Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Aortic valve repair versus mechanical valve replacement for root aneurysm: the CAVIAAR multicentric study.

OBJECTIVES: Despite growing evidence that aortic valve repair improves long-term patient outcomes and quality of life, aortic valves are mostly replaced. We evaluate the effect of aortic valve repair versus replacement in patients with dystrophic aortic root aneurysm up to 4 years. METHODS: The multicentric CAVIAAR (Conservation Aortique Valvulaire dans les Insuffisances Aortiques et les Anévrismes de la Racine aortique) prospective cohort study enrolled 261 patients: 130 underwent standardized aortic valve repair (REPAIR) consisting of remodelling root repair with expansible aortic ring annuloplasty, and 131 received mechanical composite valve and graft replacement (REPLACE). Primary outcome was a composite criterion of mortality, reoperation, thromboembolic or major bleeding events, endocarditis or operating site infections, pacemaker implantation and heart failure, analysed with propensity score-weighted Cox model analysis. Secondary outcomes included major adverse valve-related events and components of primary outcome. RESULTS: The mean age was 56.1 years, and valve was bicuspid in 115 patients (44.7%). Up to 4 years, REPAIR did not significantly differ from REPLACE in terms of primary outcome [Hazard Ratio (HR) 0.66 (0.39; 1.12)] but showed significantly less valve-related deaths (HR 0.09 [0.02; 0.34]) and major bleeding events (HR 0.37 [0.16; 0.85]) without an increased risk of valve-related reoperation (HR 2.10 [0.64; 6.96]). When accounting for the occurrence of multiple events in a single patient, the REPAIR group had half the occurrence of major adverse valve-related events (HR 0.51 [0.31; 0.86]). CONCLUSIONS: Although the primary outcome did not significantly differ between the REPAIR and REPLACE groups, the trend is in favour of REPAIR by a significant reduction of valve-related deaths and major bleeding events. Long-term follow-up beyond 4 years is needed to confirm these findings.

Transcatheter valve-in-valve implantation in a degenerated very small Mitroflow prosthesis.

OBJECTIVES: To assess the feasibility and results of 'valve-in-valve' implantation using the 23-mm CoreValve for the treatment of degenerated 19-mm and 21-mm Mitroflow bioprostheses. METHODS: We retrospectively analysed all consecutive patients who underwent transcatheter aortic valve implantation for 19-mm and 21-mm Mitroflow bioprostheses. The height of implantation with respect to the ring of the Mitroflow prosthesis was targeted at -6 mm for the first 3 cases. In the following cases, the target was higher to promote free supra-annular movement of the leaflets. RESULTS: The procedure was successful in 17 of 18 patients (94%). For implantations above the limit of -6 mm, the mean gradient was 10.4 ± 2.6 mmHg compared with 28.1 ± 11.6 mmHg for implantations below the limit of -6 mm (P < 0.01). For patients with severe stenosis as main mechanism of failure of the bioprosthesis, the mean post-procedural gradient was 31.2 ± 11.8 mmHg compared with 12.7 ± 6 mmHg in the absence of severe stenosis (P < 0.01). Patient-prosthesis mismatch (indexed effective orifice area ≤ 0.85 cm2/m2) and severe mismatch (indexed effective orifice area ≤ 0.65 cm2/m2) were present in 83% (15 of 18) and 27% (5 of 18) of patients, respectively. We did not notice any complications following the procedures. Six months after the procedure, functional status was improved in all patients. CONCLUSIONS: Our short series demonstrates the ability to perform transcatheter 'valve-in-valve' implantation in 19-mm and 21-mm Mitroflow prostheses with satisfactory results, but high post-procedural gradients and patient-prosthesis mismatch remain a relatively frequent problem mostly when severe stenosis is the main mechanism of failure. Implantation in a high position is critical to decrease the rate of high postimplantation gradients.

Standardized approach to valve repair using an expansible aortic ring versus mechanical Bentall: early outcomes of the CAVIAAR multicentric prospective cohort study.

OBJECTIVE: The study objective was to compare the 30-day outcomes of a standardized aortic valve repair technique (REPAIR group) associating root remodeling with an expansible aortic ring annuloplasty versus mechanical composite valve and graft (CVG group) replacement in treating aortic root aneurysms. METHODS: A total of 261 consecutive patients with aortic root aneurysm were enrolled in this multicentric prospective cohort (131 in the CVG group, 130 in the REPAIR group) in 20 centers. The main end point is a composite criterion including mortality; reoperation; thromboembolic, hemorrhagic, or infectious events; and heart failure. Secondary end points were major adverse valve-related events. Crude and propensity score adjusted estimates are provided. RESULTS: The mean age was 56.1 years, and the valve was bicuspid in 115 patients (44.7%). The median (interquartile range) preoperative aortic insufficiency grade was 2.0 (1.0-3.0) in the REPAIR group and 3.0 (2.0-3.0) in the CVG group (P = .0002). Thirty-day mortality was 3.8% (n = 5) in both groups (P = 1.00). Despite a learning curve and longer crossclamp times for valve repair (147.7 vs 99.8 minutes, P < .0001), the 2 groups did not differ significantly for the main criterion (odds ratio, 1.31; 95% confidence interval, 0.72-2.40; P = .38) or 30-day mortality (odds ratio, 0.99; 95% confidence interval, 0.28-3053; P = .99), with a trend toward more frequent major adverse valve-related events in the CVG group (odds ratio, 2.52; 95% confidence interval, 0.86-7.40; P = .09). At discharge, 121 patients (96.8%) in the REPAIR group had grade 0 or 1 aortic insufficiency. CONCLUSIONS: A new standardized approach to valve repair, combining an expansible aortic annuloplasty ring with the remodeling technique, presented similar 30-day results to mechanical CVG with a trend toward reducing major adverse valve-related events. Analysis of late outcomes is in process for 3- and 10-year follow-ups.

Factores emocionales y físicos relacionados a padecimientos neuromusculoesqueléticos en estudiantes de práctica clínica de la Facultad de Odontología Universidad de El Salvador / Emotional and physical factors related to neuromusculoskeletal disorders in clinical practice students of the Faculty of Dentistry, University of El Salvador. PhD thesis, University of El Salvador

La odontología está catalogada como uno de los ejercicios profesionales más estresantes y los padecimientos neuromusculoesqueléticos son problemas médicos frecuentes que pueden estar relacionados con la práctica clínica diaria. Objetivo: Determinar los factores emocionales y físicos relacionados a padecimientos neuromusculoesqueléticos en estudiantes de práctica clínica de la Facultad de Odontología Universidad de El Salvador. Materiales y Métodos: Se evaluaron 68 estudiantes del área clínica de los ciclos IX y XI, con edades entre los 21 a 32 años, 24 masculinos y 44 femeninos a través de una guía de observación se evaluaron las posturas adoptadas de trabajo y tensión muscular por movimientos estáticos y repetitivos, y para determinar el factor emocional se utilizó la escala de Maslach; y un cuestionario para determinar los padecimientos neuromusculoesqueléticos. Resultados: De 68 estudiantes evaluados en la subescala de agotamiento emocional, 38% presentaron un nivel alto, 25 % agotamiento intermedio y 36 % no presentaron agotamiento. El 75% mostró posturas inadecuadas durante la práctica clínica; los síntomas más frecuentes son dolor en el 89% de estudiantes seguido del espasmo con un 60% estos síntomas y signos se presentaron mayormente en espalda, cuello y hombros, mientras que el adormecimiento ocupa el tercer lugar con el 38% presentándose en dedos 17.65%) y espalda (14.75%). Conclusiones: Si existe relación entre factores emocionales (agotamiento mental y emocional) y padecimientos neuromusculoesqueléticos con un valor 0.006, También el factor físico posición de muslos con dolor de espalda presentó una relación significativa con un valor exacto de 0.046. No así con movimientos estáticos y repetitivos ya que en las diferentes pruebas dio un valor mayor a 0.05.

Dentistry is ranked as one of the most stressfull professional exercises related to neuromusculoskeletal disorders are common medical problems that may be related to daily clinical practice. Objective: To determine the emotional and physical factors related to neuromusculoskeletal disorders in clinical practice students of the Faculty of Dentistry University of El Salvador. Materials and Methods: 68 students of the clinical area IX and XI cycles were evaluated, aged 21 to 32 years, 24 male and 44 female through an observation working postures adopted and muscle tension were evaluated by static and repetitive movements, and to determine emotional Maslach scale factor was used, and questionnaire to determine and neuromusculoskeletal disorders. Results: Of 68 students tested in the subscale of emotional exhaustion, 38% had a high level, 25% intermediate and 36% depletion showed no fatigue. 75% had inadequate postures during clinical practice, the most common symptoms are pain in 81% of students continued to spasm, with 60% of these symptoms and signs are mostly presented in back, neck and shoulders. While the numbness is third with 38% appearing in fingers (17.65%) and back (14.75%). Results: Of 68 students tested in the subscale of emotional exhaustion, 38% had a high level, 25% intermediate and 36% depletion showed no exhaustion. 75% had inadequate postures during clinical practice; the most common symptoms are pain in 81% of students continued to spasm, Conclusions: There is relationship between emotional factors (mental and emotional exhaustion) and neuromusculoskeletal conditions with p value 0.006, also the physical factor position thighs with back pain had a significant relationship with an exact value of 0.046. Not so with static and repetitive movements as in the different test gave a p-value greater than 0.05.

Wrapping procedure for stanford type a acute aortic dissection: is there an indication for surgery without a cardiopulmonary bypass?

A wrapping procedure for acute type A aortic dissection was performed on six elderly patients at high risk for conventional surgery. Aortic valve insufficiency was mild, with no malperfusion syndrome. A Teflon plaque or Dacron vascular prosthesis was passed around the aorta and tightened from the coronary ostia to the innominate artery. No severe neurologic complications or deaths occurred in the postoperative period. Computed tomography and magnetic resonance imaging imaging during follow-up showed aortic diameters had stabilized in all patients.

Floating aortic thrombus: aortic trauma treated by heparin and delayed covered stent.

Aortic thrombus is a rare and a life-threatening consequence of aortic trauma. We report the case of a young man presenting with this complication after a motor vehicle accident, and in whom a large aortic thrombus was identified at the aortic isthmus by computed tomography of the chest. The lesion was treated initially with heparin, and a delayed covered stent was used for a false aneurysm of the aortic isthmus that was discovered secondarily.

Poorer outcome in Polynesian patients with prostate cancer treated with definitive conformational radiation therapy.

PURPOSE: To compare freedom from biochemical failure (FFBF) of French Polynesian (FP) and Native European (NE) prostate cancer patients after definitive conformal radiotherapy (RT). PATIENTS AND METHODS: Data were reviewed from medical records of 152 consecutive patients (46 FP and 106 NE) with clinically localised prostate cancer treated with definitive RT. Neoadjuvant androgen deprivation therapy (ADT) was used in 22% of cases. Definition for biochemical failure was a rise by 2 ng/mL or more above the nadir prostate-specific antigen (PSA) level. The median follow-up was 34 months. RESULTS: In comparison to NE patients, FP patients were younger (p=0.002) with a higher low-risk proportion (p=0.06). Probability of 5-year FFBF was 77% in the NE cohort and 58.0% in the FP cohort (p=0.017). Univariate analysis showed that FP ethnicity was associated with worse prognosis in high-risk tumours (p=0.004). Cox multivariate analysis showed that factors associated with FFBF were risk category (p<0.017), and FP origin (p=0.03), independently of ADT and radiation dose. CONCLUSION: FP ethnicity was an independent prognostic factor for biochemical relapse after definitive conformal RT for prostate cancer.

Surgical repair of rupture of the membranous septum after blunt chest trauma.

Rupture of the membranous septum is a very rare complication of blunt chest trauma. In this report, we describe a 22-year-old man who sustained multiple blunt trauma injuries during a motor vehicle accident. Rupture of the membranous septum was diagnosed 48 hours after the initial trauma and the defect was closed with Gore-Tex (W.L. Gore & Assoc, Flagstaff, AZ). However, the operation was complicated by complete atrioventricular block requiring implantation of a permanent DDD pacemaker.

An aortic ring: from physiologic reconstruction of the root to a standardized approach for aortic valve repair.

OBJECTIVE: We suggest standardizing aortic valve repair using a physiologic approach by associating root remodeling with resuspension of the cusp effective height and external subvalvular aortic ring annuloplasty. METHODS: A total of 187 patients underwent remodeling associated with subvalvular aortic ring annuloplasty (14 centers, 24 surgeons). Three strategies for cusp repair were evaluated: group 1, gross visual estimation (74 patients); group 2, alignment of cusp free edges (62 patients); and group 3, 2-step approach, alignment of the cusp free edges and effective height resuspension (51 patients). The composite outcome was defined as recurrence of aortic insufficiency of grade 2 or greater and/or reoperation. RESULTS: The operative mortality rate was 3.2% (n = 6). Treatment of a cusp lesion was most frequently performed in group 3 (70.6% vs 20.3% in group 1 and 30.6% in group 2, P < .001). Nine patients required reoperation during a follow-up period of 24 months (range, 12-45), 6 patients in group 1 and 3 patients in group 2. At 1 year, no patients in group 3 presented with composite outcome events compared with 28.1% in group 1 and 15% in group 2 (P < .001). Residual aortic insufficiency and tricuspid anatomy were independent risk factors for the composite outcome in groups 1 and 2. The annulus diameter, the presence of Marfan syndrome, and cusp repair had no effect on aortic insufficiency recurrence or reoperation. CONCLUSIONS: A standardized and physiologic approach to aortic valve repair, considering both the aorta (root remodeling) and the valve (resuspension of the cusp effective height and subvalvular ring annuloplasty) improved the preliminary results and might affect their long-term durability. The ongoing Conservative Aortic Valve Surgery for Aortic Insufficiency and Aneurysm of the Aortic Root (CAVIAAR) trial will compare this strategy to mechanical valve replacement.

Reappraisal of clinical outcome in adult medulloblastomas with emphasis on patterns of relapse.

BACKGROUND: Clinical outcome and prognostic factors were assessed in adult medulloblastoma patients, with emphasis on patterns of relapse. PATIENTS AND METHODS: Records of 36 consecutive adult patients with medulloblastoma were reviewed. Patients were classified into 2 prognostic groups according to the extent of disease and quality of surgical excision based on the early postoperative magnetic resonance imaging (MRI) findings. Standard-risk (SR) patients (n = 11) received postoperative craniospinal radiation therapy (RT) only, 36 Gy, 1.8 Gy per daily fraction, with a 18 Gy boost to the posterior cerebral fossa (PCF). High-risk (HR) patients (n = 25) received additional adjuvant chemotherapy. RESULTS: With a median follow-up of 46 months (range 5-155), 19 patients experienced tumour relapse. Sites of relapse(s) included tumour bed in 6 patients, resulting in a PCF control of 83.4%. Three-year overall survival (OS) and progression-free survival (PFS) were 67.3% and 57.4%, respectively. The comparison of the HR and SR populations demonstrated significant differences in OS (p = 0.005) and PFS (p = 0.001). Quality of surgical excision and extent of disease beyond the PCF were predictive factors for OS (p = 0.04, p = 0.001, respectively) and PFS (p = 0.004, and p = 0.02, respectively). CONCLUSION: The quality of resection was a significant prognostic factor, suggesting that surgery should be as extensive as possible. Systematic postoperative MRI allowed accurate selection of SR patients for whom RT alone was enough to obtain high local control. Every effort should be made to avoid RT disruption. Increased delay led to worse outcome.

Impact of meteorological conditions on the occurrence of acute type A aortic dissections.

The impact of meteorological conditions on the occurrence of various cardiovascular events has been reported. The aim of this work was to study the correlations between weather conditions and the occurrence of type A acute aortic dissections (AADs). Between 1997 and 2007, all the medical records of patients who underwent surgery for type A AADs in Toulouse University Hospital (France) were reviewed. The clinical data were confronted with the meteorological data provided by the French national meteorological office (MétéoFrance) over the same period. Two hundred and six patients with spontaneous type A AADs underwent surgery during this period. The incidence of aortic dissection was higher in winter time than in summer (P=0.018). The days with aortic dissections were colder than those without aortic dissections (P=0.017). Statistical analysis highlighted a decrease of atmospheric temperature during the three days preceding the upset of the symptoms (P=0.0009). This work demonstrates a correlation between spontaneous type A AADs and low atmospheric temperature.

Does the use of stentless aortic valves in a subcoronary position prevent patient-prosthesis mismatch for small aortic annulus?

OBJECTIVE: Freestyle stentless bioprostheses have shown excellent hemodynamic performance. However, small size subcoronary implants have yet to prove their clinical usefulness. The aim of this study was to determine the incidence of patient-prosthesis mismatch [PPM = Indexed Effective Orifice Area (iEOA) < or = 0.85 cm2/m2] after aortic valve replacement (AVR) with 19-mm and 21-mm stentless bioprostheses and to evaluate clinical and hemodynamic outcomes. METHODS: From January 1993 to December 2000, 419 patients who had undergone Freestyle bioprostheses implantation were prospectively followed. Sixty-eight patients (16%) received a 19-21-mm prosthesis. The EOA was calculated and indexed to the patient's body surface area to obtain the iEOA. Clinical as well as echographic measures were recorded at discharge and at one and five years. RESULTS: PPM was present in 91% and 80% of patients with 19-mm and 21-mm prostheses, respectively. Severe mismatch (iEOA < or = 0.65 cm2/m2) was present in 58% and 17%. Mean gradients at discharge were 22 +/- 11 mmHg for the 19-mm prostheses and 14 +/- 7 mmHg for the 21-mm prostheses. Perioperative mortality was 33% (4/12 pts) for 19-mm prosthesis and 7% (4/56 pts) for 21-mm prostheses. Five-year actuarial survival was 58% for patients with 19-mm prosthesis and 82% for patients with 21-mm prosthesis (p = 0.04). CONCLUSION: AVR with small size Freestyle subcoronary implants is associated with a high incidence of PPM and high mortality.

Long-term impact of diabetes and its comorbidities in patients undergoing isolated primary coronary artery bypass graft surgery.

BACKGROUND: The objective of this study was to identify the impact of diabetes and related comorbidities, namely chronic renal failure, peripheral vascular disease, and low ejection fraction (<35%), on long-term survival of patients undergoing coronary artery bypass graft surgery. METHODS AND RESULTS: A unicenter study was conducted on 9125 survivors of isolated coronary artery bypass graft surgery between 1992 and 2002. There were 6581 nondiabetic patients and 2544 diabetics, including 1809 patients with noninsulin-dependent diabetes mellitus and 735 patients with insulin-dependent diabetes mellitus. Cardiac-specific survival at 5 and 10 years was lower in insulin-dependent diabetes mellitus compared with both nondiabetic mellitus patients and patients with noninsulin-dependent diabetes mellitus (P<0.0001). However, freedom from cardiac-related death was similar for patients with noninsulin-dependent diabetes mellitus and nondiabetes mellitus patients up to 6 years (P=0 0.08) after surgery and was significantly lower thereafter (P=0.004). Cardiac-specific survival after coronary artery bypass graft surgery in patients with one or more comorbidities was comparable (P=0.4) for both nondiabetes mellitus patients and patients with noninsulin-dependent diabetes mellitus, but was significantly lower for those requiring insulin therapy (P<0.0001). Noninsulin-dependent diabetes mellitus was not an independent predictor of long-term cardiac death (hazard ratio: 1.09, P=0.41); however, insulin-dependent diabetes mellitus, chronic renal failure, peripheral vascular disease, and low ejection fraction were all independent risk factors for late cardiac death (all P<0.0001). The impact of comorbidities on the long-term risk of cardiac death was similar for the 3 groups. CONCLUSIONS: Noninsulin-dependent diabetes is not an independent predictor of late cardiac death after coronary artery bypass graft surgery, because cardiac-related survival is similar to that of nondiabetic patients for 6 years after surgery. In diabetic and nondiabetic patients, cardiac survival is adversely affected by the need for insulin therapy and/or the presence and number of comorbidities such as chronic renal failure, peripheral vascular disease, and low ejection fraction.

Laparoscopic repair of intrathoracic mesenterioaxial volvulus of the stomach in an adult: report of a case.

Intrathoracic gastric volvulus is an uncommon entity, in which the stomach undergoes organoaxial torsion occurring in the chest due to the concomitant presence of an enlargement of the hiatus. We herein report an unusual case of acute intrathoracic mesenterioaxial volvulus of the stomach. Gastric rotation occurred at the transverse axis and the mobile pylorus herniated in the chest through a large hiatal defect. Following a reduction of the volvulus through the use of a nasogastric tube, the patient underwent an elective laparoscopic repair. The mechanisms of volvulus with the relative diagnostic and therapeutic implications are discussed.