[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.

Antibodies to synthetic peptide from the residue 33 to 42 domain of c-Ha-ras p21 block reconstitution of the protein with different effectors.

Residues 32 to 40, which are conserved among ras proteins from different species, are likely to participate in interactions with the p21 effector system. With the goal of understanding the structural basis of the regulatory functions of c-Ha-ras p21, we produced rabbit antisera against a synthetic peptide corresponding to amino acids 33 to 42 of the protein. The affinity-purified antibodies interacted specifically with p21 and with the antigenic peptide. The epitope recognized by the antibodies appeared to be centered on threonine 35. The antibodies inhibited both in vitro p21-induced production of cyclic AMP in detergent extracts of RAS-defective yeast membranes and GAP-stimulated GTPase activity. However, monoclonal anti-ras antibodies Y13-259 and Y13-238 were not capable of specifically inhibiting interactions of p21 with these two putative effector proteins. The apparent inhibitory effect of Y13-259 on stimulation of p21 by GAP was due to a greatly reduced rate of exchange of nucleotides in the binding pocket of the protein. These findings provide additional support for the essential role of the residue 32 to 40 domain as the true effector site and further evidence of the involvement of GAP as a cellular effector of ras proteins.

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.

Control of phenylalanyl-tRNA synthetase genetic expression. Site-directed mutagenesis of the pheS, T operon regulatory region in vitro.

Previous studies of phenylalanyl-tRNA synthetase expression in Escherichia coli strongly suggested that the pheS, T operon was regulated by a phenylalanine-mediated attenuation mechanism. To investigate the functions of the different segments composing the pheS, T attenuator site, a series of insertion, deletion and point mutations in the pheS, T leader region have been constructed in vitro on a recombinant M13 phage. The effects of these alterations on the regulation of the operon were measured after transferring each mutation onto a lambda phage carrying a pheS, T-lacZ fusion. The behaviours of the various mutants agree with the predictions of the attenuation model. The role of the antiterminator (2-3 pairing) as competitor of the terminator (3-4 pairing) is demonstrated by several mutations affecting the stability of the 2-3 base-pairing. The existence of deletions and point mutations in the 3-4 base-pairing shows that the terminator is essential for both expression level and regulation of the operon. Mutations in the translation initiation site of the leader peptide show that the expression of the leader peptide is essential for attenuation control. However, alteration of the translation initiation rate of the leader peptide derepresses the pheS, T operon, which is the opposite of what is observed with the trp operon. This difference is explained in terms of different translation initiation efficiencies of the leader peptides. Finally, insertion mutations, increasing gradually the distance between the leader peptide stop codon and the first strand of the antiterminator, derepress the pheS, T operon and show that formation of the antiterminator structure is under the control of the translation of the leader peptide.

Attenuation control of the Escherichia coli phenylalanyl-tRNA synthetase operon.

The pheST operon codes for the two subunits of the essential enzyme phenylalanyl-tRNA synthetase. The nucleotide sequence of the regulatory regions of the operon, in vitro transcription data and in vivo experiments indicate that the operon is controlled by attenuation in a way similar to many amino acid biosynthetic operons. In this work the control of the pheST operon was studied in vivo by measuring the effect of deletions in the regulatory regions on downstream expression. The presence of a strong promoter followed by an approximately 90% efficient terminator in front of the structural parts of the operon is demonstrated. An open reading frame coding for a 14 amino acid long leader peptide containing five phenylalanine residues is located between the promoter and the terminator. The presence of the transcription terminator is shown to be essential to the operon's regulation. The localization of the promoter and the terminator agrees with the results of previous in vitro experiments. It is also shown that about 30% of the transcripts covering the pheST operon come from the upstream gene, rplT, which codes for the ribosomal protein L20. Although cotranscription exists between rplT and pheST, these genes are not systematically coregulated since reducing the translation of rplT about tenfold, does not change pheST expression. The pheST operon is also shown to be derepressed by a cellular excess of phenylalanyl-tRNA synthetase. This derepression is shown to be due to the pheST attenuator.

Escherichia coli phenylalanyl-tRNA synthetase operon region. Evidence for an attenuation mechanism. Identification of the gene for the ribosomal protein L20.

The nucleotide sequences of pheS and of the beginning of pheT have been determined. The genes pheS and pheT code, respectively, for the small and large subunits of phenylalanyl-tRNA synthetase, an alpha 2 beta 2 enzyme. Upstream from pheS the sequence shows another open reading frame of 354 nucleotides (rplT), which accounts for a protein of Mr 13,400. The product of this gene, previously named "P12", is identified as the ribosomal protein L20. The promoter for the pheS, T operon was located 368 nucleotides in front of pheS by transcription experiments in vitro. The promoter site is followed by a short open reading frame, which codes for a 14-residue peptide containing five phenylalanine residues. Immediately downstream from the stop codon of this open reading frame, the DNA sequence indicates that the transcript can be folded into three alternative secondary structures, one of which is a site of transcription termination. In vitro, 90% of transcription products initiated at the pheS, T promoter terminate at this site. However, long run-off transcripts proceeding through the terminator and covering the pheS structural gene are observed. No other transcription initiation could be detected between the terminator and the pheS structural gene. All these results are consistent with a mechanism by which phenylalanine-mediated attenuation controls the expression of phenylalanyl-tRNA synthetase. Further evidence is provided for this model by the features of pheS, T regulation in vivo (see the accompanying paper).

Autogenous control of Escherichia coli threonyl-tRNA synthetase expression in vivo.

The regulation of the expression of thrS, the structural gene for threonyl-tRNA synthetase, was studied using several thrS-lac fusions cloned in lambda and integrated as single copies at att lambda. It is first shown that the level of beta-galactosidase synthesized from a thrS-lac protein fusion is increased when the chromosomal copy of thrS is mutated. It is also shown that the level of beta-galactosidase synthesized from the same protein fusion is decreased if wild-type threonyl-tRNA synthetase is overproduced from a thrS-carrying plasmid. These results strongly indicate that threonyl-tRNA synthetase controls the expression of its own gene. Consistent with this hypothesis it is shown that some thrS mutants overproduce a modified form of threonyl-tRNA synthetase. When the thrS-lac protein fusion is replaced by several types of thrS-lac operon fusions no effect of the chromosomal thrS allele on beta-galactosidase synthesis is observed. It is also shown that beta-galactosidase synthesis from a promoter-proximal thrS-lac operon fusion is not repressed by threonyl-tRNA synthetase overproduction. The fact that regulation is seen with a thrS-lac protein fusion and not with operon fusions indicates that thrS expression is autoregulated at the translational level. This is confirmed by hybridization experiments which show that under conditions where beta-galactosidase synthesis from a thrS-lac protein fusion is derepressed three- to fivefold, lac messenger RNA is only slightly increased.

Escherichia coli phenylalanyl-tRNA synthetase operon is controlled by attenuation in vivo.

The two subunits of phenylalanyl-tRNA synthetase are made from two adjacent, cotranscribed genes that constitute the pheS,T operon. Three different fusions between pheS,T and lac genes were constructed in order to study the regulation of the pheS,T operon in vivo. We show, using these fusions, that phenylalanyl-tRNA synthetase transcription is derepressed when the level of aminoacylated tRNAPhe is lowered by mutational alteration of the synthetase. The pheS,T operon is also derepressed in strains carrying a trpX mutation. The gene trpX codes for an enzyme that modifies both tRNATrp and tRNAPhe and a mutation in that gene causes derepression of the trp and pheA operons, both of which are controlled by attenuation. The in vivo features of the regulation of pheS,T expression described here in correlation with the DNA sequence and in vitro transcription results described in the accompanying paper by Fayat et al. indicate that phenylalanyl-tRNA synthetase is controlled by attenuation in a way analogous to several amino acid biosynthetic operons.

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.

IS4 transposition in the attenuator region of the Escherichia coli pheS,T operon.

A cis-acting mutation which lowers phenylalanyl-tRNA synthetase operon (pheS,T) transcription about tenfold was previously isolated on a multicopy plasmid [Plumbridge and Springer, J. Bacteriol. 152 (1982) 650-668]. This mutation has now been characterized as an IS4 element inserted in orientation II in the terminator stem of the pheS,T attenuator. The identification of the insertion as IS4 is based on (i) the nature and location of restriction sites internal to the insertion element, and (ii) the DNA sequence of both the left and right Escherichia coli::IS4 junctions. The effect of the IS4 transposition on the expression of pheS,T was studied using pheS,T::lac fusions cloned in lambda phages. IS4 integration into the leader region of the pheS,T operon was shown to abolish the miaA (trpX) allele dependence which characterizes the attenuation mechanism regulating pheS,T expression [Fayat et al., J. Mol. Biol. 171 (1983) 239-261; Springer et al., J. Mol. Biol. 171 (1983) 263-279]. The IS4 insertion site described here is compared to the other known sites and the effect of IS4 transposition on the expression of neighbouring genes is discussed.

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.

Chemical synthesis of a gene coding for human angiogenin, its expression in Escherichia coli and conversion of the product into its active form.

A synthetic gene coding for human angiogenin was synthesized by solid support phosphoramidite chemistry as eight long oligodeoxynucleotides which were subsequently assembled and cloned in Escherichia coli. The gene was designed to use codons found in highly expressed E. coli proteins. A pBR322-derived expression vector was constructed containing the E. coli trp promoter, the ribosome-binding site of the bacteriophage lambda cII gene, the angiogenin coding sequence, and the transcription terminator region of the E. coli rrnB operon. Under tryptophan deprivation, angiogenin was strongly expressed in E. coli cells at a yield of 5-10% of total protein. The eukaryotic protein was found to be insoluble but could be easily renatured and purified. The purified angiogenin was demonstrated to be active as an angiogenic factor and exhibited a characteristic RNase activity.

Heterologous protein export in Escherichia coli: influence of bacterial signal peptides on the export of human interleukin 1 beta.

Expression plasmids carrying the coding sequence of mature human interleukin 1 beta (IL 1 beta) linked either to a Met start codon, or fused to different efficient Escherichia coli secretion signal sequences, have been constructed. In the latter case, we used signal peptides derived either from an outer membrane protein (OmpA) or from a periplasmic protein (PhoA). The synthesis of IL1 beta from these fusions was investigated in an otherwise strictly isogenic context using identical conditions of derepression and culture media. The Met-IL1 beta fusion produced a soluble cytoplasmic protein which could be released from the cells by osmotic shock whereas the OmpA and PhoA fusions were always insoluble. The extent of sOmpA-IL1 beta maturation was found to vary from 50 to 100%, mainly depending on the medium used, whereas no significant maturation of the signal peptide could be detected in the case of the sPhoA-IL1 beta fusion. Immuno-electron microscopy revealed that the sOmpA-IL1 beta fusion was targeted to the inner membrane, whereas the sPhoA-IL1 beta fusion remained within the cytoplasm and thus did not appear to enter the secretion pathway. Amplifying the E. coli signal peptidase lep gene on a multicopy plasmid did not improve signal peptide removal from sOmpA-IL1 beta. Moreover, these E. coli secretion vectors allowed us to produce, in high levels, IL1 beta fragments which otherwise could not be stably accumulated within the cytoplasmic compartment.

Open reading frames in the control regions of the phenylalanyl-tRNA synthetase operon of E. coli.

The pheST operon codes for the two subunits of phenylalanyl-tRNA synthetase and it expression is controlled by attenuation in a way similar to many amino acid biosynthetic operons. The nucleotide sequence of the control regions of the operon indicates the presence of several open reading frames besides that of the leader peptide. One of these open reading frames, called the alternative leader peptide, starts at about the same place as the leader peptide and ends after the terminator of the attenuator. Another open reading frame, called the terminator peptide, starts after the terminator and covers about half the distance to pheS, the first structural gene of the operon. The present report shows that, in fact, the only open reading frame to be translated efficiently is the leader peptide itself. The alternative leader peptide and the terminator peptide are both translated at a negligible rate.

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.

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.