Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.

Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients.

BACKGROUND: B-lymphoproliferative post-transplant disorder (BLPD) is a severe complication of organ and bone marrow transplantation. The reduction of immuno-suppressive therapy or surgery for localized disease may cure some BLPDs. Other therapeutic approaches such as chemotherapy and antiviral drugs are toxic and of limited efficacy. Adoptive immunotherapy with donor T-cell infusions has yielded promising results but is, at the present time, easily applicable only in bone marrow-transplanted patients. Anti-B-cell Murine monoclonal antibodies (MoAbs) have proven effective but are no longer available for human use. We report the activity of a humanized anti CD 20 Mo Ab (Rituximab-MABTHERA Roche) in 32 episodes of BLPD treated in 14 French centers. PATIENTS AND METHODS: Between November 1997 and September 1998, 32 patients were diagnosed with BLPD. Twenty-six patients had undergone solid organ transplants (liver 8, kidney 8, heart 4, lung 3, heart lung 1, kidney-pancreas 1, liver-kidney 1) and six patients had received bone marrow transplantations. The median age of the patients was 34 years (3-67 years) and the median delay between graft and tumor 5 months (1-156 months). In organ recipients, tumors were classified as polymorphic and monomorphic in 10 and 15 cases, respectively; 4 of 6 bone marrow transplant recipients were treated without pathology documentation because of a rise in EBV load, fever and lymph node enlargement. Tumors were associated with EBV in 22 of 26 tested cases. Rituximab was used as first-line therapy in 30 patients (after reduction of immunosuppressive treatment in 27 patients) and as salvage therapy in 2 patients (after failure of chemotherapy). The median time from diagnosis of BLPD to treatment with Rituximab was 14 days (1-110 days). Two patients received eight infusions, twenty-six patients four infusions, one patient three infusions and three patients two infusions of 375 mg/m2. RESULTS: The tolerance of rituximab was good. The overall response rate was 69%, with 20 complete responses and 2 partial responses. In solid organ transplant the response rate was 65% (15 CR and 2 PR) while it was 83% in bone marrow-transplanted patients (5 CR). With a median follow-up of 8 months (1-16 months) 24 patients are still alive. The one-year projected survival is 73%. Of the 22 patients who achieved response, 15 patients (11 solid organ transplant and 4 bone marrow transplant) are alive with no evidence of disease, 4 patients relapsed a median of 7 months (3-10 months) after treatment and 3 died while in CR of concurrent diseases. Of the 10 patients who did not respond to Rituximab 5 are alive with no evidence of disease after salvage therapy. CONCLUSIONS: The use of rituximab appears to be a safe and relatively efficient therapy in BLPDs. The results need to be confirmed in a prospective multicentric trial.

[Combined transplantation of liver and small intestine in an adult. First case in France. Surgical aspects]. / Transplantation combinée foie-intenstin grêle chez l'adulte.Premier cas français. Aspects chirurgicaux.

BACKGROUND: We report hare the first adult case of combined liver-small bowel transplantation performed in France. CASE REPORT: A double liver + small bowel graft was transplanted in a 21-year-old patient hospitalized for 4 years for a short bowel syndrome requiring total parenteral nutrition. The patient also had severe hepatic fibrosis. The immediate post-operative period was uneventful. Two and one-half years after the double graft, the patient is on strictly oral nutrition, no longer has a stomy and lives a normal life in his home. DISCUSSION: The advent of tacrolimus has led to long-term success of bowel grafts, developed earlier in children and now possible in adults. Combined liver-small bowel transplantation is formally indicated in patients with cirrhogenic liver disease associated with ineversible small bowel failure.

Additional copies of a 25 Mb chromosomal region originating from 17q23.1-17qter are present in 90% of high-grade neuroblastomas.

Neuroblastoma shows remarkable heterogeneity, ranging from spontaneous regression to progression toward highly malignant tumors. In search of genetic abnormalities that could explain this variability, we have characterized neuroblastoma tumors by using multiple fluorescent hybridizations. Our results indicate that chromosome 17 is rearranged very frequently in the form of unbalanced translocations with numerous chromosomal partners, all leading to the presence of supernumerary copies of a 25 Mb chromosomal region originating from 17q23.1-qter. Additional 17q material was detected in more than 90% of untreated high-grade neuroblastomas and, along with 1p36 deletion, should represent the most frequent genetic abnormality of neuroblastoma observed until now.

Peritoneal carcinomatosis in patients with digestive endocrine tumors.

BACKGROUND: Peritoneal carcinomatosis (PC) in patients with digestive endocrine tumors (DET) is considered rare but its prevalence is unknown. The objectives of this study were to assess the prevalence and prognostic implications of PC in patients with various types of DET. METHODS: One hundred and sixteen consecutive patients with DET seen over a 3-year period were studied. Fifty-nine had gastrinomas, 30 had carcinoid tumors, and 27 had other types of endocrine tumors, mainly nonfunctioning ones. Diagnosis of PC was based on clinical symptoms (ascites and König's syndrome), findings of computed tomography scans that were performed at least yearly, and pathologic confirmation of tumor nodules or positive cytology in the peritoneal fluid. Factors associated with PC were investigated and the influence of PC on patients' survival was assessed. RESULTS: PC was found in 11 patients (overall PC prevalence: 10%; with 27% in patients with carcinoid tumors, 11% in those with nongastrinoma pancreatic endocrine tumors, and 0% in patients with gastrinomas). Nine of 11 patients with PC also had liver metastases. PC was metachronous to detection of the primary tumor in 7 of 11 patients, occurring 54 months (range, 23-273 months) after the diagnosis. In addition to the nature of the primary tumor, a greatest dimension of more than 5 cm was associated with the presence of PC in two of three patients with pancreatic endocrine tumors. In patients with carcinoid tumors, an ileal primary tumor occurred more frequently in patients with PC (87.5%) than in those without PC (50%). Prevalence of liver and other metastases was not significantly increased in patients with PC. Although five patients died of their disease, no deaths were related to PC. Actuarial survival rates at 5 years were 64% and 84% in patients with and without PC, respectively (P = not significant), whereas they were 73% and 93% in patients with and without liver metastases, respectively (P < 0.02). CONCLUSIONS: PC is not a rare event in the course of DET, especially in patients with carcinoid tumors. It did not occur in the patient population with gastrinomas, which are less often malignant but may also differ from the other types of DET by several cell characteristics. In contrast to liver metastases, PC is not associated with a significant decrease in life expectancy.

[Automatic computer analysis of fetal cardiac rhythm]. / Analyse automatique du rythme cardiaque foetal par ordinateur.

In utero cardiotocographic recording is currently one of the best means of diagnosis of fetal distress. The purpose of automatic tracing of the fetal heart rate is to prevent inter- and intra-individual variability in order to better evaluate the condition of the fetus. This study was carried out with the assistance of a cardiotocograph HP 8040A connected to a microcomputer equipped with a clock card. The heart signal may then be continuously recorded and stored on floppy disks, which are then reread and processed by microcomputer. The data are divided into time intervals (3, 5 or 10 seconds), selected by the physician. At each stage, mean, median and sample variation are calculated. Losses of signal are read. In a second stage, the use of a digital, linear and predictive filter (Kalman filter) applied to heart rates, allows baseline extraction as well as the detection of variations about this baseline (accelerations, decelerations). With the use of this filter on sample variations, it is possible to detect various variability periods, via two different approaches: classification of variability values in three groups: 0-5 bpm, 5-10 bpm, greater than 10 bpm, detection of increases or decreases of the variability as compared to the mean variability during the recording. Comparison of automatic analysis and visual analysis by segmentation is satisfactory in terms of variability. Detection of accelerations and decelerations is more problematic, for two reasons: the notion of baseline, the accuracy of digital detection: 15 bpm, 15 sec. All these problems are discussed.

New technique for repair of ascending thoracic aortic dissections.

Dacron graft replacement of the ascending aorta for thoracic dissections often results in major intraoperative or postoperative hemorrhage due to tissue tearing at the suture lines. We report a promising solution to this problem: strengthening the aortic wall with glutaraldehyde solution. Using this technique, we obtained a tough, resistant tissue that could be sutured without disintegration. We have used the method successfully in 5 consecutive patients.

Steady-state breathing pattern responses to small inspiratory resistive loads in COPD patients. Application to weaning from mechanical ventilation.

We investigated the effect of small inspiratory resistive loads on the breathing patterns of patients with COPD admitted to the ICU for acute respiratory failure. Patients were in stable clinical condition three days after weaning from the acute-phase ventilation. Healthy nonsmokers served as controls. Breathing patterns were recorded for 20-min periods during unloaded breathing (R0), then with small inspiratory resistive loads (R1 = 2.5 cmH2O L/s and R2 = 5.2 cmH2O L/s) applied in random order. Respiratory parameters were memorized in real time and blood gases measured continuously with a transcutaneous PO2/PCO2 monitor and compared periodically with arterial blood gases. Minute volume (VE) and respiratory rate decreased with no modification in blood gas values. In the COPD patients, R1 was too small to be perceived; when R2 was applied, no increase in TI was observed, and VT and VT/TI decreased. The VE could not be maintained despite a shortening of expiratory time. The COPD patients did not have significant increase of occlusion pressure (P0.1). Mean blood gas values did not change during the testing, but the coefficient of variation of tcPCO2 increased. During the critical period following weaning from artificial ventilation, COPD patients did not respond in the same manner as normal subjects to inspiratory resistive loads, but did not have modified gas exchange during the 20-min period.

Diaphragmatic fatigue and breathing pattern during weaning from mechanical ventilation in COPD patients.

The medium-term outcome of weaning from mechanical ventilation in COPD patients is not easy to anticipate because a respiratory fatigue may eventually develop. We evaluated the diaphragmatic function and the breathing pattern during 40 weaning trials on 15 patients ventilated after acute respiratory failure. We formed two groups according to the success (group B, n = 18) or failure (group A, n = 19) of the medium-term attempt (group A/less than 10 hours; group B/more than 12 hours). Provided the patients showed the classic weaning criteria (tidal volume greater than 5 ml/kg, respiratory frequency less than 30 breaths per minute, PaO2 greater than 50 mm Hg), the study of the breathing pattern did not allow differentiation between the groups. However, the transdiaphragmatic pressure (Pdi) and the Pdimax, which gave an indication of the power of diaphragm contraction, dropped early in the group that could not stand weaning, with an increase in the Pdi/Pdimax ratio. In addition, this same group showed a diaphragmatic dysfunction attested for by a frequent negative gastric pressure associated with or shortly preceded by an abdominal paradoxic motion.

Sweat collection from athletes.

The difficulty in taking sweat during heavy physical exercise has drawn the authors into testing a technique of sampling generally used in paediatrics. The fact that the results, which have been dealt with statistically, should coincide with the physiological facts already published allows us to consider a use of the technique in order to investigate the physiological mechanisms in action during sweating under different metabolic conditions.