Relapse in medulloblastoma: what can be done after abandoning high-dose chemotherapy? A mono-institutional experience

Purpose

We retrospectively report strategies used for medulloblastoma patients progressing after craniospinal irradiation where we aimed for: symptom control, a satisfactory quality of life, accrual in phase 1–2 trials, when available, and the first two conditions could no longer be satisfied by already experienced second-line strategies.

Methods

Surgery was used in cases of doubtful relapse or when only one site was affected. Radiotherapy was given whenever possible, especially to relieve symptoms. The main chemotherapy regimens were oral temozolomide/etoposide, intravenous (iv.) cisplatin/etoposide, iv. gemcitabine/oxaliplatin, an oral sonic hedgehog pathway inhibitor and oral melphalan.

Results

Between 1998 and 2011, we treated 18 patients relapsed after median 20 months. Nine had relapsed locally, four had dissemination, three single metastases, and two had one synchronous local and metastatic recurrence. Responses to chemotherapy were seen in 32 % of cases. The median hospital stay for treatments/complications was 19 days. The 1- and 3-year progression-free survival (PFS) rates were 28?±?10 % and 0 %, respectively, for OS, they were 44?±?12 % and 22?±?10 % but no patient was cured. The median PFS after a first relapse was 7 months (range 1–29); the median OS was 7 months (range 4–44). No patients died due to treatment toxicity. Late recurrence (more than 1–2 years after diagnosis) and involvement of single sites were favorable prognostic factors.

Conclusions

Without succeeding in patients cure, we ensured them further treatment with short hospital stay thus affording low personal and social costs. The chances of cure may emerge from tailored therapies according to genetic stratification.     

Altered Motor Cortex Excitability to Magnetic Stimulation in Alcohol Withdrawal Syndrome

Background: Alcohol addiction is a complex brain disease caused by alterations in crucial neurotransmitter systems, including gamma‐aminobutyric acid (GABA) and glutamate. These disturbances could be revealed by changes in cortical excitability parameters, as assessed by transcranial magnetic stimulation (TMS). This study was aimed to further investigate the complex pathophysiology of alcohol withdrawal syndrome (AWS). Methods: Motor cortex excitability was examined in 13 subjects with AWS in a mild predelirial state, in 12 chronic alcoholics and in 15 age‐matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, short latency intracortical inhibition (SICI), and intracortical facilitation (ICF) to paired TMS were examined. Results: Intracortical facilitation was significantly increased in the AWS patients when compared with the chronic alcoholics and the control subjects. The other TMS parameters did not differ significantly from the controls. Administration of a single oral dose of the glutamatergic antagonist riluzole in a subgroup of 8 patients significantly reduced ICF; motor threshold and SICI were not affected by riluzole. Conclusion: Transcranial magnetic stimulation shows a selective increase in intracortical facilitation after ethanol withdrawal. Our findings support the theory that altered glutamatergic receptor function plays an important role in the pathogenesis of human alcohol withdrawal. This study provides further physiological evidence that antiglutamatergic approaches represent an efficacious alternative for treating alcohol withdrawal symptoms.     

Chronic hypoxia: a model for cyanotic congenital heart defects

OBJECTIVE: The postoperative course of cyanotic children is generally more complicated than that of acyanotic children. A possible reason is reoxygenation injury at the beginning of cardiopulmonary bypass. In this study we tested the hypothesis that reoxygenation of chronically hypoxic hearts is worse than that of normoxic hearts. METHODS: Two groups of rats (n = 9 each) were exposed to either room air (fraction of inspired oxygen, 0.21%) or chronic hypoxia (fraction of inspired oxygen, 0.10%) for 2 weeks. Hearts were then isolated and perfused for 30 minutes with hypoxic buffer (oxygen saturation, 10%), followed by 30 minutes of reoxygenation (oxygen saturation, 100%). RESULTS: In hypoxic rats hematocrit values, hemoglobin concentrations, and red cells were higher (69% +/- 6% vs 40% +/- 6%, 219 +/- 14 vs 124 +/- 12 g/L, and 10.30 +/- 0.6 vs 6.32 +/- 0.5/microL/1000, respectively; P <.0001); the amount of ingested food was less (22.3 +/- 4.8 vs 30.7 +/- 3.9 g/d, P <.001), as was the amount of ingested water (21.0 +/- 3.1 vs 50.4 +/- 14.6 mL/d, P <.0001); and body weight was lower (182 +/- 14.2 vs 351 +/- 40.1 g, P <.0001), as was heart weight (1107 +/- 119 vs 1312 +/- 128 mg, P <.005). The heart weight/body weight ratio was higher (6.10 +/- 0.8 vs 3.74 +/- 0.1 mg/g, P <.0001). Systolic and diastolic functions, not different during the hypoxic baseline period, were more impaired in hypoxic than in normoxic hearts after the reoxygenation, whereas coronary resistance remained lower. During the hypoxic perfusion, the venous partial pressure of oxygen remained low in both groups, whereas during reoxygenation, partial pressure of oxygen was higher in hypoxic hearts, with a lower (P <.01) oxygen uptake. During hypoxic baseline adenosine triphosphate turnover, lactate production and lactate turnover were lower in hypoxic hearts (P <.005, P <.0001, and P <.0001, respectively). CONCLUSIONS: Body and blood values are severely affected by chronic hypoxia, and the cardiac effects of uncontrolled reoxygenation after chronic hypoxia are more severe than after acute hypoxia.     

Severity of coronary artery stenosis at preoperative angiography and midterm mammary graft status

BACKGROUND: The purpose of this study was to evaluate the correlation between the midterm angiographic results of mammary artery grafts and the preoperative stenosis of the target vessel. METHODS: We analyzed preoperative and postoperative angiograms of 93 patients who underwent postoperative midterm (> or = 3 years) angiograms of an internal mammary artery (IMA) to left anterior descending artery graft for clinical or study purposes. Patients were divided into three groups on the basis of the percentage of the coronary artery stenosis at preoperative angiography: < 70%, 70% to 90%, and > 90% stenosis. RESULTS: Preoperative characteristics were similar in the three groups. The overall incidence of IMA occlusion was 19% in the entire population, without significant differences between groups (19% versus 29% versus 14%). The mean mammary artery diameter significantly increased in direct proportion to the severity of the coronary stenosis (2.0 +/- 0.2 mm in the < 70% versus 2.5 +/- 0.3 mm in the 70% to 90% and 2.7 +/- 0.4 mm in the > 90% series; p < 0.05). CONCLUSIONS: Chronic native competitive flow does not significantly affect midterm graft status but does influence mammary graft diameter.     

Management of pulmonary embolism during acrylic vertebroplasty

A 55-year-old man diagnosed with osteogenesis imperfecta had multiple pulmonary embolism from acrylic cement during vertebroplasty. The patient immediately developed respiratory distress, renal failure, and right cardiac failure. A computed tomographic scan showed the presence of cement in the right and left pulmonary arteries, and in both lungs. Cardiac and respiratory functions did not improve with medical treatment, therefore the patient underwent pulmonary artery embolectomy. Cement was easily removed from both pulmonary arteries. The patient quickly recovered from respiratory and cardiac failure. We believe pulmonary embolectomy is a reliable and effective procedure to treat this rare and dreadful complication of acrylic vertebroplasty.     

Tobacco smoke exposure and serum cotinine in a random sample of adults living in Verona,Italy

In this study, the authors attempted to validate answers to smoking-habit questions contained in the European Community Respiratory Health Survey questionnaire. The respondents were invited to visit the chest clinic at Verona, Italy, and their serum cotinine levels were measured. The authors invited each of 504 subjects to complete a respiratory interview and to give a blood sample for a radioimmunoassay serum cotinine measurement. A total of 375 subjects responded, of whom 129 were smokers (34.4%), 79 were exsmokers (21.1%), and 167 (44.5%) had never smoked. Exposure to environmental tobacco smoke was reported by 216 subjects (57.6% [mean exposure = 3.8 hr/day (+/- 3.4 hr/day standard deviation)]). In smokers, serum cotinine levels were directly related to the number of cigarettes smoked/day. The authors excluded from analysis nonsmokers who had serum cotinine levels that were > or = 14 ng/ml, and the resulting mean values were 1.7 ng/ml (+/- 2.1 ng/ml standard deviation) in nonsmokers unexposed to environmental tobacco smoke and 2.6 ng/ml (+/- 2.6 ng/ml standard deviation) (p < .002) in nonsmokers exposed to environmental tobacco smoke. There was a relationship between serum cotinine levels and hours of exposure to environmental tobacco smoke (R2 = .136, p < .05). Serum cotinine, which is an objective and accepted measure of tobacco exposure, confirmed the validity of the European Community Respiratory Health Survey questionnaire with respect to smoking habits and environmental tobacco smoke exposure.     

Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale

BACKGROUND: A prospective, randomized Phase III trial was performed to determine whether, compared with gemcitabine (GEM) alone, the addition of cisplatin (CDDP) to GEM was able to improve the time to disease progression and the clinical benefit rate in patients with advanced pancreatic adenocarcinoma. The objective response rate, overall survival rate, and toxicity patterns of patients in the two treatment arms were evaluated as secondary end points. METHODS: Patients with measurable, locally advanced and/or metastatic pancreatic adenocarcinoma were randomized to receive GEM (Arm A) or a combination of GEM and CDDP (Arm B). In Arm A, a dose of 1000 mg/m(2) GEM per week was administered for 7 consecutive weeks, and, after a 2-week rest, treatment was resumed on Days 1, 8, and 15 of a 28-day cycle for 2 cycles. In Arm B, CDDP was given at a dose of 25 mg/m(2) per week 1 hour before GEM at the same dose that was used in Arm A. On Day 22, only GEM was administered. Patients were restaged after the first 7 weeks of therapy and then again after the other 2 cycles. RESULTS: A total of 107 patients entered the trial: Fifty-four patients were randomized to Arm A, and 53 patients were randomized to Arm B. The median time to disease progression was 8 weeks in Arm A and 20 weeks in Arm B; this difference was statistically significant (P = 0.048). In Arm A, one complete response and four partial responses were recorded on the basis of an intent-to-treat analysis, with an overall response rate of 9.2% (95% confidence interval [95%CI], 3-20%). In Arm B, there were no complete responses, whereas 14 partial responses were achieved, with an overall response rate of 26.4% (95%CI, 15-40%). This difference in the overall response rates was statistically significant (P = 0.02). The tumor growth control rate (i.e., total number of patients who achieved complete responses, partial responses, and stable disease) was 42.6% (95%CI, 29-57%) in Arm A and 56.6% (95%CI, 42-70%) in Arm B. A clinical benefit was observed in 21 of 43 patients (49%) in Arm A and in 20 of 38 patients (52.6%) in Arm B without any significant difference. The median overall survival was 20 weeks for patients in Arm A and 30 weeks for patients in Arm B (P = 0.43). Toxicity was mild in both treatment arms, with no significant differences between the two groups except for the statistically higher incidence of Grade 1-2 asthenia in Arm B (P = 0.046). CONCLUSIONS: The addition of CDDP to GEM significantly improved the median time to disease progression and the overall response rate compared with GEM alone. The clinical benefit rate was similar in both arms, whereas the median overall survival rate was more favorable for Arm B, although the difference did not attain statistical significance. The authors conclude that the combination of CDDP and GEM currently may be considered as an optimal treatment for patients with locally advanced and/or metastatic adenocarcinoma of the pancreas.     

Correlation between umbilical arterial pH values and fetal vertebral artery Doppler waveforms at the beginning of the second stage of labor: a pilot prospective study

Objective: The aim of this study was to evaluate the association between umbilical arterial pH and fetal vertebral artery Doppler velocimetry waveforms measured at the beginning of the second stage of labor in physiological term pregnancies.

Methods: This was a prospective cohort study of 250 pregnancies. The resistance index, pulsatility index, and peak systolic velocity were measured. The relationship between the fetal Doppler and the umbilical arterial pH was evaluated. A simple linear regression and a general linear model were used to explore possible correlations of Doppler parameters with fetal and neonatal outcome adjusted for confundents.

Results: Umbilical arterial pH values were directly associated with vertebral artery pulsatility index. Fetuses with lower pulsatility index values were at increased risk of a subsequent diagnosis of pathological fetal heart rate tracing patterns (presence of decelerations or reduced variability according to FIGO criteria during the second stage of labor). We estimated a decrease in pulsatility index of 10% in those fetuses destined to show a pathological fetal heart rate tracing.

Conclusion: Vertebral artery Doppler waveforms correlates with umbilical pH in normal pregnancies and is also a function of fetal heart rate patterns. If this proportional association would be demonstrated also for abnormal pH values, vertebral artery pulsatility index might be useful to evaluate fetal wellbeing in those cases of suspected hypoxia/academia.     

Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia

Elderly patients are more prone than younger patients to develop cerebral desaturation because of the reduced physiologic reserve that accompanies aging. To evaluate whether monitoring cerebral oxygen saturation (rSO(2)) minimizes intraoperative cerebral desaturation, we prospectively monitored rSO(2) in 122 elderly patients undergoing major abdominal surgery with general anesthesia. Patients were randomly allocated to an intervention group (the monitor was visible and rSO(2) was maintained at > or =75% of preinduction values; n = 56) or a control group (the monitor was blinded and anesthesia was managed routinely; n = 66). Cerebral desaturation (rSO(2) reduction <75% of baseline) was observed in 11 patients of the treatment group (20%) and 15 patients of the control group (23%) (P = 0.82). Mean (95% confidence intervals) values of mean rSO(2) were higher (66% [64%-68%]) and the area under the curve below 75% of baseline (AUCrSO2(2)< 75% of baseline) was lower (0.4 min% [0.1-0.8 min%]) in patients of the treatment group than in patients of the control group (61% [59%-63%] and 80 min% [2-144 min%], respectively; P = 0.002 and P = 0.017). When considering only patients developing intraoperative cerebral desaturation, a lower Mini Mental State Elimination (MMSE) score was observed at the seventh postoperative day in the control group (26 [25-30]) than in the treatment group (28 [26-30]) (P = 0.02), with a significant correlation between the AUCrSO(2) < 75% of baseline and postoperative decrease in MMSE score from preoperative values (r(2)= 0.25, P = 0.01). Patients of the control group with intraoperative cerebral desaturation also experienced a longer time to postanesthesia care unit (PACU) discharge (47 min [13-56 min]) and longer hospital stay (24 days [7-53] days) compared with patients of the treatment group (25 min [15-35 min] and 10 days [7-23 days], respectively; P = 0.01 and P = 0.007). Using rSO(2) monitoring to manage anesthesia in elderly patients undergoing major abdominal surgery reduces the potential exposure of the brain to hypoxia; this might be associated with decreased effects on cognitive function and shorter PACU and hospital stay.