Bubbles and capital flows

This paper presents a stylized model of international trade and asset price bubbles. Its central insight is that bubbles tend to appear and expand in countries where productivity is low relative to the rest of the world. These bubbles absorb local savings, eliminating inefficient investments and liberating resources that are in part used to invest in high productivity countries. Through this channel, bubbles act as a substitute for international capital flows, improving the international allocation of investment and reducing rate-of-return differentials across countries. This view of asset price bubbles could eventually provide a simple account of some real world phenomenae that have been difficult to model before, such as the recurrence and depth of financial crises or their puzzling tendency to propagate across countries.

Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial.

OBJECTIVE: To evaluate the effectiveness of 200 mg of daily vaginal natural progesterone to prevent preterm birth in women with preterm labour. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. SETTING: Twenty-nine centres in Switzerland and Argentina. POPULATION: A total of 385 women with preterm labour (24(0/7) to 33(6/7)  weeks of gestation) treated with acute tocolysis. METHODS: Participants were randomly allocated to either 200 mg daily of self-administered vaginal progesterone or placebo within 48 hours of starting acute tocolysis. MAIN OUTCOME MEASURES: Primary outcome was delivery before 37 weeks of gestation. Secondary outcomes were delivery before 32 and 34 weeks, adverse effects, duration of tocolysis, re-admissions for preterm labour, length of hospital stay, and neonatal morbidity and mortality. The study was ended prematurely based on results of the intermediate analysis. RESULTS: Preterm birth occurred in 42.5% of women in the progesterone group versus 35.5% in the placebo group (relative risk [RR] 1.2; 95% confidence interval [95% CI] 0.93-1.5). Delivery at <32 and <34 weeks did not differ between the two groups (12.9 versus 9.7%; [RR 1.3; 95% CI 0.7-2.5] and 19.7 versus 12.9% [RR 1.5; 95% CI 0.9-2.4], respectively). The duration of tocolysis, hospitalisation, and recurrence of preterm labour were comparable between groups. Neonatal morbidity occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%) cases on placebo (RR: 1.2; 95% CI 0.82-1.8), whereas there were 4 (2%) neonatal deaths in each study group. CONCLUSION: There is no evidence that the daily administration of 200 mg vaginal progesterone decreases preterm birth or improves neonatal outcome in women with preterm labour.

Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93.

BACKGROUND: The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials to assess whether a treatment-free gap during adjuvant chemotherapy influenced outcome. PATIENTS AND METHODS: From 1993 to 1999, IBCSG Trials 13-93 and 14-93 enrolled 2215 premenopausal and postmenopausal women with axillary node-positive, operable breast cancer. All patients received cyclophosphamide (Cytoxan, C) plus either doxorubicin (Adriamycin, A) or epirubicin (E) for four courses followed immediately (No Gap) or after a 16-week delay (Gap) by classical cyclophosphamide, methotrexate, and fluorouracil (CMF) for three courses. The median follow-up was 7.7 years. RESULTS: The Gap and No-Gap groups had similar disease-free survival (DFS) and overall survival (OS). No identified subgroup showed a statistically significant difference, but exploratory subgroup analysis noted a trend towards decreased DFS for Gap compared with No Gap for women with estrogen receptor (ER)-negative tumors not receiving tamoxifen, especially evident during the first 2 years. CONCLUSIONS: A 16-week gap between adjuvant AC/EC and CMF provided no benefit and may have increased early recurrence rates in patients with ER-negative tumors.

Previous microvascular decompression decreases the chances of pain free in patients treated with Gamma Knife radiosurgery for TIC

Object: The authors sought to establish whether the safety-efficacy of Gamma Knife radiosurgery (GKRS) as a second treatment for intractable trigeminal neuralgia (ITN) are influenced by prior microvascular decompression (MVD) which remains, for some of the authors, the reference technique. Methods: Between July 1992 and November 2010, 737 patients have been operated with GKRS for ITN and prospectively evaluated in Timone University Hospital in Marseille, France. Among these, 54 patients had a previous MVD history. Radiosurgery using a Gamma Knife (model B or C or Perfexion) was performed relying on both MR and CT targeting. A single 4 mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range 3.9- 11.9) anteriorly to the emergence of the nerve (retrogasserian target). A median maximum dose of 85 Gy (range 70-90) was delivered. Are further analyzed only 45 patients with previous MVD and a follow-up longer than one year (the patients with megadolichobasilar artery compression and multiple sclerosis were excluded). Results: The median age in this series was 56.75 years (range 28.09-82.39). The median follow-up period was 39.48 months (range 14.10-144.65). All the patients had a past history of surgery, with at least one previous failed MVD, but also a radiofrequency lesion (RFL) in 16 (35.6%) patients, balloon microcompression in 7 (15.6%) patients and glycerol rhizotomy in 1 case (2.2%). Thirty-five patients (77.8%) were initially pain free in a median time of 14 days (range 0, 180). Patients from this group had less probability of being pain free compared to our global population of essential trigeminal neuralgia without previous MVD history (p=0.010, hazard ratio of 0.64). Their probability of remaining pain free at 3, 5, 7 and 10 years was 66.5%, 59.1%, 59.1% and 44.3%, respectively. Twelve patients (34.3%) initially pain free experienced a recurrence with a median delay of 31.21 months (range 3.40-89.93). The hypoesthesia actuarial rate at 1 year was 9.1% and remained stable till 12 years with a median delay of onset of 8 months (range 8-8). Conclusions: Retrogasserian GKRS proofed to be safe and effective on the long-term basis even after failed previous MVD. Even if the initial result of pain free was of only 77.8%, the toxicity was low with only 9.1% hypoesthesia. No patient reported a bothersome hypoesthesia. The probability of maintaining pain relief in long-term was of 44.3% at 10 years.

Cancer du sein : la pathologie, pierre angulaire de la décision therapeutique [Breast cancer: pathology, the cornerstone of therapeutic decision]

Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.

Superficial soft tissue sarcomas (S-STS): a study of 367 patients from the French Sarcoma Group (FSG) database.

AIM: The specific natural history of superficial soft tissue sarcomas (S-STS) has been rarely considered. We describe the clinical characteristics of a large series of S-STS (N=367) from the French Sarcoma Group (GSF-GETO) database and analyse the prognostic factors affecting outcome. METHODS: We performed univariate and multivariate analyses for overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). RESULTS: The median age was 59 years. Fifty-eight percent patients were female. Tumour locations were as follows: extremities, 55%; trunk wall, 35.4%; head and neck, 8% and unknown, 1.6%. Median tumour size was 3.0 cm. The most frequent tumour types were unclassified sarcoma (24.3%) and leiomyosarcoma (22.3%). Thirty-three percent of cases were grade 3. Median follow-up was 6.18 years. The 5-year OS, MFS and LRFS rates were 80.9%, 80.7% and 74.7%, respectively. Multivariate analysis retained histological type and wide resection for predicting LRFS and histological type and grade as prognostic factors of MFS. The factors influencing OS were age, histological type, grade and wide resection. STS with early invasion into but not through the underlying fascia had a significantly poorer MFS than with strict S-STS. CONCLUSION: S-STS represent a separate category characterised by a better outcome. Adequate surgery, i.e. wide resection, is essential in the management of S-STS.

Perioperative nerve blockade: clues from the bench.

Peripheral and neuraxial nerve blockades are widely used in the perioperative period. Their values to diminish acute postoperative pain are established but other important outcomes such as chronic postoperative pain, or newly, cancer recurrence, or infections could also be influenced. The long-term effects of perioperative nerve blockade are still controversial. We will review current knowledge of the effects of blocking peripheral electrical activity in different animal models of pain. We will first go over the mechanisms of pain development and evaluate which types of fibers are activated after an injury. In the light of experimental results, we will propose some hypotheses explaining the mitigated results obtained in clinical studies on chronic postoperative pain. Finally, we will discuss three major disadvantages of the current blockade: the absence of blockade of myelinated fibers, the inappropriate duration of blockade, and the existence of activity-independent mechanisms.

Laparoscopic inguinal hernia repair with extraperitoneal double-mesh technique.

Totally extraperitoneal laparoscopic hernia repair is an efficient but technically demanding procedure. As mechanisms of hernia recurrence may be related to these technical difficulties, we have modified a previously described double-mesh technique in an effort to simplify the procedure. Extraperitoneal laparoscopic hernia repairs were performed in 82 male and 17 female patients having inguinal, femoral, and recurrent bilateral hernias. A standard propylene mesh measuring 15 x 15 cm was cut into two pieces of 4 x 15 cm and 11 x 15 cm. The smaller mesh was placed over both inguinal rings without splitting. The larger mesh was then inserted over the first mesh and stapled to low-risk zones, reinforcing the large-vessel area and the nerve transition zone. The mean procedure duration was 60 minutes for unilateral and 100 minutes for bilateral hernia repair. Patients were discharged from the hospital within 48 hours. The mean postoperative follow-up was 22 months, with no recurrences, neuralgia, or bleeding complications. Over a 2-year period, this technique was found to be satisfactory without recurrences or significant complications. In our hands, this technique was easier to perform: it allows for a less than perfect positioning of the meshes and avoids most of the stapling to crucial zones.

Test of four colon cancer risk-scores in formalin fixed paraffin embedded microarray gene expression data.

BACKGROUND: Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification. METHODS: Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase. RESULTS: All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score. CONCLUSIONS: The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different.

Outcome and patterns of failure in testicular lymphoma: a multicenter Rare Cancer Network study.

PURPOSE: To assess the outcome and patterns of failure in patients with testicular lymphoma treated by chemotherapy (CT) and/or radiation therapy (RT). METHODS AND MATERIALS: Data from a series of 36 adult patients with Ann Arbor Stage I (n = 21), II (n = 9), III (n = 3), or IV (n = 3) primary testicular lymphoma, consecutively treated between 1980 and 1999, were collected in a retrospective multicenter study by the Rare Cancer Network. Median age was 64 years (range: 21-91 years). Full staging workup (chest X-ray, testicular ultrasound, abdominal ultrasound, and/or thoracoabdominal computer tomography, bone marrow assessment, full blood count, lactate dehydrogenase, and cerebrospinal fluid evaluation) was completed in 18 (50%) patients. All but one patient underwent orchidectomy, and spermatic cord infiltration was found in 9 patients. Most patients (n = 29) had CT, consisting in most cases of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with (n = 17) or without intrathecal CT. External RT was delivered to scrotum alone (n = 12) or testicular, iliac, and para-aortic regions (n = 8). The median RT dose was 31 Gy (range: 20-44 Gy) in a median of 17 fractions (10-24), using a median of 1.8 Gy (range: 1.5-2.5 Gy) per fraction. The median follow-up period was 42 months (range: 6-138 months). RESULTS: After a median period of 11 months (range: 1-76 months), 14 patients presented lymphoma progression, mostly in the central nervous system (CNS) (n = 8). Among the 17 patients who received intrathecal CT, 4 had a CNS relapse (p = NS). No testicular, iliac, or para-aortic relapse was observed in patients receiving RT to these regions. The 5-year overall, lymphoma-specific, and disease-free survival was 47%, 66%, and 43%, respectively. In univariate analyses, statistically significant factors favorably influencing the outcome were early-stage and combined modality treatment. Neither RT technique nor total dose influenced the outcome. Multivariate analysis revealed that the most favorable independent factors predicting the outcome were younger age, early-stage disease, and combined modality treatment. CONCLUSIONS: In this multicenter retrospective study, CNS was found to be the principal site of relapse, and no extra-CNS lymphoma progression was observed in the irradiated volumes. More effective CNS prophylaxis, including combined modalities, should be prospectively explored in this uncommon site of extranodal lymphoma.

Fluoreszenzdiagnostik bei Patienten mit nicht muskelinvasivem Harnblasenkarzinom: Ergebnisse einer Metaanalyse [Fluorescence diagnosis in patients with non-muscle invasive bladder cancer: results of a metaanalysis]

Purpose: Heterogeneous results of single studies with photodynamic diagnosis (PDD) in bladder cancer have been reported. A metaanalysis of prospective studies has now been performed. Material and Methods: The effect of PDD in addition to WLC on a) the diagnosis and b) the therapeutic outcome of primary or recurrent non-muscle invasive bladder cancer (NMIBC) investigated by cystoscopy or transurethral resection was analysed. An electronic database search was performed. Trials were included if they prospectively compared WLC with PDD in bladder cancer. Primary endpoints were additional detection rate, residual tumour at second resection and recurrence-free survival. Results: Significantly more tumour-positive patients were detected with PDD in all patients with non-muscle invasive tumours (= 20%) [95% confidence interval (CI): 8 to 35%] and in CIS patients (= 39%) (CI: 23 to 57%). Residual tumour was significantly less often found after PDD (odds ratio 0.28, CI: 0.15 to 0.52, p<0.0001). Recurrence-free survival was significantly higher at 12 and 24months in the PDD groups than in WLC only groups. Conclusions: More bladder tumour-positive patients are detected by PDD. Best results were found in CIS patients. Diagnosis with PDD results in a more complete resection and a longer recurrence-free survival.

Video-assisted right supradiaphragmatic thoracic duct ligation for non traumatic recurrent chylothorax

Introduction : Un chylothorax est une pathologie comprenant des manifestations respiratoires, nutritionnelles et immunologiques. La récidive du chylothorax ou l'échec du traitement conservateur imposent un traitement chirurgical. Ce travail rapporte notre expérience de ligature supra-diaphragmatique, vidéo-assistée du canal thoracique, pour chylothorax récurrent non traumatique. Patients et méthodes : Entre 1999 et 2004, nous avons recensé six observations (quatre du côté droit, un du côté gauche et un bilateral) Le chylothorax s'est développé chez trois patients traités par radio et chimiothérapie pour tumeur (deux lymphomes et une tumeur du sein) un dans le contexte d'une lymphangioléiomatose et un après greffe cardiaque. Résultats : Les patients ont bénéficié sous anesthésie générale, d'une ligature du canal thoracique supra-diaphragmatique, vidéo-assistée. Le temps opératoire moyen a été de 102 minutes. Le chylothorax a régressé chez cinq des six patients en sept jours. Un patient a été repris par thoracotomie droite au huitième jour pour chylothorax persistant. Dans la phase post-opératoire, un patient a développé une détresse respiratoire nécessitant une ventilation mécanique. Un autre patient a présenté un chylopéritoine important traité par un stent de Le Veen®. Le séjour moyen a été de quatorze jours sans mortalité péri-opératoire. Conclusion : Le traitement du chylothorax non traumatique récurrent est, en première intention, un traitement médical. En cas de récidive ou d'échec du traitement conservateur, le traitement chirurgical par ligature du canal thoracique supra- diaphragmatique, vidéo-assistée, permet de traiter avec succès le chylothorax récurrent non traumatique. -- Background: Chylothorax is an uncommon disorder with respiratory, nutritional and immunological manifestations. Surgical management is indicated in case of recurrence or failure after conservative treatment. We report our experience with video-assisted right-sided supradiaphrag¬matic thoracic duct ligation for non-traumatic, non-postoperative persistent or recurrent chylothorax. Patients and methods: The medical records of six patients operated at our institution between 1999 and 2004 were retrospectively reviewed. A right-sided chylothorax was found in four patients, a left-sided in one, and a bilateral in one. Three patients developed chylothorax after chemotherapy and chest irradiation for malignant diseases (lymphoma in two patients and breast cancer in one), one in the context of lymphangioleiomyomatosis, one due to a non-diagnosed lymphoma, and one after heart transplantation. Results: The mean operative time was 102 min, with an average length of hospital stay of 14 days. Persistent cessation of chylous effusion within 7 days after surgery was observed in 5/6 patients without recurrence during a mean follow-up time of 41 months. One patient with undiagnosed mediastinal lymphoma required re-operation and thoracic duct ligation on day 8 by right-sided thoracotomy due to persistent chylothorax. No 30-day mortality was recorded. Two patients presented postoperative complications including respiratory insufficiency requiring mechanical ventilation in one, and chylous ascites development requiring peritoneo-venous LeVeen shunting in one patient. Conclusions: Recurrent or persistent non-traumatic chylothorax may be successfully treated by video-assisted right supradiaphragmatic thoracic duct ligation.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Radiothérapie externe accélérée postopératoire des carcinomes épidermoïdes localement évolués de la sphère ORL: étude prospective de phase II [Prospective study of accelerated postoperative radiation therapy in patients with squamous-cell carcinoma of the head and neck]

PURPOSE: To assess the feasibility and efficacy of accelerated postoperative radiation therapy (RT) in patients with squamous-cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Between December 1997 and July 2001, 68 patients (male to female ratio: 52/16; median age: 60-years (range: 43-81) with pT1-pT4 and/or pN0-pN3 SCCHN (24 oropharynx, 19 oral cavity, 13 hypopharynx, 5 larynx, 3 unknown primary, 2 maxillary sinus, and 2 salivary gland) were included in this prospective study. Postoperative RT was indicated because extracapsular infiltration (ECI) was observed in 20 (29%), positive surgical margins (PSM) in 20 (29%) or both in 23 patients (34%). Treatment consisted of external beam RT 66 Gy in 5 weeks and 3 days. Median follow-up was 15 months. RESULTS: According to CTC 2.0, acute morbidity was acceptable: grade 3 mucositis was observed in 15 (22%) patients, grade 3 dysphagia in 19 (28%) patients, grade 3 skin erythema in 21 (31%) patients with a median weight loss of 3.1 kg (range: 0-16). No grade 4 toxicity was observed. Median time to relapse was 13 months; we observed only three (4%) local and four (6%) regional relapses, whereas eight (12%) patients developed distant metastases without any evidence of locoregional recurrence. The 2 years overall-, disease-free survival, and actuarial locoregional control rates were 85, 73 and 83% respectively. CONCLUSION: The reduction of the overall treatment time using postoperative accelerated RT with weekly concomitant boost (six fractions per week) is feasible with local control rates comparable to that of published data. Acute RT-related morbidity is acceptable.