilizing treatment to support high-dose chemotherapy in breast cancer.

BACKGROUND: In order to combine an active regimen with a simultaneous efficient mobilization of peripheral blood precursor cells (PBPC), we explored the combination of Docetaxel 75 mg/m2 and Epirubicin 120 mg/m2 with G-CSF 5 mcg/Kg/day s.c. to mobilize PBPC in breast cancer patients to support high-dose chemotherapy (HDC). PATIENTS AND METHODS: Forty patients were enrolled: 27 high risk and 13 metastatic. The entire procedure, including chemotherapy and PBPC collection, was on an outpatient basis. RESULTS: The median day of starting apheresis was day +10 (range 10-12) and the average value of circulating CD34+ cells at peak was 175/microliter (range 33-403). The median yield of CD34+ cells per apheresis was 8.76 x 10(6)/Kg (range 1.83-27.87). None of the patients developed side effects which required hospitalization. All patients enrolled successively received HDC as consolidation treatment. High risk patients received one and metastatic patients two HDC with PBPC reinfusion. All patients obtained a complete engraftment. No significant differences between high-risk and metastatic patients were observed. CONCLUSIONS: Our study suggests that the combination of Docetaxel, Epirubicin, and G-CSF is feasible, safe and efficient outpatient mobilizing treatment for patients with breast cancer receiving HDC.

Detection of breast cancer cells in the bone marrow or peripheral blood: methods and prognostic significance.

Tumor cells can reach every anatomic district, organ and tissue through the peripheral blood circulation. Tumor cell shedding is considered an early event in the multi-phase process of metastasis, and the possibility of detecting tumor cells in the bloodstream and/or bone marrow before clinical evidence of distant metastases needs to be explored. The use of new sophisticated diagnostic and investigative techniques has boosted the study of tumor cell contamination of bone marrow and peripheral blood. Molecular techniques, such as reverse-transcriptase polymerase chain reaction, may be useful tools to reach this target, but, today, immunocytochemistry is still considered the gold standard to assess new techniques to detect isolated tumor cells in hematopoietic tissue. Little is known about the biology of isolated tumor cells in the peripheral blood or bone marrow. Two crucial points need to be evaluated: the identification of specific markers of breast cancer cells with clonogenic potential and their biologic properties, and the prognostic impact of the detection of isolated tumor cells in the bone marrow or peripheral blood stem cell collections.

Does adjuvant chemotherapy improve the prognosis of cervical carcinoma with lymph-node metastasis? A long-term follow-up.

OBJECTIVE: to verify the efficacy of adjuvant therapy in the prevention of neoplastic recurrence in patients at high risk for lymph-node involvement on surgical examination. METHODS: 72 patients, suffering from squamous cell cervical carcinoma Stage IB-IIB (FIGO) who underwent radical hysterectomy with lymph-node involvement confirmed at the final histological examination, were enrolled. All the patients were treated with adjuvant chemotherapy (AC), which included cisplatin, bleomycin and vinblastine, and were followed for a minimum period of six years. The results were compared with those obtained with a historical group of 78 patients, with comparable age, stage and lymph-node involvement, on whom only radical surgery (RS) was performed. RESULTS: the average total survival rate of the two groups (RS + AC vs RS) at five years was 63.9% and 55.1%, respectively (chi2 = 1.191; p = NS). The disease-free interval was 55.6% vs 46.2% (chi2 = 1.324; p = NS). The best results were obtained in cases where the common iliac lymph-nodes were affected, with the highest survival rate of 16.9% in the RS+AC group, out of a total of 25 cases. CONCLUSIONS: adoption of adjuvant chemotherapy in patients at high risk for lymph-node positivity did not produce statistically significant results in terms of overall and disease-free survival; however, a small number of these patients, approximately 9%, could receive benefit from the treatment.

The role of neoadjuvant chemotherapy for squamous cell cervical cancer (Ib-IIIb): a long-term randomized trial.

OBJECTIVE: to verify whether a regimen of preventive chemotherapy in the treatment of cervical carcinoma allows surgical treatment in a larger number of patients and whether cases treated with this combined neoadjuvant polychemotherapy/surgery regimen improves overall and disease-free survival rates. DESIGN: prospective randomized clinical study. SETTING: Department of Gynaecology and Obstetrics, University of Rome "La Sapienza". METHODS: 192 patients suffering from squamous cell carcinoma of the uterine cervix in Stages Ib-IIb were randomized to one of the following treatments: three courses of neoadjuvant chemotherapy with cisplatin, vincristine, bleomycin (NACT arm; n = 106); conventional surgery or radiotherapy alone (CO arm; n = 86). One hundred and fifty-six patients in Stage Ib-IIb (n = 86, NACT arm and n = 70, CO arm) and 16 patients in Stage III (NACT arm) who proved to be sensitive to the neoadjuvant chemotherapy, underwent radical hysterectomy. Four Stage III patients not sensitive to chemotherapy and 16 patients, Stage III, of the CO arm underwent radiotherapy. RESULTS: the 5-year overall survival rates for the NACT and CO arm, respectively, were 78.6% and 73.2% in Stages Ib-IIa (p = NS), 68.7% and 64.3% in Stage IIb (p = NS). A 5-year disease-free survival rate for the NACT arm and CO arm, respectively, of 77.1% and 64.3% in Stages Ib-IIa (p < .05), 56.2% and 57.1% in Stage IIb (p = NS) was found. CONCLUSIONS: the responsiveness of cervical cancer to neoadjuvant chemotherapy allows surgical treatment in a larger number of patients and results in longer overall and disease-free survival.

Sonographic, hysteroscopic, histological correlation in the early diagnosis of endometrial carcinoma.

The authors evaluate the diagnostic role of hysteroscopy and sonography in the early detection of endometrial cancer. In their experience diagnostic accuracy of transabdominal ultrasound was 87.5%; the introduction of transvaginal sonography increased it up to 95.8%, whereas hysteroscopy had diagnostic accuracy of 100%. The hysteroscopy allowed us to establish cervical canal involvement in 100% of cases. Since sonography is well accepted by patients, the authors propose to perform it in high risk patients once a year as a first level exam to show abnormal endometrial echoes. Therefore patients can be selected to undergo hysteroscopy and, if necessary, biopsy.

Biologic prognostic factors in ovarian cancer: a review.

The need of foreseeing the prognosis of ovarian cancer beyond the limits of classical methods based on clinical and histopathological staging has recently caused great interest in a large number of biologic prognostic markers. Studies concern proliferation associated proteins, suppressor genes, abnormal expressions of growth factors, cytokins, and many more. Here some of the most recent and promising factors being studied are described together with their significance for future clinical application.

Intracystic carcinoma of the breast. Our experience.

Malignant tumours of the breast occurring as cysts present an incidence from 0.3% to 0.7%. The Authors report their experience during 15 years in 470 patients with carcinoma of the breast. Endocystic carcinoma appeared in 0.6% of patients: the diagnosis is not always possible with cytology, but ultrasound scans make possible to identiphy cysts which have to undergo biopsy because solid areas within the cystic cavity have been detected. In this case surgery is advised even if the cytological examination has been negative.

Ondansetron in chemotherapy-induced emesis. Our experience.

UNLABELLED: Chemotherapy-induced nausea and vomiting is one of the major side effects of antiblastic treatment in cancer patients, seriously affecting both the compliance of the patient to therapy and his or her quality of life. OBJECTIVE: The Authors present their experience in the use of ondansetron in 47 patients receiving 186 cycles of chemotherapy for breast or genital neoplasms. RESULTS: Successful control of vomiting was achieved in the first 24 hours, in 74% of the cycles containing cisplatin and 82% of the cycles without cisplatin, if ondansetron was used. On delayed vomiting the difference in results was not as striking as on acute emesis. CONCLUSIONS: The major side effects with ondansetron were headaches (42.4%) and constipation (48.9%). As expected, no extra-pyramidal symptoms were observed in this group, versus 13.3% of the patients treated with metoclopramide.

Pre-operative staging of endometrial carcinoma: magnetic resonance imaging versus ultrasounds and hysteroscopy.

Ultrasound, hysteroscopy and magnetic resonance imaging has been considerated to assess the loco-regional or extrapelvic extension of the endometrial carcinoma. Sonography has demonstrated a certain inaccuracy in predicting myometrial invasion or the involvement of the canal. Hysteroscopy allows us to characterize neoplasia and to assess its extension in the cervical canal. MR imaging is more helpful in the diagnosis of channel invasion. The assessment of ovarian metastasis requires ultrasonography or coronal planes RM imaging. As regards the involvement of the pelvic and extrapelvic lymph nodes MR is more accurate than ultrasound scan.

Considerations on the prognostic significance of bone marrow micrometastases in breast cancer.

Research of bone marrow micrometastases in patients with breast cancer was proposed as a prognostic factor in order to detect those patients at high risk for early recurrence. The Authors present a review of current literature and describe the different methods used, with particular regard to monoclonal antibodies. The biological significance and prognostic value of the presence of bone marrow micrometastases in clinically Mo patients with breast cancer are discussed.

[Current role of progesterone therapy in the prevention of spontaneous abortion and in the treatment of threatened abortion]. / Ruolo attuale della terapia progestinica nella prevenzione dell'aborto spontaneo e nel trattamento della minaccia d'aborto.

Progesterone therapy is often used to prevent spontaneous abortion. In this paper the most significant studies on the benefits and risks of this treatment over the last 30 years are analyzed. None of these studies about the effects of progesterone as non-specific therapy in abortion risk and recurrent miscarriage, proved a reduced pregnancy wastage in treated patients compared with patients who received no treatment. The results concerning the use of progesterone in recurrent miscarriage for luteal phase inadequacy are more controversial, but they are still inadequate to encourage progesterone supplementation. To obtain a definitive conclusion about progesterone therapy real effectiveness, it is necessary to carry out randomized double-blind prospected trials. As regards the risks of using progesterone therapy during pregnancy, even if a possible teratologic role has certainly been reduced, it cannot be excluded completely yet. Moreover a high incidence of respiratory problems has been noticed in newborns from patients treated with progesterone, compared with control groups.

[Deep venous thrombosis in pregnancy: diagnostic difficulties and therapeutic indications. Discussion of a clinical case]. / La trombosi venosa profonda in gravidanza: difficoltà diagnostiche e indirizzi terapeutici. Discussione di un caso clinico.

Pregnancy is a risk factor for deep and superficial venous thrombosis because of hemodynamic changes and modifications of the coagulation and fibrinolitic systems. In case of a patient suffering from a congenital or acquired thrombophilia, risk of severe and recurrent thrombosis becomes much higher, with the possibility of a life threatening complication as pulmonary embolism. Recently a number of congenital thombophilic syndromes have been described, in particular congenital hereditary deficit of coagulation inhibitors. Among the acquired pathologies, the antiphospholipid syndrome has been recently object of studies. Diagnostic and therapeutic options are still controversial. The authors present a case of recurrent deep vein thrombosis in pregnancy treated with positioning of a caval filter for the prophylaxis of pulmonary embolism. Diagnostic difficulties are discussed, as the patient presented with low levels of the coagulation inhibitor protein S, and also circulating antibodies anticardiolipin.

[Neoadjuvant chemotherapy in the treatment of breast cancer. Results and prospectives]. / La chemioterapia neoadiuvante nel trattamento del carcinoma della mammella. Risultati e prospettive.

Preoperative chemotherapy for breast cancer has been originally proposed in the treatment of locally advanced tumors (T3b-T4) in order to allow radiotherapy or radical mastectomy. Later, it has been employed also for less advanced stages of the disease (T2-T3), to allow conservative surgery. Personal series of 45 patients that underwent preoperative chemotherapy (FAC) for breast cancer stages T2-T3 is reported. A partial response in terms of reduction of tumor volume was obtained in 80% of these patients, a complete response in 6.6% of the cases. In 48.8% a quadrantectomy has been performed, as the lesion diameter was < 2.5 cm after chemotherapy. The survival rate was 70% at 10 years, and 80% for initially T2 tumors, compared with 50% 10 year survival rate in a group of patients with T2 tumors treated before the introduction of neoadjuvant chemotherapy at our Department. Neoadjuvant chemotherapy allows reduction of the initial volume of breast cancer and performance of conservative instead or radical surgery, with better cosmetic results. Moreover these data suggest that they may improve the plateau of the survival curve of patients with locally advanced breast cancer.