Successful therapeutic plasma exchange in cold autoimmune hemolytic anemia in patient with disseminated tuberculosis.

An association of autoimmune hemolytic anemia with disseminated tuberculosis is an exceedingly rare entity. We describe herein a case of cold hemolytic autoimmune anemia associated with miliary tuberculosis resolved with blood transfusions, therapeutic plasma exchange, and antituberculous agents. We discuss the advantages of therapeutic plasma exchange at an early stage in the management of this condition.

A single-arm multicentre phase II trial of doxorubicin in combination with trabectedin in the first-line treatment for leiomyosarcoma with long-term follow-up and impact of cytoreductive surgery.

BACKGROUND: Uterine leiomyosarcomas (U-LMSs) and soft tissue leiomyosarcomas (ST-LMSs) are rare tumours with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with manageable toxicity. Herein, we report the updated and long-term results of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients received 60 mg/m2 intravenous doxorubicin followed by trabectedin 1.1 mg/m2 as a 3-h infusion on day 1 and pegfilgrastim on day 2, every 3 weeks, up to six cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. RESULTS: One-hundred and eight patients were enrolled, mainly with metastatic disease (85%), and 20 patients (18.5%) had surgical resection of metastases after chemotherapy. With a median follow-up of 7.2 years [95% confidence interval (CI) 6.9-8.2 years], the median PFS was 10.1 months (95% CI 8.5-12.6 months) in the whole population, and 8.3 months (95% CI 7.4-10.3 months) and 12.9 months (95% CI 9.2-14.1 months) for U-LMSs and ST-LMSs, respectively. The median OS was 34.4 months (95% CI 26.9-42.7 months), 27.5 months (95% CI 17.9-38.2 months), and 38.7 months (95% CI 31.0-52.9 months) for the whole population, U-LMSs, and ST-LMSs, respectively. The median OS of the patients with resected metastases was not reached versus 31.6 months in the overall population without surgery (95% CI 23.9-35.4 months). CONCLUSIONS: These updated results confirm the impressive efficiency of the doxorubicin plus trabectedin combination given in first-line therapy for patients with locally advanced/metastatic LMS in terms of PFS and OS. Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing the doxorubicin plus trabectedin combination versus doxorubicin alone in first-line therapy in metastatic LMSs, are pending.

Laparoscopic treatment for choledocholithiasis: a prospective evaluation in 247 consecutive unselected patients.

BACKGROUND/AIMS: Evaluation of the feasibility and results of the one-stage treatment combining routine intraoperative cholangiography and laparoscopic common bile duct exploration for choledocholithiasis. PATIENTS AND METHODS: Multicentric (5 centers-9 surgeons) prospective study in 247 consecutive patients (mean age 68 years; range 21-92) during a 50-month period (November 1991-December 1995). Laparoscopic treatment of choledocholithiasis was attempted irrespective of the circumstances leading to the diagnosis of biliary lithiasis or the preoperative suspicion of choledocholithiasis. RESULTS: One out of four patients (n = 61) had unsuspected choledocholithiasis disclosed by routine intraoperative cholangiography. A laparoscopic complete clearance of choledocholithiasis was achieved in 208 of 236 attempted cases (88%), with either transcystic duct extraction (n = 116) or choledochotomy (n = 92). Open surgery was required in 20 patients for failure of laparoscopic treatment and in 3 patients despite successful extraction. Twenty-one of 25 patients (84%) referred for failure of retrograde endoscopic stone extraction had successful laparoscopic choledocholithiasis clearance. The mean duration for the laparoscopic transcystic approach and choledochotomy were 108 min (range 50-300) and 173 min (range 70-480), respectively. Eleven patients had retained stones (4.4%). Minor and major complications were recorded in 9 and 22 patients respectively. The operative mortality was 0.4% (95% confidence interval: 0-1.2%). CONCLUSION: Intraoperative cholangiography during laparoscopic cholecystectomy and laparoscopic common bile duct exploration when required should be considered as the simplest and most efficient treatment for choledocholithiasis. The multicenter character of this study including consecutive patients from public and private practices, strengthens our conclusions and is consistent with a wide diffusion of this diagnostic and therapeutic strategy.

[Treatment of common bile duct lithiasis under laparoscopy. A prospective multicenter study in 189 patients]. / Traitement de la lithiase de la voie biliaire principale sous laparoscopie.

OBJECTIVES: The aim of this study was to assess the feasibility and results of common bile duct laparoscopic treatment and exploration in patients with choledocholithiasis. PATIENTS AND METHODS: From November 1991 to December 1994, 189 consecutive malades (120 females; mean age 68 years, range: 21-92) with choledocholithiasis identified during routine intraoperative cholangiogram underwent surgical exploration of common bile duct in 5 surgical centers. Twenty patients were referred to surgery after unsuccessful endoscopic sphincterotomy. RESULTS: Following laparoscopic exploration and intraoperative cholangiography, common bile duct stone extraction by laparoscopy was not attempted in 11 patients (5.8%). The common bile duct was successfully cleared of all stones in 153 patients (81% of the overall population and 86% of laparoscopic attempts), either via the transcystic route (n = 97) or through choledocotomy (n = 56). Eighteen patients required conversion to open surgery, 16 for unsuccessful stone extraction and 2 despite successful stone extraction. Postoperative endoscopic sphincterotomy was required in 7 patients (4.4%) for retained stones after laparoscopic treatment. There were no postoperative deaths (95% confidence interval 0-1.6%), and follow-up, ranging from 3 to 42 months, has shown no further clinical evidence of retained stones. CONCLUSION: Diagnosis and treatment of common bile duct stones is feasible by laparoscopy, and the results in this series compare favorably with those of conventional surgical treatment. Complete treatment of biliary lithiasis, in one operation, avoids the pitfalls of patient selection for preoperative endoscopic retrograde cholangiography and the risks of endoscopic sphincterotomy.

[Chemotherapy and targeted treatments in glioblastomas]. / Chimiothérapie et traitements ciblés des glioblastomes.

BACKGROUND AND PURPOSE: We review the indications and limitations of chemotherapy in glioblastoma multiform (GBM), including the role played by alkylating and other cytotoxic agents and the increased input of clinical research on targeted agents in GBM management. METHODS: In 2005, a phase III study clearly concluded in the benefit of adding temozolomide during and after radiotherapy treatment in GBM and thus defined the new standard of treatment in this devastating disease. This schedule increased the median survival from 12.1 to 14 months and the two- and five-year survival rates from 8 to 26%, and 3 to 10%, respectively, with a good tolerance profile. Moreover, methylation of the promoter of the O6 methylguanine DNA transferase (MGMT) gene exhibits a prognostic impact independently of therapeutic schedule but may also predict the benefit of adding temozolomide to radiotherapy. However, pitfalls in MGMT determination and lack of prospective validation have to be solved before considering MGMT as a decisional marker. More recently, antiangiogenic agents including enzastaurin, cediranib, bevacizumab, and others that target mainly the VEGF pathway, have been evaluated in this highly angiogenic disease. Among them, only bevacizumab has been associated with clear anti-tumor activity, although the lack of control studies limits the impact of the results to date. CONCLUSIONS: Recent studies conducted in GBM, both in the adjuvant and recurrent setting, have changed the natural course of the disease and opened a new area of clinical research, including imaging and response evaluation, predictive markers, and other targeted therapies.

Ventilatory and circulatory adjustments in the European eel (Anguilla anguilla L.) exposed to short term hypoxia.

Respiratory and circulatory (measured and calculated) variables were obtained at the same time in resting eels, during normoxia and after 1 h exposure to environmental hypoxia (water PO2 of 40 torr). In normoxia, values of respiratory and circulatory variables appeared less than those reported for most other fish. These differences could be partly explained by a lower level of standard metabolism and a greater uptake of O2 through the skin. Hypoxia caused a marked decrease in heart rate (40%), cardiac output (37%), ventral and dorsal arterial blood pressures (22% and 32%), associated with a constriction of prebranchial veno-venous shunt, and an increase in branchial vascular resistance (30%). Atropine treatment during hypoxia reduced, but did not abolish, bradycardia, and branchial vascular resistance remained unchanged. The lack of increase in cardiac stroke volume as well as the slowing of the heart in atropine-treated eel, could be regarded as metabolic effects of sustained hypoxia. The increase in branchial resistance and constriction of prebranchial veno-venous shunt could be regarded as a direct myogenic effect of hypoxia. Hypoxic exposure resulted in an increase in ventilatory water flow Vg (more than twofold), a decrease in gill O2 uptake (50%) and oxygen partial pressure in arterial (PaO2 80%) and mixed venous blood (PvO2 78%), and in increase in the transfer factor for O2 of the gills, TO2, (+66%). The ventilatory convection requirement increased (fivefold) while extraction (EwO2%) and effectiveness (Eff%) of gill oxygen transfer were maintained in spite of hyperventilation. Hypoxic hyperventilation reduced partial pressure of CO2 (PaCO2 from 3.4 to 0.7 torr) and markedly raised pH (pHa from 7.98 to 8.33) in arterial blood, thus causing a typical respiratory alkalosis, which resulted in increased O2 affinity and capacity of eel haemoglobin.

A study of barosensitivity in the European eel (Anguilla anguilla, L.): effects of arterial pressure changes on heart rate and ventilation.

A study of the effects of arterial pressure changes on heart rate and ventilation was carried out on the eel (Anguilla anguilla L.). The anatomical characteristics of this fish enabled extracorporeal circulation in both the ventral and dorsal aorta to be set up. The pressure was changed mechanically, either by clamping external circulations or, in some cases, by modifying the frequency of a pulsatory pump placed in series with the heart, thus ensuring constant blood flows in the ventral aorta. The maximal pressure decreases obtained by clamping the external ventral aorta circulation (70%-80%) failed to induce significant changes in either heart rate or ventilation. An increase of arterial pressure up to about 50% of the control values did not induce bradycardia and ventilatory response. In the range of 50%-100% increase, a weak decrease of heart rate and slight hyperventilation were observed. Such a ventilatory response was contrary to the hypoventilation classically reported in mammals when systemic arterial pressure was increased, but similar to the hyperventilation observed when blood pressure was increased in the pulmonary arteries. The results emphasized functional analogies in regulation, originating from the circulatory bed, between the two highly compliant circulatory systems: fish circulation and pulmonary circulation of mammals.

Mediation of serotonin-induced hyperventilation via 5-HT3-receptor in European eel Anguilla anguilla.

The effects of serotonin (5-hydroxytryptamine) on ventilation were investigated by continuous measurements of intrabuccal pressure in unrestrained eel. Intravenous administration of 5-hydroxytryptamine (30 micrograms.kg-1) caused a large increase in ventilatory frequency (+ 100%) and amplitude (+ 140%). The 5-hydroxytryptamine-induced hyperventilation was blocked by the 5-HT3-receptor antagonists metoclopramide (1.0 mg.kg-1) or MDL72222 (1.0 mg.kg-1), and was insensitive to the 5-HT1/2-receptor antagonist methysergide (3.0 mg.kg-1) and to the 5-HT4-receptor antagonist DAU 6285 CL (3.0 mg.kg-1). The hyperventilatory response to 5-hydroxytryptamine could be mimicked by the 5-HT3 receptor agonist 1-phenylbiguanide (300 micrograms.kg-1). These results strongly implicate the 5-HT3-receptor as the mediator of the 5-hydroxytryptamine-induced hyperventilation in eel.

Effects of serotonin on the cardio-circulatory system of the European eel (Anguilla anguilla) in vivo.

The effects of serotonin on continuously recorded cardiac parameters (heart rate, cardiac output, cardiac stroke volume), ventral and dorsal aortic blood pressures, branchial and systemic vascular resistances were investigated in the European eel in vivo. Intravenous administration of serotonin (30 micrograms.kg-1) caused a marked bradycardia (45%) and a simultaneous decrease in cardiac output (50%), ventral (35%) and dorsal (50%) aortic blood pressures. Branchial resistance was markedly increased (60%) and systemic resistance decreased (30%). Cardiac stroke volume remained unchanged. The effects of serotonin on cardiac parameters were suppressed either by methysergide or a bilateral section of the cardiac vagus. Bradycardia could then be regarded as the consequence of a vagal mechanism triggered by serotonin action on central methysergide-sensitive serotonergic receptors. No inotropic effect of serotonin was observed. This lack of myocardiac contractility modification is discussed. The serotonin-mediated branchial vasoconstriction was attenuated by vagotomy, whereas the residual increase in branchial resistance (40%) was suppressed by methysergide. The serotonin-mediated branchial vasoconstriction could be the consequence of both a passive mechanism (compliance) caused by the decrease in cardiac output and an active mechanism involving methysergide-sensitive serotonergic receptors of the branchial vasculature. A possible involvement of this vasomotor effect in gill oxygen uptake is discussed. The serotonin-induced systemic vasodilation was insensitive either to cardiac vagotomy or to 5-HT1/2, 5-HT3 and 5-HT4 receptor antagonists, suggesting the involvement of a local mechanism which remains to be assessed.

Relative estimation of ventilatory fow rate in the eel (Anguilla anguilla L.)

Freshwater eels (Anguilla anguilla L.) were experimented on in order to measure ventilatory flow rate (by means of a direct method of collecting expired water), and simultaneously, to record sub-opercular pressure changes and opercular displacements (operculogram). Significant correlations (p less than 0.01) were found between the ventilatory flow rate (V) and various characteristics of operculiogram records. The relationships which are significant in each fish experimented on are; V = a(f.lo) + b; V = a(f.Ao) % b and V = a(f.Ao2) + b(f: ventilatory frequency: Ao and lo: mean amplitude and result of integration of opercular tracings). Considering the technical difficulties in measuring the ventilation flow rate of the eel, the easier operculographic recording methods lead to a correct estimation of relative changes in ventilatory flow rate, by using the refined relationship: V = a(Ao1.63).

Cutaneous and gill O2 uptake in the European eel (Anguilla anguilla L.) in relation to ambient PO2, 10-400 Torr.

The partition of O2 uptake between gills and skin was examined in the freshwater eel (Anguilla anguilla L.) at ambient PO2 ranging from hyperoxia (PO2 = 400 Torr) to severe hypoxia (PO2 = 10 Torr), using a technique of open-flow respirometry. All the expired water was collected, and the ventilatory flow and the mixed expired water PO2 were directly measured. The ventilatory water flow decreased moderately in hyperoxia, increased markedly between normoxia and 40 Torr, and below 40 Torr, hyperventilation was gradually reduced. Between PO2 400 and 70 Torr, the total O2 uptake was constant and the skin O2 uptake was lower than gill O2 uptake (32% of total uptake in normoxia). Between 70 and 10 Torr, the skin contribution to the total O2 uptake progressively increased, and was higher than gill O2 uptake in severe hypoxia. A possible facilitation of cutaneous O2 uptake in hypoxia is discussed from estimates of the O2 diffusing capacity of the skin.

Physiological evidence for the occurrence of pathways shunting blood away from the secondary lamellae of eel gills.

1. Several cardiovascular and respiratory measurements have been performed in eels before and after intravenous injections of adrenaline. These experiments have allowed a comparison to be made of values for the cardiac output determined directly (Q) and using the Fick principle (QF) on individual fish under these two conditions. 2. Under control conditions it was shown that QF/Q = 0.72, indicating that about 30% of the mixed venous blood afferent to the gills is returned directly to the heart and bypasses the lamellar circulation via veno-venous anastomoses between the afferent filament arteries and the central venous space of the gill filaments. 3. Adrenaline, which during winter only has its action due to stimulation of alpha-adrenoreceptors, induced a hypoventilation but no changes in cardiac output in spite of a bradycardia. The oxygen content of the mixed venous blood was markedly increased whereas Ca,O2 remained unchanged as did the percentage utilization of oxygen from the water as it passed over the gills. The efferent blood flow from the gills after injection of adrenaline was almost equal to the total cardiac output. It is suggested that such a circulatory change was due to adrenaline-mediated constriction of veno-venous anastomoses in the gills of the eel.

[Cardiorespiratory effects of exogenous hypercapnia in eels]. / Etude des effets cardio-ventilatoires de l'hypercapnie exogène chez l'anguille

The study of electrocardiogram and opercular movement records, from eels exposed for prolonged periods to hypercarbic water (saturation by the gaseous mixture 2% CO2, 98% air) shows that 1) heart rate is not significantly changed; 2) the duration of spontaneous apnea phases and the magnitude of opercular movements during ventilatory phases are increased under hypercapnic conditions. Because the integrated records of opercular movements only give an arbitrary estimate of changes in ventilation rate, direct measurements of the ventilation volume were performed in order to state the way of the dominant action of CO2. This method allows us to conclude that exogenous hypercapnia significantly decreases the ventilatory rate in eels.

PCV chemotherapy for oligodendroglioma: response analyzed on T2 weighted-MRI.

OBJECTIVE: Because oligodendroglioma are infiltrative tumors, the Mac Donald's response criteria, usually used for solid and contrast-enhanced tumors, seem not to be adapted. To precise more relevant radiological criteria, the radiological response of oligodendroglioma to PCV chemotherapy was evaluated on T2 weighted-MRI sequences only. METHODS: 25 patients with oligodendroglioma grade A or B were retrospectively analyzed. They were treated with up to six cycles of PCV standard regimen. Tumor size was calculated before and at the end of the treatment, on T2 weighted-MRI, by two methods: volumetric reconstruction (method 1) and maximal cross-sectional area (method 2). Responses were defined according to new criteria on T2 weighted-MRI. RESULTS: According to these criteria and with the method 1, 7 of 25 patients (28%) had a partial response to the PCV, 14 patients (56%) had stabilized disease, and 4 patients (16%) had progressive disease. With the method 2, 6 had partial response (24%), 18 had stabilized disease (72%) and 1 had progressive disease. CONCLUSION: Response rate to PCV chemotherapy in this study was lower than response observed in the literature. Because of the infiltrative feature of oligodendroglioma, we think that the radiological response of these tumors should be evaluated on T2 weighted-MRI. The two methods of tumor size estimation used in this study were almost equivalent. Then, the maximal cross-sectional area measurement, more practical, could be retained.

Prospective evaluation in 121 consecutive unselected patients undergoing laparoscopic treatment of choledocholithiasis.

Laparoscopic common bile duct (CBD) exploration was attempted in 115 of 121 consecutive unselected patients with choledocholithiasis (mean age 69 (range 21-92) years) found during routine intraoperative cholangiography. The CBD was successfully cleared of all stones in 100 patients (87 per cent). Ten of 11 patients referred for surgery after failure of endoscopic sphincterotomy had complete laparoscopic choledocholithiasis. Eleven patients (10 per cent) required conversion to open CBD exploration, and laparoscopic exploration was not attempted in six (5 per cent) because of inflammation or fibrosis. Postoperative endoscopic sphincterotomy was required in four patients (4 per cent) for retained stones after laparoscopic exploration. There were no postoperative deaths (39 per cent of patients were aged 75 years or more). Routine intraoperative cholangiography, and when required laparoscopic CBD exploration, should be compared in randomized trials with preoperative endoscopic retrograde cholangiography in patients with suspected choledocholithiasis.