Cecil O. Borel

Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

PURPOSE To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy.

The aim of this study was to evaluate the predictive value of five different biological factors in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy: (1) tumour grade scored according to the Elston-Ellis classification, (2) hormonal receptor (HR) status; (3) tumour cell proliferation evaluated by Ki-67 staining, (4) HER-2 and topoisomerase II alpha (TopoIIalpha) expression evaluated by immunohistochemistry (IHC), (5) HER-2 and TopoIIalpha amplification evaluated by real-time polymerase chain reaction (PCR). 119 patients with operable breast cancer were treated with six cycles of FEC (100 5-fluorouracil (5-FU) 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2). Tumour response was assessed clinically and by computed tomography (CT) scan, then by pathological assessment. The clinical overall response (OR) was 80%, with 19% of complete responders (CR). The radiological OR was 71%, with 16% of CR. A pathological CR was demonstrated in 13% of the patients according to the Sataloff classification. In the multivariate analysis, the absence of HR expression and Ki-67 > or = 20% were predictive for a clinical CR. A high tumour grade was predictive for a pathological CR. Overexpression or amplification of HER2 or Topollcalpha were not predictive of response.

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

BackgroundRemifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.MethodsSixty-three adults gave written informed consent for

Sequential chemoimmunotherapy with cisplatin, interleukin-2, and interferon alfa-2a for metastatic melanoma.

PURPOSE To evaluate the activity and the toxicity of the combination of cisplatin (CDDP)/recombinant interleukin-2 (rIL-2) and interferon alfa-2a (IFN alpha) in disseminated malignant melanoma (DMM). PATIENTS AND METHODS Between December 1990 and March 1992, 39 patients with biopsy-proven metastatic malignant melanoma (MM), bidimensionally measurable lesions and an Eastern Cooperative Oncology Group (ECOG) performance status < or = 2 entered this protocol. Seventy-nine percent had received previous chemotherapy including platinum complex (15%) and alpha interferon (44%). They received CDDP (100 mg/m2 on day 0) followed by IL-2 18.10(6) IU/m2/d continuous intravenous (IV) infusion from day 3 to day 6 and from day 17 to day 21. The cycle was repeated on day 28. Subcutaneous IFN alpha 9.10(6) IU three times weekly was administered throughout the treatment period. From day 66 or 94, patients were administered a maintenance cycle with CDDP 100 mg/m2, subcutaneous IL-2 5.10(6) IU/m2/d from day 15 to day 19 and from day 22 to day 26 and IFN alpha 9.10(6) IU three times weekly repeated every 5 weeks (maximum four cycles). RESULTS Among 39 assessable patients, five patients achieved complete responses (CRs). Sixteen patients had partial responses (PRs). The overall objective response rate was 53.8%. The number of metastatic sites was the only response-predictive factor. Toxicity was manageable in a routine patient setting and there was no life-threatening toxicity. CONCLUSION These results seem to indicate a possible synergy between CDDP/rIL-2 and IFN alpha in MM.

Possible Role for Vascular Cell Proliferation in Cerebral Vasospasm After Subarachnoid Hemorrhage

Background and Purpose— During vasospasm after subarachnoid hemorrhage (SAH), cerebral blood vessels show structural changes consistent with the actions of vascular mitogens. We measured platelet-derived vascular growth factors (PDGFs) in the cerebrospinal fluid (CSF) of patients after SAH and tested the effect of these factors on cerebral arteries in vivo and in vitro. Methods— CSF was sampled from 14 patients after SAH, 6 patients not suffering SAH, and 8 normal controls. ELISA was performed for PDGF-AB, transforming growth factor-&bgr;1, and vascular endothelial growth factor. A mouse model was used to compare cerebral vascular cell proliferation and PDGF staining in SAH compared with sham-operated controls. Normal human pial arteries were incubated for 7 days in vitro, 2 groups with human blood clot and 1 with and 1 without PDGF antibodies. Results— PDGF-AB concentrations in CSF from SAH patients were significantly higher than those from non-SAH patients and normal controls, both during the first week after SAH and for all time points measured. Smooth muscle and fibroblast proliferation was observed after SAH in the mouse model, and this cellular replication was observed in conjunction with PDGF protein at the sites of thrombus. In human pial arteries, localized thrombus stimulated vessel wall proliferation, and proliferation was blocked by neutralizing antibodies directed against PDGFs. Conclusions— Vascular mitogens are increased in the CSF of patients after SAH. Proliferation of cells in the vascular wall is associated with perivascular thrombus. Cellular proliferation and subsequent vessel wall thickening may contribute to the syndrome of delayed cerebral vasospasm.

Intensive management and treatment of severe Guillain-Barré syndrome.

ObjectiveTo review the management and therapeutic approaches to severe acute Guillain-Barré syndrome, with emphasis on the ventilatory dysfunction, and cardiovascular instability seen in patients with this syndrome. Data Sources/Study SelectionClinical studies on Guillain-Barré syndrome patients, physiologic studies on animals and humans. Data Extraction/SynthesisGuillain-Barré syndrome is an acutely evolving, immune-mediated, inflammatory disorder of the peripheral nervous system, leading to demyelination and axonal loss. Clinical hallmarks are symmetric flaccid muscle paresis and areflexia in the presence of an increased cerebrospinal fluid protein content, and electrophysiologic studies demonstrating evolving demyelination. The only well-investigated, efficacious immunomodulatory therapy is plasmapheresis. Plasmapheresis has been shown to decrease ventilator dependence in severe Guillain-Barré syndrome. Ventilatory failure and cardiovascular instability are the main reasons for intensive care support. Ventilatory failure is caused by involvement of airway and respiratory muscles, particularly the diaphragm. Cardiovascular instability is due to involvement of the autonomic nervous system and results in labile blood pressure, cardiac arrhythmias, and hypovolemia. After admission to the intensive care unit, the most serious complications result from mechanical ventilation, circulatory disturbances, thrombosis, starvation, and sepsis. Special emphasis should be given to psychologic support and management of pain. ConclusionsWith modern intensive care support, the outcome is excellent (>80% recovery). In severe cases, a higher frequency of persistent residual paresis occurs; however, the majority of this group ultimately have a good functional recovery. (Crit Care Med 1993; 21:433–446)

Development of a new state-of-the-art beamline optimized for monochromatic single-crystal and powder X-ray diffraction under extreme conditions at the ESRF.

A new state-of-the art synchrotron beamline fully optimized for monochromatic X-ray diffraction at high pressure and high (or low) temperature is presented. In comparison with the old high-pressure beamline ID30, this new beamline exhibits outstanding performance in terms of photon flux and focusing capabilities. The main components of this new instrument will be described in detail and compared with the performance of beamline ID30. In particular, the choices in terms of X-ray source, X-ray optics, sample environment and detectors are discussed. The first results of the beamline commissioning are presented.

Analysis of the brain bioavailability of peripherally administered magnesium sulfate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia

Objective:Based on preclinical investigations, magnesium sulfate (MgSO4) has gained interest as a neuroprotective agent. However, the ability of peripherally administered MgSO4 to penetrate the blood-brain barrier is limited in normal brain. The current study measured the passage of intravenously administered Mg2+ into cerebrospinal fluid in patients with brain injury requiring ventricular drainage. Design:A prospective evaluation of the cerebrospinal fluid total and ionized magnesium concentration, [Mg2+], during sustained hypermagnesemia was performed. Setting:Neurosciences intensive care unit at a major teaching institution. Patients:Thirty patients with acute brain injury secondary to subarachnoid hemorrhage, traumatic brain injury, primary intracerebral hemorrhage, subdural hematoma, brain tumor, central nervous system infection, or ischemic stroke were studied. Interventions:Patients underwent 24 hrs of induced hypermagnesemia during which total and ionized cerebrospinal fluid [Mg2+] was measured. Serum [Mg2+] was adjusted to 2.1–2.5 mmol/L. Cerebrospinal fluid [Mg2+] was measured at baseline, at 12 and 24 hrs after onset of infusion, and at 12 hrs following infusion termination. Measurements and Main Results:At baseline, total (1.25 ± 0.14 mmol/L) and ionized (0.80 ± 0.10 mmol/L) cerebrospinal fluid [Mg2+] was greater than serum total (0.92 ± 0.18 mmol/L) and ionized (0.63 ± 0.07 mmol/L) [Mg2+] (p < .05). Total (1.43 ± 0.13 mmol/L) and ionized (0.89 ± 0.12 mmol/L) cerebrospinal fluid [Mg2+] was maximally increased by 15% and 11% relative to baseline, respectively, during induced hypermagnesemia (p < .05). Conclusions:Hypermagnesemia produced only marginal increases in total and ionized cerebrospinal fluid [Mg2+]. Regulation of cerebrospinal fluid [Mg2+] is largely maintained following acute brain injury and limits the brain bioavailability of MgSO4.

A retrospective analysis of a remifentanil/propofol general anesthetic for craniotomy before awake functional brain mapping.

We performed this study to summarize drug dosing, physiologic responses, and anesthetic complications from an IV general anesthetic technique for patients undergoing craniotomy for awake functional brain mapping. Review of 98 procedures revealed “most rapid” IV infusion rates for remifentanil 0.05, 0.05–0.09 &mgr;g · kg−1 · min−1 and propofol 115, 100–150 &mgr;g · kg−1 · min−1. The infusions lasted for 78, 58-98 min. Intraoperative emergence from general anesthesia was 9 (6–13) min after discontinuing IV infusions to allow for brain mapping and was independent of infusion duration and duration of craniotomy before mapping. Spontaneous ventilation was generally satisfactory during drug infusion, as evidenced by Sao2 = 95% (92%–98%) and Paco2 = 50 (47–55) mm Hg. However, we recorded at least one 30-s epoch of apnea in 69 of 96 patients. Maximum systolic arterial blood pressure was 150 (139–175) mm Hg and minimal systolic arterial blood pressure was 100 (70–150) mm Hg during drug infusion. Three patients experienced intraoperative seizures. Two patients did not tolerate the awake state and required reinduction of general anesthesia. No patients required endotracheal intubation or discontinuation of surgery. This general anesthetic technique is effective for craniotomy with awake functional brain mapping and offers an alternative to continuous wakefulness or other IV sedation techniques.

A randomized, double-blinded comparison of ondansetron, droperidol, and placebo for prevention of postoperative nausea and vomiting after supratentorial craniotomy

UNLABELLED Nausea or vomiting occurs frequently after craniotomy. Because of the need for frequent postoperative neurological assessment, an effective antiemetic with minimal sedative side effects is needed. Therefore, we compared ondansetron to droperidol in a randomized, double-blinded, placebo-controlled study. A total of 60 adults requiring elective supratentorial craniotomy received standardized IV anesthesia with 4 mg of ondansetron, 0.625 mg of droperidol, or placebo at skin closure. The incidence of postoperative nausea, emesis, pain and sedation scores, and rescue antiemetic use were recorded at 0, 0.5, 1, 4, 8, 12, 24, and 48 h. All groups were demographically similar. Differences existed for cumulative 8, 12, and 24 h incidences of nausea (24 h, P = 0.03) and emesis (24 h, P = 0.04). Within 4 h, when maximal effect could be expected from treatment, 20% of the ondansetron group, 25% of the droperidol group and 50% of the placebo group received rescue antiemetic (P = 0.12). No differences in pain (P = 0.82) or sedation (P = 0.74) scores were detected. Both ondansetron and droperidol prevent nausea; however, only droperidol reduces emesis after supratentorial craniotomy. The dose of droperidol used was not more sedating than ondansetron. Sustained reduction in nausea and emesis over 24 h indicates a preemptive benefit of prophylactic antiemetic in this surgical population. IMPLICATIONS Nausea and vomiting after brain surgery are particularly troubling, because effective treatment may cause sedation, making postoperative neurological assessment difficult. Our study shows that both ondansetron and droperidol are effective in reducing nausea, and that droperidol is particularly effective in reducing vomiting. Neither drug caused more sedation than placebo.