Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma : a prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06) : 4570

Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4-8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47-71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders.

The use of 3D planning in facial surgery: Preliminary observations.

Three-dimensional (3D) planning is becoming a more commonly used tool in maxillofacial surgery. At first used only virtually, 3D planning now also enables the creation of useful intraoperative aids such as cutting guides, which decrease the operative difficulty. In our center, we have used 3D planning in various domains of facial surgery and have investigated the advantages of this technique. We have also addressed the difficulties associated with its use. 3D planning increases the accuracy of reconstructive surgery, decreases operating time, whilst maintaining excellent esthetic results. However, its use is restricted to osseous reconstruction at this stage and once planning has been undertaken, it cannot be reversed or altered intraoperatively. Despite the attractive nature of this new tool, its uses and practicalities must be further evaluated. In particular, cost-effectiveness, hospital stay, and patient perceived benefits must be assessed.

Decreased Probability of Initial Pain Cessation in Classic Trigeminal Neuralgia Treated With Gamma Knife Surgery in Case of Previous Microvascular Decompression: A Prospective Series of 45 Patients With >1 Year of Follow-up.

BACKGROUND: Microvascular decompression (MVD) is the reference technique for pharmacoresistant trigeminal neuralgia (TN). OBJECTIVE: To establish whether the safety and efficacy of Gamma Knife surgery for recurrent TN are influenced by prior MVD. METHODS: Between July 1992 and November 2010, 54 of 737 patients (45 of 497 with >1 year of follow-up) had a history of MVD (approximately half also with previous ablative procedure) and were operated on with Gamma Knife surgery for TN in the Timone University Hospital. 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 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range, 70-90 Gy) was delivered. RESULTS: The median follow-up time was 39.5 months (range, 14.1-144.6 months). Thirty-five patients (77.8%) were initially pain free in a median time of 14 days (range, 0-180 days), much lower compared with our global population of classic TN (P = .01). Their actuarial probabilities of remaining pain-free without medication at 3, 5, 7, and 10 years were 66.5%, 59.1%, 59.1%, and 44.3%. The hypoesthesia actuarial rate at 1 year was 9.1% and remained stable until 12 years (median, 8 months). CONCLUSION: Patients with previous MVD showed a significantly lower probability of initial pain cessation compared with our global population with classic TN (P = .01). The toxicity was low (only 9.1% hypoesthesia); furthermore, no patient reported bothersome hypoesthesia. However, the probability of maintaining pain relief without medication was 44.3% at 10 years, similar to our global series of classic TN (P = .85). ABBREVIATIONS: BNI, Barrow Neurological InstituteCI, confidence intervalCTN, classic trigeminal neuralgiaGKS, Gamma Knife surgeryHR, hazard ratioMVD, microvascular decompressionTN, trigeminal neuralgia.

Long-term Outcome and Late Side Effects in Endometrial Cancer Patients Treated with Surgery and Postoperative Radiation Therapy.

BACKGROUND: We retrospectively reviewed the long-term outcome and late side effects of endometrial cancer (EC) patients treated with different techniques of postoperative radiotherapy (PORT). METHODS: Between 1999 and 2012, 237 patients with EC were treated with PORT. Two-dimensional external beam radiotherapy (2D-EBRT) was used in 69 patients (30 %), three-dimensional EBRT (3D-EBRT) in 51 (21 %), and intensity-modulated RT (IMRT) with helical Tomotherapy in 47 (20 %). All patients received a vaginal brachytherapy (VB) boost. Seventy patients (29 %) received VB alone. RESULTS: After a median of 68 months (range, 6-154) of follow-up, overall survival was 75 % [95 % confidence interval (CI), 69-81], disease-free survival was 72 % (95% CI, 66-78), cancer-specific survival was 85 % (95 % CI, 80-89), and locoregional control was 86 % (95 % CI, 81-91). The 5-year estimates of grade 3 or more toxicity and second cancer rates were 0 and 7 % (95 % CI, 1-13) for VB alone, 6 % (95 % CI, 1-11) and 0 % for IMRT + VB, 9 % (95 % CI, 1-17) and 5 % (95 % CI, 1-9) for 3D-EBRT + VB, and 22 % (95 % CI, 12-32) and 12 % (95 % CI, 4-20) for 2D-EBRT + VB (P = 0.002 and P = 0.01), respectively. CONCLUSIONS: Pelvic EBRT should be tailored to patients with high-risk EC because the severe late toxicity observed might outweigh the benefits. When EBRT is prescribed for EC, IMRT should be considered, because it was associated with a significant reduction of severe late side effects.

Submacular fluid after encircling buckle surgery for inferior macula-off retinal detachment in young patients.

PURPOSE: Characterization of persistent diffuse subretinal fluid using optical coherence tomography (OCT) after successful encircling buckle surgery for inferior macula-off retinal detachment in young patients. METHODS: Institutional retrospective review of six young patients (mean age 31 +/- 6 years; five female, one male) with spontaneous inferior rhegmatogenous macula-off retinal detachment. All patients were treated with encircling buckle surgery and five out of six underwent additional external drainage of subretinal fluid. Mean follow-up was 37 +/- 25 months (range 17-75 months) and included complete ophthalmic and OCT examination. RESULTS: At 6 months, 100% of patients showed persistence of subretinal fluid on OCT. Four patients had diffuse fluid accumulation, whereas two patients showed a 'bleb-like' accumulation of fluid. This fluid was present independent of whether or not patients had been treated with external fluid drainage. Subretinal fluid only started to disappear on OCT between 6 and more than 12 months after surgery. CONCLUSION: Young patients with inferior macula-off retinal detachments and a marginally liquefied vitreous may show persisting postoperative subclinical fluid under the macula for longer periods of time than described previously.

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients.

INTRODUCTION: Oxidative stress is involved in the development of secondary tissue damage and organ failure. Micronutrients contributing to the antioxidant (AOX) defense exhibit low plasma levels during critical illness. The aim of this study was to investigate the impact of early AOX micronutrients on clinical outcome in intensive care unit (ICU) patients with conditions characterized by oxidative stress. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, single-center trial in patients admitted to a university hospital ICU with organ failure after complicated cardiac surgery, major trauma, or subarachnoid hemorrhage. Stratification by diagnosis was performed before randomization. The intervention was intravenous supplements for 5 days (selenium 270 microg, zinc 30 mg, vitamin C 1.1 g, and vitamin B1 100 mg) with a double-loading dose on days 1 and 2 or placebo. RESULTS: Two hundred patients were included (102 AOX and 98 placebo). While age and gender did not differ, brain injury was more severe in the AOX trauma group (P = 0.019). Organ function endpoints did not differ: incidence of acute kidney failure and sequential organ failure assessment score decrease were similar (-3.2 +/- 3.2 versus -4.2 +/- 2.3 over the course of 5 days). Plasma concentrations of selenium, zinc, and glutathione peroxidase, low on admission, increased significantly to within normal values in the AOX group. C-reactive protein decreased faster in the AOX group (P = 0.039). Infectious complications did not differ. Length of hospital stay did not differ (16.5 versus 20 days), being shorter only in surviving AOX trauma patients (-10 days; P = 0.045). CONCLUSION: The AOX intervention did not reduce early organ dysfunction but significantly reduced the inflammatory response in cardiac surgery and trauma patients, which may prove beneficial in conditions with an intense inflammation. TRIALS REGISTRATION: Clinical Trials.gov RCT Register: NCT00515736.

Nouveautés en médecine ambulatoire [Innovations in ambulatory care]

During 2008, we selected 8 studies of interest. It seems important to continue to treat high tension for old patients. To give a good medication against pain, to maintain activity and to reassure patient is the treatment for acute back pain; surgery for spinal stenosis has better results than other treatments at two years of evolution. Pregabalin seems to provide clinically benefit to patients with fibromyalgia. Helicobacter pylori test and treat has the same results than proton pomp inhibitor in initial management of dyspepsia; extending triple therapy beyond 7 days is unlikely to be a clinical useful strategy. Syphilis testing algorithms using treponemal tests for initial screening could be inversed. Finally, selective reporting of clinical trials results for antidepressant are relatively frequent.

Laparoscopic aortic surgery: Techniques and results.

OBJECTIVE: This review describes and evaluates the results of laparoscopic aortic surgery. METHODS: We describe the different laparoscopic techniques used to treat aortic disease, including (1) total laparoscopic aortic surgery (TLS), (2) laparoscopy-assisted procedures including hand-assisted laparoscopic surgery (HALS), and (3) robot-assisted laparoscopic surgery, with their current indications. Results of these techniques are analyzed in a systematic review of the clinical series published between 1998 and 2008, each containing >10 patients with complete information concerning operative time, clamping time, conversion rate, length of hospital stay, morbidity, and mortality. RESULTS: We selected and reviewed 29 studies that included 1073 patients. Heterogeneity of the studies and selection of the patients made comparison with current open or endovascular surgery difficult. Median operative time varied widely in TLS, from 240 to 391 minutes. HALS had the shortest operating time. Median clamping time varied from 60 to 146 minutes in TLS and was shorter in HALS. Median hospital stay varied from 4 to 10 days regardless of the laparoscopic technique. The postoperative mortality rate was 2.1% (95% confidence interval, 1.4-3.0), with no significant difference between patients treated for occlusive disease or for aneurysmal disease. Conversion to open surgery was necessary in 8.1% of patients and was slightly higher with TLS than with laparoscopy-assisted techniques (P = .07). CONCLUSIONS: Analysis of these series shows that laparoscopic aortic surgery can be performed safely provided that patient selection is adjusted to the surgeon's experience and conversion is liberally performed. The future of this technique in comparison with endovascular surgery is still unknown, and it is now time for multicenter randomized trials to demonstrate the potential benefit of this type of surgery.

The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.

Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.

Impact de la chirurgie bariatrique sur la santé et la qualité de vie du patient obèse [Impact of bariatric surgery on health and quality life of obese patients]

The important weight loss due to bariatric surgery allows to improve and even correct, a great part of the comorbidities induced by obesity, as well as quality of life, and to reduce the coming out of cardiovascular and metabolic diseases in operated patients. The impact of surgical treatment on the patient's health and quality of life also allows to reduce direct and indirect costs of morbid obesity. However, its effects on mortality have not yet been clearly proved. The preoperative evaluation and the long term follow-up by a skilled team are essential to reduce potential complications, especially on the nutritional field and the risks of recovered weight linked to binge eating disorders.

Invasion of lesion territory by regenerating fibers after spinal cord injury in adult macaque monkeys.

In adult macaque monkeys subjected to an incomplete spinal cord injury (SCI), corticospinal (CS) fibers are rarely observed to grow in the lesion territory. This situation is little affected by the application of an anti-Nogo-A antibody which otherwise fosters the growth of CS fibers rostrally and caudally to the lesion. However, when using the Sternberger monoclonal-incorporated antibody 32 (SMI-32), a marker detecting a non-phosphorylated neurofilament epitope, numerous SMI-32-positive (+) fibers were observed in the spinal lesion territory of 18 adult macaque monkeys; eight of these animals had received a control antibody infusion intrathecally for 1month after the injury, five animals an anti-Nogo-A antibody, and five animals received an anti-Nogo-A antibody together with brain-derived neurotrophic factor (BDNF). These fibers occupied the whole dorso-ventral axis of the lesion site with a tendency to accumulate on the ventral side, and their trajectories were erratic. Most of these fibers (about 87%) were larger than 1.3μm and densely SMI-32 (+) stained. In the undamaged spinal tissue, motoneurons form the only large population of SMI-32 (+) neurons which are densely stained and have large diameter axons. These data therefore suggest that a sizeable proportion of the fibers seen in the lesion territory originate from motoneurons, although fibers of other origins could also contribute. Neither the presence of the antibody neutralizing Nogo-A alone, nor the presence of the antibody neutralizing Nogo-A combined with BDNF influenced the number or the length of the SMI-32 (+) fibers in the spinal lesion area. In summary, our data show that after a spinal cord lesion in adult monkeys, the lesion site is colonized by fibers, a large portion of which presumably originate from motoneurons.