Do you want to perform endovascular therapy? Perspectives from neurology trainees across Europe.

BACKGROUND AND PURPOSE: Endovascular therapy (EVT) has become standard care for acute ischaemic stroke caused by large-vessel occlusion in the anterior circulation. However, access to this treatment in Europe remains poor. The lack of operators is a contributing factor and there is on-going discussion as to whether other specialists, including neurologists, could contribute to the EVT workforce. The question remains whether the next generation of neurologists want to become 'interventional neurologists'. The aim of this study was to address this question. METHODS: We conducted a short survey within the National Representatives Network (a division of the Resident and Research Fellow Section, European Academy of Neurology) in order to determine the interest of future neurologists in performing EVT. RESULTS: A total of 1218 responses from 27 European countries were received, with some variation in the number of respondents and results among individual countries. In total, 568 neurology trainees (47%) stated that they would want to be an 'interventional neurologist'. CONCLUSION: Our findings suggest that neurologists could make a significant contribution to the workforce performing EVT and have important implications for the development and uptake of training programmes in Europe.

Cortical plasticity after hand prostheses use: Is the hypothesis of deafferented cortex "invasion" always true?

OBJECTIVE: To study motor cortex plasticity after a period of training with a new prototype of bidirectional hand prosthesis in three left trans-radial amputees, correlating these changes with the modification of Phantom Limb Pain (PLP) in the same period. METHODS: Each subject underwent a brain motor mapping with Transcranial Magnetic Stimulation (TMS) and PLP evaluation with questionnaires during a six-month training with a prototype of bidirectional hand prosthesis. RESULTS: The baseline motor maps showed in all three amputees a smaller area of muscles representation of the amputated side compared to the intact limb. After training, there was a partial reversal of the baseline asymmetry. The two subjects affected by PLP experienced a statistically significant reduction of pain. CONCLUSIONS: Two apparently opposite findings, the invasion of the "deafferented" cortex by neighbouring areas and the "persistence" of neural structures after amputation, could vary according to different target used for measurement. Our results do not support a correlation between PLP and motor cortical changes. SIGNIFICANCE: The selection of the target and of the task is essential for studies investigating motor brain plasticity. This study boosts against a direct and unique role of motor cortical changes on PLP genesis.

Medical treatment of resistant or recurrent epithelial ovarian cancer.

Epidemiologic analysis reveals that mortality rates from ovarian cancer are continuously decreasing due to the improvement of surgery and chemotherapy. However, overall, the prognosis of ovarian cancer patients is still unsatisfactory considering that only 30% of the patients are alive after 5 years. In fact, although surgery and first-line systemic chemotherapy induce complete and partial response in up to 80% of patients, with about a 25% pathological complete remission rate, recurrences occur in the majority of patients. Most of these patients are subject to repetitive treatment cycles that, although palliative in nature, are also able to prolong survival. Important results have been obtained, in particular in platinum sensitive recurrent disease where a platinum base chemotherapy is able to prolong progression-free survival and overall survival. Overall, our armamentarium for the treatment of progressive or recurrent ovarian cancer is significantly richer than in the past, and in many patients it is possible to achieve the objective to reach a chronic history of the disease.

Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix.

PURPOSE: To evaluate the activity and toxicity of the combination of cisplatin (80 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1 and 8) in patients with carcinoma of the uterine cervix that has not been previously treated with chemotherapy. PATIENTS AND METHODS: Fifty patients with cervical cancer were enrolled onto this study (27 stage IB-III, 23 stage IVB-recurrent). A two-stage optimal Simon design was applied. Thirteen responders of 29 treated patients were required to proceed beyond the first stage, and 28 responders were needed overall. RESULTS: Hematologic toxicity was mild, with neutropenia being the most frequent side effect. Nonhematologic toxicity was frequent but never severe; one patient had grade 3 peripheral neurotoxicity. Objective responses were recorded for 32 patients (64%): 11 patients (22%) achieved a complete response (CR) and 21 patients (42%) achieved a partial response (PR). The response rate was 81.5% in patients with IB-III stage (25.9% CR rate) and 43.5% in patients with IVB-recurrent disease (17.4% CR rate). Responses were seen both in stage IVB patients (one CR and two PRs, for an overall rate of 37.5%) and in patients with recurrent disease (three CRs + four PRs, for an overall rate of 46.7%). CONCLUSION: The combination of cisplatin and vinorelbine is an active regimen in the treatment of patients with early-stage and advanced carcinoma of the uterine cervix. The hematologic and nonhematologic toxicity of this combination is mild.

Preoperative radio-chemotherapy response as prognostic factor in colorectal cancer.

In order to demonstrate if radiotherapy (RT) is able to reduce the number of local recurrences and to increase the survival rate of patients (pts) with colorectal cancer, the authors are participating in a large randomized international trial with the goal of comparing patients treated with preoperative radiotherapy plus surgery and patients treated only by surgery. The authors noticed that some patients treated with preoperative radiotherapy showed a reduction in tumor size at the time of endorectal ultrasonography. The authors considered the incidence of recurrences in patients responsive to radiotherapy (RT responsive group), in patients non responsive to radiotherapy (RT non responsive group) and in patients not treated with radiotherapy (no RT group) with the aim of establishing if the responsiveness to preoperative radiotherapy could be considered a prognostic factor in colorectal cancer. After a three year follow-up RT responsive group (41 pts) showed no recurrences (0%); RT non responsive group (27 pts) showed 7 (25%) recurrences; no RT group (66 pts) showed 27 (41%) recurrences. Our data indicates that responsiveness to preoperative RT can be considered a prognostic factor. A large number of patients is required to confirm this observation.

Uterine carcinosarcoma. Case report.

The authors describe the clinical and pathologic features of uterine carcinosarcoma. In the case of a 45 year old patient the rarity of this double tumor is pointed out.

Primary malignant melanoma of the vagina: case report.

Primary vaginal melanoma is a very rare gynecological malignant tumor (less than 150 reported cases to-date). Prognosis is poor in spite of treatment. Due to the fact that only small groups of patients have been compared, conservative treatment has usually been recommended. In recent times, radical pelvic surgery has appeared to improve the chances of survival. We present an unusual case of primitive melanoma of the upper-third of the vagina with urethral and urinary bladder infiltration in a 47-year-old woman. Treatment consisted of preliminary pelvic bilateral lymphadenectomy, anterior exenteration, and urinary bladder reconstruction according to the Bricker technique. Four months after surgical treatment, liver metastases were found. Chemotherapy was initiated consisting of 8 cycles every 21 days of fotemustine 100 mg/m2 (day 1) and dacarbazine (DTIC) 250 mg/m2 (days 2-5). Interferon alpha-2-b, 3 MU thrice weekly, for the whole period of chemotherapy, was also administered. The patient is in partial remission one year after surgical treatment.

Treatment of severe diabetic acidosis with tris-hydroxymethyl aminomethane in a thirteen-year-old child.

Diabetic ketoacidosis is a severe complication of type I diabetes. A 13-year-old female (40 kg) patient was admitted to our Intensive Care Unit with severe metabolic acidosis (pH: 6.8), hyperglycemia (835 mg/dL) and coma. Her hemodynamic conditions were unstable and, even though a large amount of plasma expanders, crystalloids, and inotropic support were supplied, the patient went into cardiac arrest in the first hour of treatment. After resuscitation, a better hemodynamic balance was achieved and metabolic acidosis was treated with fluid replacement therapy, continuous insulin infusion, and Tris-hydroxymethyl aminomethane (THAM) as a buffering agent. This therapy rapidly improved her metabolic conditions. The patient was discharged 5 days after Intensive Care Unit admission in good condition and without neurological sequelae.

Hemodynamic and ventilatory effects of intravenous salbutamol in patients affected by cold.

Hemodynamic and ventilatory effects of i.v. administration of salbutamol (3 micrograms/kg body weight) have been studied in 6 patients affected by chronic obstructive lung disease. A fall of mean pulmonary arterial pressure (PAP), pulmonary vascular resistances index (PVRI), left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistances index (SVRI) have been found significant. Furthermore, heart rate (HR), cardiac index (CI) and left ventricle dp/dt max (LV dp/dt max) were early and remarkably increased. At 30 min after drug administration such effects disappeared in all patients. Regarding the ventilatory data, the authors assume that a significant and precocious FEV1 and vital capacity increase was still present at 30 min. Hemodynamic effects can be related to either an increased venous return due to peripheral vasodilatation or to a beta 1-cardiac receptor stimulation.

Urinary neopterin and kynurenine in patients submitted to surgical stress with different inhalational anesthetics (halothane or isoflurane).

Measurements were taken of urinary levels of neopterin (NPT) and kynurenine (KYN), using an HPLC method for their simultaneous analysis in patients submitted to anesthetical surgical stress with two different inhalational anesthetics (halothane and isoflurane). We studied twenty-one women affected by uterine fibromyomatosis and submitted to total hysterectomy (mean age of 42.7+/-5.4 years). They showed the same pre-operative evaluation (ASA-1), and underwent the same i.v. anesthetic treatment. Our patients were randomized in two groups: Group A: 11 patients had halothane as an inhalational anesthetic drug for the maintenance of the anesthetic induction (mean time= 1 h). Group B: 10 patients had isoflurane. A significant decrease in urinary NPT and KYN, parallel to serum-NPT, was found 4 h after anesthetic induction. Raised NPT levels appeared 24 h after A.I. with significant increased levels after 7 days. A strong correlation between urinary and serum NPT levels was seen (Rs= 0.74; p < 0.001). Significantly low KYN levels were observed both 4 h and 24 h after A.I.. In addition to the delayed increase of the excretory KYN levels, significantly raised KYN levels in Group B (isoflurane) 48 h after A.I. (10.59+/-14.31 vs 5.99+/-7.17 micromol/mol creat.; p < 0.01) were shown, whereas in Group A (halothane) we observed a progressive increase as compared to the pre-surgery values starting from 72 h after surgery. Our data seem to show that: (a) it is possible to have a biochemical and non invasive monitoring of the anesthetical-surgical stress on MM "priming" activity; (b) the activation of the phagocyte compartment is one of the earlier immunological events after surgery (NPT), but the efficiency of this "priming" appears to be delayed (KYN); (c) isoflurane appears to induce an earlier recovery in MM activation.

Phase I study with weekly cisplatin-paclitaxel and concurrent radiotherapy in patients with carcinoma of the cervix uteri.

BACKGROUND: Cisplatin and paclitaxel are active in cervical cancer and both are able to potentiate the effects of radiotherapy. In this study we evaluated the maximum-tolerated dose (MTD) of paclitaxel in combination with a fixed dose of cisplatin when given weekly concurrently with pelvic radiotherapy to patients with carcinoma of the cervix uteri. PATIENTS AND METHODS: Eighteen patients with cervical cancer were enrolled in this study. Cisplatin (30 mg/m2) and paclitaxel (starting dose 40 mg/m2; 5 mg/m2 escalation per level) were given on day 1 of radiotherapy and then weekly for six times. Radiotherapy was given to the pelvis with a four-field box technique for five days each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of three patients were enrolled at each level and three further patients were included if one or two dose-limiting severe adverse events (SAE) were recorded. SAE was defined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomiting and alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (> 1 week) neutropenia or thrombocytopenia. RESULTS: Four levels were studied (paclitaxel 40, 45, 50, 55 mg/m2) with three, five, four and six patients enrolled, respectively. The MTD of paclitaxel was found at 50 mg/m2/wk and cisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity. Thirteen patients were evaluable for response: seven complete and five partial responses were obtained with an overall response rate of 92.3%. CONCLUSIONS: The MTD of paclitaxel is 50 mg/m2/wk when associated to cisplatin 30 mg/m2/wk and concurrent pelvic radiotherapy. Diarrhea is the dose limiting side effect. Preliminary data suggest that concurrent chemoradiotherapy with paclitaxel and cisplatin could be a very active treatment for patients with locally advanced carcinoma of the cervix.

Evaluation of the utility of serological tests in the diagnosis of candidemia.

BACKGROUND: It has been observed that the incidence and prevalence of candida infections in critically ill non-immunocompromised patients has increased. This study aims to evaluate the utility of the use of serological tests (double immunodiffusion and Cand-Tec Test) for the determination of candidemia. METHODS: A retrospective evaluation is made of 214 patients admitted to the Intensive Care Unit (ICU) of the Agostino Gemelli University Polyclinic during a period of 42 months. The double immunodiffusion technique was utilized for the determination of Candida antibodies. The Cand-Tec latex agglutination test was performed to evaluate the presence of Candida antigen. Four hundred and fifty-five antigen and antibody tests were performed. RESULTS: Thirty-six patients (16.8%) developed an invasive candidiasis. The sensitivity and specificity of antibody detection tests was 29 and 67 respectively; the positive predictive value was 15 and the negative predictive value was 82. The sensitivity and specificity of the antigen detection test ranged between 82 and 3 and between 8 and 98 respectively according to different cut-off titre; the positive predictive value was low (13-17%) and the negative predictive value decreased from 70 to 29. CONCLUSIONS: The utility of the use of serological tests in the diagnosis of candidemia is extremely limited. The gold standard for the determination of Candida sepsis remains the demonstration of candida in blood or in tissues.

A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer.

BACKGROUND: Gemcitabine is active in patients with otherwise resistant or refractory ovarian cancer. As the drug is well tolerated, studies using gemcitabine combined with other antineoplastic agents are needed. The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with gemcitabine, with and without support of G-CSF. PATIENTS AND METHODS: Patients with platinum-resistant or refractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800 mg/m2 day 1 and 8; 200 mg/m2 escalation per level) and epirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2 escalation per level) were given every 21 days for four to six cycles. G-CSF (filgrastim 5 microg/kg/die) was given in case of grade 4 neutropenia (levels without support) or from day 9 up to leukocyte count > 10.000/mm3 after nadir (levels with support). Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. MTD was determined first without and then with G-CSF. RESULTS: Four levels were studied (G 800 + E 60; G 1000 + E 60; G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and three patients enrolled, respectively. DLT (grade 4 febrile neutropenia) was observed in two patients at level 3. Thus, G1000 + E 60 mg/m2 was the MTD without G-CSF. The addition of prophylactic G-CSF did not allow a further increase of the dose and grade 4 thrombocytopenia was the DLT at level 4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in four patients. Among the 13 patients with measurable or evaluable disease, 3 partial responses were observed for an overall response rate of 23.1%. CONCLUSIONS: The combination of gemcitabine 1000 mg/m2 (day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasible therapy. Grade 4 neutropenia is frequent and G-CSF support is often required. With prophylactic support of G-CSF, the DLT is thrombocytopenia.

A phase I study of paclitaxel and epirubicin, without and with filgrastim, for the treatment of platinum-resistant advanced ovarian cancer.

The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with a fixed dose of paclitaxel, without and with support of filgrastim, in patients with platinum resistant or refractory ovarian cancer. Paclitaxel (150 mg/m2) and epirubicin (starting dose 90 mg/m2, 15 mg/m2 escalation per level) were given on day 1, every 28 days for 4-6 cycles. Filgrastim (F) (5 microg/kg/die) was given in case of grade 4 leukopenia (levels without support) or from day 4 up to leukocyte count >10,000/mm3 after nadir (levels with support). Cohorts of 3 patients were enrolled at each level and further 3 patients were planned if 1 or 2 unacceptable toxic events (UTE) were registered. MTD was determined first without and then with filgrastim. Four levels were studied (90, 90+F, 105+F, 120+F) with 4, 6, 5 and 4 patients enrolled, respectively. UTE (grade 4 neutropenia) were observed in 3 patients at level 1. Thus, 90 mg/m2 was the MTD for epirubicin without filgrastim. MTD of epirubicin with filgrastim was not reached at 120 mg/m2. Hematological toxicity was mild. Grade 3 mucositis was reported in 1 patient. Among the 14 patients with measurable or evaluable disease, 3 objective responses were observed (1 complete and 2 partial) for an overall response rate of 21.4%. The combination of paclitaxel 150 mg/m2 and epirubicin at 120 mg/m2 with filgrastim is a feasible therapy. Grade 4 leukopenia is the dose limiting toxicity using epirubicin at 90 mg/m2 without filgrastim.

An escalating dose finding study of liposomal doxorubicin and vinorelbine for the treatment of refractory or resistant epithelial ovarian cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) of liposomal doxorubicin (LD)-vinorelbine (V) in patients with refractory or resistant ovarian cancer. PATIENTS AND METHODS: Thirty patients were eligible. Seven levels were studied [LD 25-V20 (three patients enrolled); LD 30-V20 (three); LD 35-V20 (three); LD 20-V25 (three); LD 25-V25 (three); LD 30-V25 (10); LD 35-V25 (five)]. LD was given on day 1, while V was given on days 1 and 8 every 21 days. Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. RESULTS: DLT was observed in four patients: two febrile neutropenia, one grade 4 thrombocytopenia and one grade 3 palmar-plantar erythrodysesthesia (PPE) at level 7 (LD 35-V25). Thus, liposomal doxorubicin 30 mg/m(2) plus vinorelbine 25 mg/m(2) was the MTD. The most frequent toxicity was neutropenia. Fifteen patients (50%) experienced grade 3 neutropenia and 10 (33.3%) grade 4 neutropenia. Non-hematological toxicity was mild. Mucositis and PPE were the most frequent toxicities, but in most cases were grade 1. Out of 29 assessable patients, six (20.7%; 95% confidence interval 10%-39%) experienced an objective response, with one complete response. CONCLUSIONS: In patients with refractory or resistant ovarian cancer, the recommended doses for the combination studied are liposomal doxorubicin 30 mg/m(2) (day 1) plus vinorelbine 25 mg/m(2) (day 1 and 8). Neutropenia is the most frequent toxicity, while non-hematological toxicity is mild. Substantial activity was recorded and a phase II study is justified.