[Non-invasive ventilation in acute respiratory failure of oncology-hematology patients: What are its current benefits and limitations?] / Ventilation non invasive dans l'insuffisance respiratoire aiguë des patients d'onco-hématologie : quelle place en 2023 ?

Acute respiratory failure (ARF) is a leading cause, along with sepsis, of admission to the intensive care unit (ICU) of patients with active cancer. Presenting variable clinical severity, ARF in onco-hematological patients has differing etiologies, primarily represented by possibly opportunistic acute infectious pneumonia (de novo hypoxemic ARF), and decompensation in chronic cardiac or respiratory diseases (e.g., acute pulmonary edema or exacerbated chronic obstructive pulmonary disease). In these patients, orotracheal intubation is associated with a doubled risk of in-hospital mortality. Consequently, over the last three decades, numerous researchers have attempted to demonstrate and pinpoint the precise role of non-invasive ventilation (NIV) in the specific context of ARF in onco-hematological patients. While the benefits of NIV in the management of acute pulmonary edema or alveolar hypoventilation (hypercapnic ARF) are well-demonstrated, its positioning in de novo hypoxemic ARF is debatable, and has recently been called into question. In the early 2000s, based on randomized controlled trials, NIV was recommended as first-line treatment, one reason being that it allowed significantly reduced use of orotracheal intubation. In the latest randomized studies, however, the benefits of NIV in terms of survival orotracheal intubation have not been observed; as a result, it is no longer recommended in the management of de novo hypoxemic ARF in onco-haematological patients.

Clinical features and outcomes of patients with pancreatic cancer requiring unplanned medical ICU admission: A retrospective multicenter study.

BACKGROUND: We sought to describe the reasons for intensive care unit (ICU) admission and outcomes of patients with pancreatic cancer requiring unplanned medical ICU admission. PATIENTS AND METHODS: Retrospective cohort study in five ICUs from 2009 to 2020. All patients with pancreatic cancer admitted to the ICU were included. Patients having undergone recent surgery were excluded (< 4 weeks). RESULTS: 269 patients were included. Tumors were mainly adenocarcinoma (90%). Main reason for admission was sepsis/septic shock (32%) with a biliary tract infection in 44 (51%) patients. Second reason for admission was gastrointestinal bleeding (28%). ICU and 3-month mortality rates were 26% and 59% respectively. Performance status 3-4 (odds ratio OR 3.58), disease status (responsive/stable -ref-, newly diagnosed OR 3.25, progressive OR 5.99), mechanical ventilation (OR 8.03), vasopressors (OR 4.19), SAPS 2 (OR 1.69) and pH (OR 0.02) were independently associated with ICU mortality. Performance status 3-4 (Hazard ratio HR 1.96) and disease status (responsive/stable -ref-, newly diagnosed HR 2.67, progressive HR 4.14) were associated with 3-month mortality. CONCLUSION: Reasons for ICU admissions of pancreatic cancer patients differ from those observed in other solid cancer. Short- and medium-term mortality are strongly influenced by performance status and disease status at ICU admission.

Severe atypical pneumonia in critically ill patients: a retrospective multicenter study.

BACKGROUND: Chlamydophila pneumoniae (CP) and Mycoplasma pneumoniae (MP) patients could require intensive care unit (ICU) admission for acute respiratory failure. METHODS: Adults admitted between 2000 and 2015 to 20 French ICUs with proven atypical pneumonia were retrospectively described. Patients with MP were compared to Streptococcus pneumoniae (SP) pneumonia patients admitted to ICUs. RESULTS: A total of 104 patients were included, 71 men and 33 women, with a median age of 56 [44-67] years. MP was the causative agent for 76 (73%) patients and CP for 28 (27%) patients. Co-infection was documented for 18 patients (viruses for 8 [47%] patients). Median number of involved quadrants on chest X-ray was 2 [1-4], with alveolar opacities (n = 61, 75%), interstitial opacities (n = 32, 40%). Extra-pulmonary manifestations were present in 34 (33%) patients. Mechanical ventilation was required for 75 (72%) patients and vasopressors for 41 (39%) patients. ICU length of stay was 16.5 [9.5-30.5] days, and 11 (11%) patients died in the ICU. Compared with SP patients, MP patients had more extensive interstitial pneumonia, fewer pleural effusion, and a lower mortality rate [6 (8%) vs. 17 (22%), p = 0.013]. According MCA analysis, some characteristics at admission could discriminate MP and SP. MP was more often associated with hemolytic anemia, abdominal manifestations, and extensive chest radiograph abnormalities. SP-P was associated with shock, confusion, focal crackles, and focal consolidation. CONCLUSION: In this descriptive study of atypical bacterial pneumonia requiring ICU admission, mortality was 11%. The comparison with SP pneumonia identified clinical, laboratory, and radiographic features that may suggest MP or CP pneumonia.

Noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: Trends in use and outcome.

PURPOSE: The objectives of our study were to describe the outcome of patients with malignancies treated for acute respiratory distress syndrome (ARDS) with noninvasive ventilation (NIV) and to evaluate factors associated with NIV failure. METHODS: Post hoc analysis of a multicenter database within 20 years was performed. All patients with malignancies and Berlin ARDS definition were included. Noninvasive ventilation use was defined as NIV lasting more than 1 hour, whereas failure was defined as a subsequent requirement of invasive ventilation. Conditional backward logistic regression analyses were conducted. RESULTS: A total of 1004 met the Berlin definition of ARDS. Noninvasive ventilation was used in 387 patients (38.6%) and NIV failure occurred in 71%, with an in-hospital mortality of 62.7%. Severity of ARDS defined by the partial pressure arterial oxygen and fraction of inspired oxygen ratio (odds ratio [OR], 2.20; 95% confidence interval [CI], 1.15-4.19), pulmonary infection (OR, 1.81; 95% CI, 1.08-3.03), and modified Sequential Organ Failure Assessment (SOFA) score (OR, 1.13; 95% CI, 1.06-1.21) were associated with NIV failure. Factors associated with hospital mortality were NIV failure (OR, 2.52; 95% CI, 1.56-4.07), severe ARDS as compared with mild ARDS (OR, 1.89; 95% CI, 1.05-1.19), and modified SOFA score (OR, 1.12; 95% CI, 1.05-1.19). CONCLUSION: Noninvasive ventilation failure in ARDS patients with malignancies is frequent and related to ARDS severity, SOFA score, and pulmonary infection-related ARDS. Noninvasive ventilation failure is associated with in-hospital mortality.

Adenovirus related lymphohistiocytic hemophagocytosis: Case report and literature review.

INTRODUCTION: Adenoviral infection is a classic cause of lymphohistiocytic hemophagocytosis (LH) in bone marrow transplantation but is rare outside this setting. CASE REPORT: A 31-year-old female, with a history of treated mesencephalic astrocytoma, was hospitalized for fever, pancytopenia, elevated liver enzymes, hyperferritinemia and hypertriglyceridemia. Adenovirus viral load in blood was 7.3×10(9) copies/mL. Bone marrow aspirate examination confirmed LH. The patient recovered without specific LH or adenovirus-directed treatment. CONCLUSION: Adenovirus-related LH, common in bone marrow transplant recipients, should also be considered in patients with chemotherapy in solid tumors.

What is the outcome of cancer patients admitted to the ICU after cardiac arrest? Results from a multicenter study.

AIM: Low survival rate was previously described after cardiac arrest in cancer patients and may challenge the appropriateness of intensive care unit (ICU) admission after return of spontaneous circulation (ROSC). Objectives of this study were to report outcome and characteristics of cancer patients admitted to the ICU after cardiac arrest. METHODS: A retrospective chart review in seven medical ICUs in France, in 2002-2012. We studied consecutive patients with malignancies admitted after out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA). RESULTS: Of 133 included patients of whom 61% had solid tumors, 48 (36%) experienced OHCA and 85 (64%) IHCA. Cardiac arrest was related to the malignancy or its treatment in 47% of patients. Therapeutic hypothermia was used in 51 (41%) patients. The ICU mortality rate was 98/133 (74%). Main causes of ICU death were refractory shock or multiple organ failure (n = 64, 48%) and neurological injury (n = 27, 20%); 42 (32%) patients died in ICU after treatment-limitation decisions. Twenty-four (18%) patients were discharged alive from the hospital. Overall 6-month survival rate was 14% (18/133, 95% confidence interval, 8-21%). Survival rates at ICU discharge and after 6 months did not differ significantly across type of malignancy or between the OHCA and IHCA groups, and neither were they significantly different from those in matched controls who had cardiac arrest but no malignancy. CONCLUSIONS: Even if low, the 6-month survival rate of 14% observed in cancer patients admitted to the ICU after cardiac arrest and ROSC may support the admission of these patients to the ICU and may warrant an initial full-code ICU management.

Prognosis of neutropenic patients admitted to the intensive care unit.

PURPOSE: The prognosis of critically ill cancer patients has improved recently. Controversies remain as regard to the specific prognosis impact of neutropenia in critically ill cancer patients. The primary objective of this study was to assess hospital outcome of critically ill neutropenic cancer patients admitted into the ICU. The secondary objective was to assess risk factors for unfavorable outcome in this population of patients and specific impact of neutropenia. METHODS: We performed a post hoc analysis of a prospectively collected database. The study was carried out in 17 university or university-affiliated centers in France and Belgium. Neutropenia was defined as a neutrophil count lower than 500/mm(3). RESULTS: Among the 1,011 patients admitted into the ICU during the study period 289 were neutropenic at the time of admission. Overall, 131 patients died during their hospital stay (hospital mortality 45.3 %). Four variables were associated with a poor outcome, namely allogeneic transplantation (OR 3.83; 95 % CI 1.75-8.35), need for mechanical ventilation (MV) (OR 6.57; 95 % CI 3.51-12.32), microbiological documentation (OR 2.33; CI 1.27-4.26), and need for renal replacement therapy (OR 2.77; 95 % CI 1.34-5.74). Two variables were associated with hospital survival, namely age younger than 70 (OR 0.22; 95 % CI 0.1-0.52) and neutropenic enterocolitis (OR 0.37; 95 % CI 0.15-0.9). A case-control analysis was also performed with patients of the initial database; after adjustment, neutropenia was not associated with hospital mortality (OR 1.27; 95 % CI 0.86-1.89). CONCLUSION: Hospital survival was closely associated with younger age and neutropenic enterocolitis. Conversely, need for conventional MV, for renal replacement therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) were associated with poor outcome.

pCOR: a new design of plasmid vectors for nonviral gene therapy.

A totally redesigned host/vector system with improved properties in terms of safety has been developed. The pCOR plasmids are narrow-host range plasmid vectors for nonviral gene therapy. These plasmids contain a conditional origin of replication and must be propagated in a specifically engineered E. coli host strain, greatly reducing the potential for propagation in the environment or in treated patients. The pCOR backbone has several features that increase safety in terms of dissemination and selection: (1) the origin of replication requires a plasmid-specific initiator protein, pi protein, encoded by the pir gene limiting its host range to bacterial strains that produce this trans-acting protein; (2) the plasmid's selectable marker is not an antibiotic resistance gene but a gene encoding a bacterial suppressor tRNA. Optimized E. coli hosts supporting pCOR replication and selection were constructed. High yields of supercoiled pCOR monomers were obtained (100 mg/l) through fed-batch fermentation. pCOR vectors carrying the luciferase reporter gene gave high levels of luciferase activity when injected into murine skeletal muscle.

Efficient purification of plasmid DNA for gene transfer using triple-helix affinity chromatography.

Plasmid DNA used for nonviral therapeutic gene transfer or nucleic acid vaccination has to be highly purified devoid of contaminating components such as bacterial proteins, endotoxins, or bacterial chromosomal DNA. We have developed a new affinity chromatography technique for plasmid DNA purification: triple-helix affinity chromatography (THAC). This technique is based on the sequence-specific interaction of an oligonucleotide forming a triple-helix with plasmid DNA. The oligonucleotide was covalently linked to a chromatographic matrix, thus providing a reusable affinity support. By inserting a suitable homopurine sequence in the plasmid DNA, it is possible to obtain a triple-helix interaction that will only be stable at mild acidic pH and that will dissociate in alkaline conditions. A crude lysate from a recombinant E. coli, or a pre-purified plasmid DNA, is thus applied at acidic pH on to a THAC column. After extensive washing of the column, purified plasmid DNA is eluted using an alkaline buffer. The binding conditions of the plasmid DNA on to the column have been optimized, as well as the hybridization sequence and the linker group between the matrix and the third strand oligonucleotide. The THAC technique makes it possible to purify in one step supercoiled plasmid DNA, and to significantly reduce the level of contaminating RNA, endotoxins and chromosomal DNA. In particular, a 100-fold reduction of chromosomal DNA contamination over that obtained with conventional techniques can be achieved through a single additional THAC step. Further improvements of THAC technology are possible, and we anticipate that this technique can be scaled up for integration into a full commercial-scale DNA production process.

Recombinational construction in Escherichia coli of infectious adenoviral genomes.

A two-step gene replacement procedure was developed that generates infectious adenoviral genomes through homologous recombination in Escherichia coli. As a prerequisite, a human adenovirus serotype 5 (Ad5)-derived genome was first introduced as a PacI restriction fragment into an incP-derived replicon which, in contrast to ColE1-derivatives (e.g., pBR322 or pUC plasmids), is functional in a polA mutant of E. coli. Any modification can be introduced at will following two consecutive homologous recombinations between the incP/Ad5 replicon and the ColE1 plasmid. The overall procedure requires only the in vitro engineering of the ColE1-derivative by flanking the desired modification with small stretches of identical sequences. In the first step, a cointegrate between the tetracycline-resistant incP/Ad5 replicon and the kanamycin-resistant ColE1-derivative is selected by growing the polA host in the presence of both antibiotics. Resolution of this cointegrate is further selected in sucrose growth conditions due to the loss of a conditional suicide marker (the sacB gene of Bacillus subtilis) present in the ColE1 plasmid, leading to unmodified and modified incP/Ad5 replicons that can be differentiated upon restriction analysis. Consecutive rounds of this two-step cloning procedure allowed the introduction of multiple independent modifications within the virus genome, with no requirement for an intermediate virus. The potential of this procedure is demonstrated by the recovery of several E1E3E4-deleted adenoviruses following transfection of the corresponding E. coli-derived genomes in IGRP2 cells.

Virus-sized self-assembling lamellar complexes between plasmid DNA and cationic micelles promote gene transfer.

Gene therapy is based on the vectorization of genes to target cells and their subsequent expression. Cationic amphiphile-mediated delivery of plasmid DNA is the nonviral gene transfer method most often used. We examined the supramolecular structure of lipopolyamine/plasmid DNA complexes under various condensing conditions. Plasmid DNA complexation with lipopolyamine micelles whose mean diameter was 5 nm revealed three domains, depending on the lipopolyamine/plasmid DNA ratio. These domains respectively corresponded to negatively, neutrally, and positively charged complexes. Transmission electron microscopy and x-ray scattering experiments on complexes originating from these three domains showed that although their morphology depends on the lipopolyamine/plasmid DNA ratio, their particle structure consists of ordered domains characterized by even spacing of 80 A, irrespective of the lipid/DNA ratio. The most active lipopolyamine/DNA complexes for gene transfer were positively charged. They were characterized by fully condensed DNA inside spherical particles (diameter: 50 nm) sandwiched between lipid bilayers. These results show that supercoiled plasmid DNA is able to transform lipopolyamine micelles into a supramolecular organization characterized by ordered lamellar domains.

Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action.

A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.

Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry.

A novel series of omega-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the omega-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. "Time of addition" experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process.

Molecular cloning of a functional human galanin receptor.

The ubiquitous neuropeptide galanin controls numerous functions such as endocrine secretions, intestinal motility, and behavioral activities. These regulatory effects of galanin are mediated through the interaction with specific membrane receptors and involve the pertussis toxin-sensitive guanine nucleotide binding proteins Gi/Go as transducing elements. We report here the isolation of a cDNA coding for a human galanin receptor from a Bowes melanoma cell line cDNA expression library, by using a radioligand binding strategy. The nucleotide sequence of the cloned receptor reveals an open reading frame encoding a 349-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the guanine nucleotide binding protein-coupled neuropeptide receptor family. The cloned receptor expressed in COS cells specifically binds human, porcine, and rat galanin with high affinity (Kd in the nanomolar range) and mediates the galanin inhibition of adenylate cyclase. A 2.8-kb galanin receptor transcript was identified in several human tissues. Cloning of this galanin receptor should enhance our knowledge of its distribution, structure, and function in human physiology and pathophysiology.

Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells.

A series of triterpene compounds characterized by a stringent structure-activity relationship were identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Currently studied botulinic derivatives have 50% inhibitory concentrations (IC50) against HIV-1 strain IIIB/LAI in the 10 nM range in several cellular infection assays but are inactive against HIV-2. These compounds did not significantly inhibit the in vitro activities of several purified HIV-1 enzymes. Rather, they appeared to block virus infection at a postbinding, envelope-dependent step involved in the fusion of the virus to the cell membrane.

Septide: an agonist for the NK1 receptor acting at a site distinct from substance P.

The hexapeptide [pGlu6,Pro9]substance P (SP)6-11, septide, has been shown to be an agonist as potent as SP in eliciting smooth muscle contraction in several in vitro preparations, while being a poor competitor of labeled SP binding. These results, as well as other pharmacological data, have suggested the existence of either a specific septide receptor or a septide site on the neurokinin (NK)1 receptor distinct from that for SP. We have used rat recombinant NK1 receptor expressed in COS-1 cells to address this issue. Both functional (agonist-induced inositol phosphate accumulation) and radioligand binding studies were conducted on transiently transfected cells. SP and septide elicited similar maximal increases (4-6-fold) in inositol phosphate levels in transfected cells, with EC50 values of 0.05 +/- 0.02 nM for SP and 5 +/- 2 nM for septide. No additivity of the maximal responses to the two agonists was observed, and neither agonist evoked any response in sham-transfected cells. RP 67580 was a competitive inhibitor of SP responses, with an inhibition constant (KB) of 13 +/- 2 nM, in agreement with displacement studies of [3H]SP binding to membranes and intact transfected cells (Ki values of 10 +/- 4 nM, and 1.16 +/- 0.06 nM, respectively). In comparison, septide responses were inhibited by RP 67580 in an uncompetitive fashion, with an apparent KB* value of 1.5 +/- 0.2 nM. Septide was a weak competitor of [3H]SP binding, with dissociation constants (Ki) of 2.9 +/- 0.6 microM and 3.7 +/- 0.9 microM for membranes and intact transfected cells, respectively. Similarly, septide at concentrations up to 10 microM did not affect [3H]RP 67580 binding. In conclusion, we have demonstrated that septide is a potent functional agonist of the NK1 receptor but it seems to act at a specific subsite different from that for SP. Although not ruling out the existence of selective septide receptors in some tissues, these results could explain some of the discrepancies with regard to the pharmacological properties of septide. Furthermore, a specific septide site on the NK1 receptor could represent an original pharmacological target.

Cloning and primary structure of the wide-spectrum amidase from Brevibacterium sp. R312: high homology to the amiE product from Pseudomonas aeruginosa.

A Brevibacterium sp. R312 DNA fragment encoding the wide-spectrum amidase (EC 3.5.1.4) has been cloned and sequenced, using limited amino acid (aa) sequence information obtained from the purified enzyme. The deduced aa sequence showed more than 80% strict identity with the Pseudomonas aeruginosa aliphatic amidase, the product of the amiE gene, suggesting a horizontal transfer of the gene during evolution between Gram+ and Gram- bacteria.

Purification, cloning, and primary structure of a new enantiomer-selective amidase from a Rhodococcus strain: structural evidence for a conserved genetic coupling with nitrile hydratase.

A new enantiomer-selective amidase active on several 2-aryl propionamides was identified and purified from a newly isolated Rhodococcus strain. The characterized amidase is an apparent homodimer, each molecule of which has an Mr of 48,554; it has a specific activity of 16.5 mumol of S(+)-2-phenylpropionic acid formed per min per mg of enzyme from the racemic amide under our conditions. An oligonucleotide probe was deduced from limited peptide information and was used to clone the corresponding gene, named amdA. As expected, significant homologies were found between the amino acid sequences of the enantiomer-selective amidase of Rhodococcus sp., the corresponding enzyme from Brevibacterium sp. strain R312, and several known amidases, thus confirming the existence of a structural class of amidase enzymes. Genes probably coding for the two subunits of a nitrile hydratase, albeit in an inverse order, were found 39 bp downstream of amdA, suggesting that such a genetic organization might be conserved in different microorganisms. Although we failed to express an active Rhodococcus amidase in Escherichia coli, even in conditions allowing the expression of an active R312 enzyme, the high-level expression of the active recombinant enzyme could be demonstrated in Brevibacterium lactofermentum by using a pSR1-derived shuttle vector.