[Impact on quality of life and autonomy of patients aged over 75 years treated with anti-PD-1 for metastatic melanoma: A single-centre prospective study]. / Impact sur la qualité de vie et l'autonomie des patients de plus de 75 ans traités par anti-PD-1 pour un mélanome métastatique : étude prospective monocentrique.

INTRODUCTION: We previously studied anti-PD-1 safety in elderly (≥80 years) patients and reported a retrospective two-centre cohort with a similar safety profile in elderly and in younger patients. Quality-of-life evaluation data is still lacking in this specific population. MATERIALS AND METHODS: A prospective, single-centre study in patients aged over 75 years presenting metastatic melanoma treated with anti-PD-1. The endpoint was monitoring of quality of life (by a specific survey) and onco-geriatric assessment at the beginning of therapy, then at 3 and 6 months (nutritional status, comorbidities, autonomy, thymic and cognitive disorders). RESULTS: Fourteen patients were included of median age 86.5 years [range: 78-94] from March to September 2018. General status was good, with a median Charlson score of 0 [extremes 0-4]. Nine patients were evaluated at 3 months and six patients at 6 months. There was no significant difference in quality-of-life scores obtained at baseline, 3 months and 6 months. DISCUSSION: This study shows that neither quality of life nor autonomy appears to be affected by anti-PD-1 treatment in patients aged over 75 years. However, these results should be interpreted with caution due to the small number of patients included, the short follow-up period and the single-centre data. Nevertheless, the prospective analysis and the complete onco-geriatric evaluation and monitoring yielded unique and original data.

[Preoperative prognostic factors for squamous cell carcinomas of the thoracic esophagus]. / Facteurs pronostiques préopératoires des cancers épidermoïdes de l'oesophage thoracique.

AIM OF THE STUDY: To identify preoperative survival prognostic factors in patients with resectable squamous cell carcinoma of the thoracic esophagus. POPULATION: From January 1982 to September 1999, 868 patients underwent surgery for esophageal carcinoma in our department, including 493 for squamous cell carcinoma of the thoracic esophagus. The following parameters were retrospectively included in univariate and multivariate analysis: age, sex, undernutrition, dysphagia, tumor diameter and nodal involvement on the CT-scan, preoperative treatment, surgical technique, curative resection, pTNM classification, histologic type and postoperative complications. The actuarial survival was determined. RESULTS: Survival prognostic factors were dysphagia, nodal involvement on CT-scan and depth of tumor invasion at pathological examination. Three groups of patients were identified on the two preoperative variables: group 1: patients without dysphagia (n=102), group 2: patients with dysphagia but without nodal involvement on the CT- scan (n=244), group 3: patients with dysphagia and with nodal involvement on the CT- scan (n=147). The median survivals were 62.4, 19.1 and 14.4 months in groups 1, 2 and 3, respectively, and 5-year actuarial survivals were 50%, 21% and 11% (P<0.009). CONCLUSION: Our study confirms that dysphagia and nodal involvement on the CT-scan are simple preoperative prognostic factors in patients with resectable squamous cell carcinoma of the thoracic esophagus.

[Effect of smoking on blood rheology]. / Influence du tabagisme sur la rhéologie sanguine.

The aim of this study was to compare the effects of cigarette smoking on biologic and rheologic tests, chiefly on the red blood cells (RBC) in measuring the deformability by the Cell Transit Analyser (CTA) and their aggregation by using an ultrasonic interferometry method based on A-mode echography allowed for the measurement of the accumulation rate of particles in a solid plate which is related to their sedimentation rate (Echo-Cell). Nine male smoker subjects with a high nicotine addiction measured by Fagerström questionnaire (> 8) and level of carbon monoxide (CM) in the breathed out air (> 20 ppm), have been compared with ten healthy no-smoker volunteers (CM < 3 ppm). One smoker has been eliminated of statistic evaluations because his glucose level showed a diabetes (10.5 mmol/l). A nailfold capillaroscopy performed in all subjects has eliminated the patterns of latent vasculitis or scleroderma. RBC and platelets counts, hemoglobin, ionogram, gamma GT, ASAT, ALAT, uric acid, total cholesterol and glucose levels were not significantly different between the two groups. On the other hand, in the smoker group, white blood cells count, serum triglycerides and especially fibrinogen values were higher than in the non-smoker's group. RBC sedimentation rate was normal in the two groups but was higher in smoker's group too. Without consumption of alcohol, the mean RBC volume was more important in smokers (91.9 +/- 1.2 versus 87.5 +/- 0.4, p = 0.003). Rheologic tests were more pathologic in smokers. The transit time or RBC by CTA was longer than in control group (1.6 ms +/- 0.02 versus 1.2 +/- 0.05, p = 0.0003). Echo-Cell technic showed a number and size of RBC aggregates more important with a rate of speed of accumulation higher than in the control group. These results demonstrated the toxic effects of smoking alone on blood toward a propensity for thrombotic status.

The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication.

AIMS: Fluid retention is a phenomenon associated with taxoids. The principal objective of this study was to investigate the pathophysiological mechanism of docetaxel-induced fluid retention in advanced cancer patients. METHODS: Docetaxel was administered as a 1 h intravenous infusion every 3 weeks, for at least 4-6 consecutive cycles, to patients with advanced breast (n = 21) or ovarian (n = 3) carcinoma, who had received previous chemotherapy, 21 for advanced disease. Phase II clinical trials have shown that 5 day corticosteroid comedication, starting 1 day before docetaxel infusion, significantly reduces the incidence and severity of fluid retention. This prophylactic corticosteroid regimen is currently recommended for patients receiving docetaxel but was not permitted in this study because of its possible interference with the underlying pathophysiology of the fluid retention. RESULTS: Fluid retention occurred in 21 of the 24 patients but was mainly mild to moderate, with only five patients experiencing severe fluid retention. Eighteen patients received symptomatic flavonoid treatment, commonly prescribed after the last cycle. Specific investigations for fluid retention confirmed a relationship between cumulative docetaxel dose and development of fluid retention. Capillary filtration test analysis showed a two-step process for fluid retention generation, with progressive congestion of the interstitial space by proteins and water starting between the second and the fourth cycle, followed by insufficient lymphatic drainage. CONCLUSIONS: A vascular protector such as micronized diosmine hesperidine with recommended corticosteroid premedication and benzopyrones may be useful in preventing and treating docetaxel-induced fluid retention.

[Obstacles to stopping smoking among patients with vascular risk]. / Les difficultés de l'arrêt du tabac chez les sujets à risque vasculaire.

Despite the risk, smoking has only slightly decreased and the percentage of heavy smokers increases. The reason for the paradoxical situation has now been identified in more than 95% of the cases and is due to behaviour amplified by a pharmacological dependence on nicotine. The psycho-active effects of nicotine binding to nicotine receptors in the brain, produce a quasi constant physical dependence and a psychic dependence in certain smokers.

Effect of buflomedil on the neutrophil-endothelial cell interaction under inflammatory and hypoxia conditions.

In hypoxia/ischaemia and ischaemia/reperfusion, human neutrophils are likely to play an important role in the development of endothelial cell damage in the microcirculation. Buflomedil hypochloride improves the capillary perfusion in such related situations, evoking a possible effect upon neutrophils. Using in vitro models of cell adhesion, buflomedil decreased 100% of histamine related neutrophil adhesion (flow system) and partially inhibited adhesion after IL-1-4 hours (flow and stable systems). Hypoxia induced neutrophil adhesion (4 hours) was also reduced by buflomedil, which decreased the expression of P-selectin at the surface of endothelial cells. As adenosine (NECA) exhibited the same results in hypoxia and theophylline inhibited them, such results support an action of buflomedil presumably via the A2 receptor.

Improvement of microcirculation abnormalities in sickle cell patients upon buflomedil treatment.

The efficacy of the vasoactive compound buflomedil on previously described microcirculation abnormalities observed in sickle cell disease (SCD) was investigated using bulbar conjunctival angioscopy (BCA) and laser doppler flux metering. Eleven sickle cell disease patients at steady state were studied in a double-blind randomized parallel-versus-placebo study (5 patients were given placebo and 6 patients received 600 mg buflomedil per day for 21 days after a washout period of 15 days). The blood flux score measured by BCA improved, indicating reduced entrapment of sickle red blood cells. There was a striking improvement of reactive alterations of vasomotion in the buflomedil group, particularly in postocclusive reactive hyperemia; the half return time was also significantly reduced. These results encourage further studies with buflomedil to investigate long-term effects of this compound in SCD, potential prevention of acute vaso-occlusive events, and degenerative complications.

Observations on experimental flow-through venous flaps.

The aim of this work was to compare the survival of an arteriovenous island flap with the survival of an island flap with a flow-through venous supply. Our experimental studies were performed on 95 Wistar rats randomised into six groups: Group 1: Indian ink injection of flow-through venous flaps with capillary network; Group 2: control group deprived of vascularisation; Group 3: control group with arteriovenous supply; Group 4: flow-through venous flaps of group 1; Group 5: epigastric flow-through venous flaps with a main venous trunk; Group 6: histological examination of flow-through venous flaps. The survival of flaps was monitored by direct examination, histological examination, capillaroscopy, and laser Doppler. Three out of 50 flow-through venous flaps survived. There was a statistically significant difference in the delay of clinical necrosis between the composite non vascularised free grafts (2.8 +/- 1.2 days) and the flow-through venous flaps (4.1 +/- 1.3 to 4.9 +/- 1.1 days depending on the type of flap). A 20% decreased venous blood flow was observed in the flow-through venous flaps.

Comparative evaluation of laser Doppler flux metering, bulbar conjunctival angioscopy, and nail fold capillaroscopy in sickle cell disease.

Eleven adult patients with stable sickle cell disease (SCD) were investigated twice at a 15-day interval by nail fold capillaroscopy (NFC), bulbar conjunctival angioscopy (BCA), and laser Doppler flux metering (LDF). NFC and BCA are essentially descriptive. NFC revealed, in some patients, network patterns similar to those observed in vasculitis. BCA provides a reproducible method for the visual assessment of the microcirculation. When using a rating scale with five criteria it identified abnormalities related to both altered red blood cells and vascular morphology but failed to discriminate between patients. LDF, in contrast, is quantifiable and showed reproducible characteristic reactive alterations of vasomotion in response to ischemia after 3 min of occlusion. The SCD patients had a delayed response, best measured by the recovery half time, which was four to five times longer than that of normal subjects. In addition, the cold provocative test was always abnormal, as evidenced by a significant drop in the contralateral flux, and was often poorly tolerated. The observed trends suggest that BCA and LDF should be performed in a large cohort of patients, both in the steady state and during vasoocclusive crises. These methods seem to be useful complementary noninvasive procedures to cellular and clinical evaluation monitoring for therapeutic trials.

[Cutaneous microvascular flow studied by laser-Doppler. A study of 100 healthy volunteers]. / Flux microcirculatoire cutané étudié par laser-doppler. Etude sur une population de 100 sujets volontaires sains.

Cutaneous capillary flow (tip of the 3rd right finger) was measured with a laser Doppler (Periflux, Perimed), in 100 healthy volunteers without any history of hypertensive or vasospatic diseases, 15 females smoke and were taking contraceptive drugs. Smokers (n = 16 M, 25 F) stopped smoking 3 hours before the study. Basal laser Doppler flux (BLDF), amplitude of vasomotion waves (AV), post-occlusive reactive hyperthermia peakflow (F Max), difference between BLDF and F Max (delta F Max), time to reach 50 percent of the initial value (t1/2 r) and total recovery (tr), t Max (peak of over-shoot) and t/2 over shoot were measured. F Max after heating stimulus (40 degrees) (f Max H), delta F Max H (difference between BLDF and F Max H) and t Max H time (mn) to reach F Max H were measured before a cold stimulus was applied. Results were expressed in arbitrary units (cvolts), BLDF showed inter-individual variation but was reproducible over months in the same subject. The basal flux was statistically different between males (352.7 +/- 21.7) and females (249.6 +/- 22.4). Spontaneous vasomotion waves and different times (in sec.) to reach the peak after three minutes of arterial occlusion could be measured with this technique. These normal range of values can allow comparison and assessment of variations in pathological conditions, mainly Raynaud's phenomenon, high blood pressure, diabetes, smokers, sickle-cell anemia. Acute pharmacological tests can be carried out with drugs showing specific action on microcirculation and spontaneous vasomotion.

In vitro studies of the effect of buflomedil on platelet responsiveness.

The effect of buflomedil (Fonzylane; Laboratoire Lafon, Maisons-Alfort, France) on platelet function, a drug used clinically for the treatment of peripheral vascular diseases, was investigated in vitro. The compound significantly inhibits epinephrine-induced aggregation at the micromolar level. At higher doses (approximately 1 mM), a weak inhibition of ADP- and collagen-induced aggregation was observed; at these concentrations, buflomedil inhibits granular secretion and the interaction of fibrinogen with its receptor on platelet. Further investigations indicate that the drug affects calcium uptake at the membrane level and inhibits the binding of [3H]-yohimbine to the same extent as observed with phentolamine. The IC50 determined from competition binding assays was 1 +/- 0.5 microM. This value was consistent with the affinity constant approximated for the binding of [3H]-buflomedil to non-stimulated platelets. Taken-together, these results indicate that the vasoactive compound buflomedil is a weak antiaggregating agent which exhibits alpha 2-adrenergic antagonistic properties.