Incidence and associated factors of cetuximab-induced hypersensitivity infusion reactions in 1392 cancer patients treated in four French areas: a possible association with Lyme disease?

BACKGROUND: Previous studies have observed an increased incidence of Cetuximab-induced hypersensitivity infusion reactions (CI-IRs) in the southeastern states of the USA. Tick's bites were suspected of generating cross-reactions between cetuximab and alpha-gal. This study aims was to describe the incidence and associated risk factors of CI-IRs, in the French areas chosen according to their Lyme disease incidence. PATIENTS AND METHODS: A retrospective chart review was conducted on patients that received cetuximab infusion from January 2010 to June 2019 in 4 French areas with different Lyme disease incidence rates. RESULTS: Of 1392 patients, 117 (8.4%) experienced a CI-IR, including 68 severe (grade 3 or 4) reactions (4.9%). This CI-IR incidence was significantly higher in the Lyme disease high-risk area than in the other areas (13.2% versus 7.1%, 8.1% and 6.4%; P = 0.016). Sex (P = 0.53), premedication (P = 0.91), primary cancer location (P = 0.46) and chemotherapy regimen type (P = 0.78) had no impact on CI-IR incidence in the overall population. In the head and neck squamous cell carcinoma (HNSCC) patient subgroup, CI-IRs were significantly more frequent in the high-risk area (16.4% versus 6.7%, 7.1% and 7.0%; P = 0.0015). CONCLUSION: This study suggests that patients treated in the French area with the highest incidence of Lyme disease are at a higher risk of CI-IRs.

Time intervals to diagnosis and chemotherapy do not influence survival outcome in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: The effect of treatment delay on survival in pancreatic ductal adenocarcinoma (PDAC) remains unclear. AIMS: This study aimed to assess the prognostic impact of time to diagnosis and chemotherapy in advanced PDAC and factors influencing the time intervals. METHODS: advanced PDAC patients receiving chemotherapy in five centers in the decade 2007-2016 were included. Key time points during care pathway from clinical presentation to beginning of chemotherapy were retrospectively collected. Multivariate Cox proportional hazard model was performed. RESULTS: A total of 409 patients were included (mean age 66.1 ± 10.3 years; 250 metastatic (61%); 139 received FOLFIRINOX chemotherapy (34%). The median overall survival (OS) was 7.2 months. The median times from first symptoms and from first specialist visit to the beginning of chemotherapy were respectively 100 days and 47 days. None of time intervals was significantly associated with OS. Significant prognostic factors were FOLFIRINOX chemotherapy (HR 0.6 [0.5-0.8]; P < 0.001), metastasis (HR 1.6 [1.3-2.0]; P = 0.001), WHO PS ≥ 2 (HR 1.6 [1.2-2.1]; P < 0.001) and acute pancreatitis as first symptom (HR 2.9 [1.7-4.9]; P < 0.001). Jaundice shortened time to diagnosis (P < 0.001). Acute pancreatitis (P < 0.001) and diabetes (P = 0.01) increased time to treatment. CONCLUSION: Wait times from clinical presentation to beginning of chemotherapy do not influence survival in advanced PDAC.

[Conservative placenta percreta management using uterine arterial embolization procedure: A series of 12 cases]. / Prise en charge conservatrice du placenta percreta vésical avec embolisation des artères utérines : à partir d'une série continue de 12 cas.

We report a retrospective series of 12 placentas percreta with bladder invasion and for which an expected initially multidisciplinary conservative surgical treatment associated with uterine artery embolization was programmed. Conservative surgical treatment was only performed in 7 women. Radical surgical treatment was necessary during the caesarean section and complicated by massive hemorrhage in three women and secondary in two other women for infectious diseases. Radical surgical treatment was associated with partial cystectomy complicated with urinary disorder sequelae in three women. Maternal morbidity of the placenta percreta bladder remains high despite the establishment of a multidisciplinary care protocol.

Neurodevelopmental long-term outcome in children with hydrocephalus requiring neonatal surgical treatment.

PURPOSE: To assess long-term neurodevelopmental outcome in children with hydrocephalus requiring neurosurgical treatment during the neonatal period. METHODS: This prospective longitudinal population-based study included 43 children with neonatal shunted hydrocephalus. The 43 children were prospectively reviewed in the presence of their parents at the outpatient clinic. Cognitive and motor outcomes were assessed respectively using different Wechsler scales according to age and Gross Motor Function Classification System (GMFCS). Postoperative MRI was routinely performed. RESULTS: The mean gestational age at birth of the 43 consecutive children with neonatal hydrocephalus (sex ratio M/F: 1.39) was 34.5±5.4 weeks of gestation. At mean follow-up of 10.4±4 years, mean total IQ was 73±27.7, with equivalent results in mean verbal and mean performance IQ. Of the 33 children with IQ evaluation, 18 presented an IQ≥85 (41.9%). Efficiency in walking without a mobility device (GMFCS≤2) was obtained in 37 children (86%). Only severity of postoperative ventricular dilation was significantly associated with unfavorable outcome (Evans index>0.37; odds ratio: 0.16, P=0.03). CONCLUSION: This information could be provided to those families concerned who often experience anxiety when multi-disciplinary management of neonatal hydrocephalus is required.

Distortion of the anterior part of the interhemispheric fissure: significance and implications for prenatal diagnosis.

In order to illustrate the significance of a new anatomical finding, distortion of the interhemispheric fissure (DIHF) associated with impacted medial borders of the frontal lobes, we report a retrospective observational study of 13 fetuses in which DIHF was identified on prenatal imaging. In 10 cases there were associated anatomical anomalies, including mainly midline anomalies (syntelencephaly (n=2), lobar holoprosencephaly (n=1), Aicardi syndrome (n=2)), but also schizencephaly (n=1), cortical dysplasia (n=1) and more complex cerebral malformations (n=3), including neural tube defect in two cases. Chromosomal anomaly was identified in two cases, including 6p deletion in a case without associated central nervous system anomalies and a complex mosaicism in one of the cases with syntelencephaly. In two cases, the finding was apparently isolated on both pre- and postnatal imaging, and the children were doing well at follow-up, aged 4 and 5 years. The presence of DIHF on prenatal imaging may help in the diagnosis of cerebral anomalies, especially those involving the midline. If DIHF is apparently isolated on prenatal ultrasound, magnetic resonance imaging is recommended for careful analysis of gyration and midline, especially optic and olfactory structures. Karyotyping is also recommended.

Effects of irradiation on bone remodelling around mandibular implants: an experimental study in dogs.

This research focuses on the effects of radiotherapy on bone remodelling around mandibular implants in dogs. After bilateral extraction of the mandibular premolars and first 2 molars, each of 11 beagles received 8 mandibular implants. Four animals were irradiated 4 weeks after implantation and 4 others 8 weeks before implantation; the remaining 3 did not receive radiotherapy. Irradiation consisted of 10 daily fractions of 4.3Gy (60)Co. Fluorochromes were given at implantation and irradiation to allow the measurement of bone apposition. The dogs were killed 6 months after implantation. Each hemi-mandible was processed according to bone-specific histological techniques. New bone formation was visible around 85 of the 88 implants. Stimulated mandibular remodelling was attested in both irradiated groups by increased porosity and numerous labelled osteons. Resorption was more pronounced in the group irradiated after implantation, but osteon formation appeared unvarying. Osseointegration was thus shown to be compatible with bone irradiation as bone turnover activities were maintained throughout the experiment. As the apposition stage of the remodelling cycle appears crucial to achieve optimal osseointegration, its normal completion should be taken into account in clinical practice by respecting a 6-month period between irradiation and implantation.

A chemiluminescent microtiter plate assay for sensitive detection of protein kinase activity.

A chemiluminescent protein kinase assay using biotinylated substrate peptides captured on a streptavidin-coated microtiter plate and monoclonal antibodies to detect their phosphorylation is described. Assay conditions were optimized and validated for sensitive measurement of protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II (CAM-KII), receptor interacting protein, and src activities. The newly developed chemiluminescent assay has several advantages over currently used radioactive or colorimetric methods. It is highly sensitive at low enzyme and substrate concentrations and high, close to physiological ATP levels. It is fast, simple to perform and amenable to automation and high-throughput drug screening. The assay is also robust, exhibiting minimum interference from solvents and test substances from various sources. Overall, among the presently available methods for the detection of protein kinase activity, chemiluminescence was found to provide the highest sensitivity under conditions most closely mimicking the intracellular environment. This assay is expected to be useful in both academic and industrial laboratories, especially in identifying novel classes of protein kinase inhibitors.

Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation.

Strenuous exercise may be associated with immune suppression. However, the underlying mechanism is not known. A decrease in the plasma level of glutamine, which is utilised at a high rate by cells of the immune system, and an increase in the plasma level of some cytokines may impair immune functions such as lymphocyte proliferation after prolonged, exhaustive exercise. In two separate studies of the Brussels marathon, using similar protocols, the time course of the changes in the plasma concentrations of some amino acids (glutamine, glutamate, alanine, tryptophan and branched chain amino acids), acute phase proteins and cytokines (interleukins IL-1 alpha, IL-2, IL-6, tumour necrosis factor type a) was measured in male athletes. The numbers of circulating leucocytes and lymphocytes were also measured. Amino acid and cytokine concentrations have not previously been measured concomitantly in marathon runners; the measurement of some of these parameters the morning after the marathon (16 h) is novel. Another novel feature is the provision of glutamine versus placebo to marathon runners participating in the second study. In both studies the plasma concentrations of glutamine, alanine and branched chain amino acids were decreased immediately after and 1 h after the marathon. Plasma concentrations of all amino acids returned to pre-exercise levels by 16 h after exercise. The plasma concentration of the complement anaphylotoxin C5a increased to abnormal levels after the marathon, presumably due to tissue damage activating the complement system. There was also an increase in plasma C-reactive protein 16 h after the marathon. The plasma levels of IL-1 alpha were unaffected by the exercise, while that of IL-2 was increased 16 h after exercise. Plasma IL-6 was increased markedly (approximately 45-fold) immediately after and at 1 h after exercise. Neopterine, a macrophage activation marker, was significantly increased post-exercise. There was a marked leucocytosis immediately after the marathon, which returned to normal 16 h later. At the same time there was a decrease in the number of T-lymphocytes, which was further reduced within 1 h to below pre-exercise levels. Glutamine supplementation, as administered in the second study, did not appear to have an effect upon lymphocyte distribution.

Components of a Stat recognition code: evidence for two layers of molecular selectivity.

Latent and activated forms of Stat1 and Stat6 have been expressed and purified, enabling biochemical experiments relating to their functional activities. Stat1 bound to a phosphotyrosine peptide derived from the IFN gamma receptor with a KD of 50 nM, whereas Stat6 bound to an IL-4 receptor peptide with a KD of 300 nM. Stat-receptor peptide interactions were specific and dependent upon tyrosine phosphorylation. Activated forms of Stat1 and Stat6 were used to select their optimal DNA binding sites. Stat1 selected a recognition site having dyad half-sites separated by 3 bp. Stat6 selected a recognition site composed of the same dyad half-sites, yet separated by 4 bp. Chimeric Stat1-Stat6 recombinants were expressed, purified, and assayed for receptor coupling and DNA binding specificity. Such studies led to the identification of polypeptide domains that specify these activities. These observations provide a framework for understanding how different cytokines elicit distinctive patterns of gene expression.

Antimicrobial peptides in the stomach of Xenopus laevis.

Antimicrobial peptides are widely distributed in nature and appear to play a role in the host defense of plants and animals. In this study we report the existence of antimicrobial peptides in the stomach of the vertebrate Xenopus laevis, an animal previously shown to store high concentrations of antimicrobial peptides in its skin. Antimicrobial activity was detected in extracts of X. laevis stomach tissue and nine antimicrobial peptides were then purified. A novel 24-amino acid peptide, designated PGQ, was isolated from these extracts, and has the following amino acid sequence: GVLSNVIGYLKKLGTGALNAVLKQ. PGQ is relatively basic and has the potential to form an amphipathic alpha-helix. The other peptides isolated are members of the magainin family of antimicrobial peptides, and include magainins I and II, PGLa, xenopsin precursor fragment, and four caerulein precursor fragments. None of these peptides had been previously identified in tissues other than the skin. The purification of the peptides from stomach extracts and subsequent protein sequence analysis reveals that the peptides have undergone the same processing as their dermal counterparts, and that they are stored in their processed forms. Northern blot analysis indicates that the magainin family of peptides are synthesized in the stomach, and immunohistochemical studies demonstrate that magainin is stored in a novel granular multinucleated cell in the gastric mucosa of Xenopus. This study demonstrates that the magainin family of antimicrobial peptides is found in the gastrointestinal system of X. laevis and offers an opportunity to further define the physiological role of these defense peptides.

Tracheal antimicrobial peptide, a cysteine-rich peptide from mammalian tracheal mucosa: peptide isolation and cloning of a cDNA.

Extracts of the bovine tracheal mucosa have an abundant peptide with potent antimicrobial activity. The 38-amino acid peptide, which we have named tracheal antimicrobial peptide (TAP), was isolated by a sequential use of size-exclusion, ion-exchange, and reverse-phase chromatographic fractionations using antimicrobial activity as a functional assay. The yield was approximately 2 micrograms/g of wet mucosa. The complete peptide sequence was determined by a combination of peptide and cDNA analysis. The amino acid sequence of TAP is H-Asn-Pro-Val-Ser-Cys-Val-Arg-Asn-Lys-Gly-Ile-Cys-Val-Pro-Ile-Arg-Cys-Pr o- Gly-Ser-Met-Lys-Gln-Ile-Gly-Thr-Cys-Val-Gly-Arg-Ala-Val-Lys-Cys-Cys-Arg- Lys-Lys - OH. Mass spectral analysis of the isolated peptide was consistent with this sequence and indicated the participation of six cysteine residues in the formation of intramolecular disulfide bonds. The size, basic charge, and presence of three intramolecular disulfide bonds is similar to, but clearly distinct from, the defensins, a well-characterized class of antimicrobial peptides from mammalian circulating phagocytic cells. The putative TAP precursor is predicted to be relatively small (64 amino acids), and the mature peptide resides at the extreme carboxyl terminus and is bracketed by a short putative propeptide region and an inframe stop codon. The mRNA encoding this peptide is more abundant in the respiratory mucosa than in whole lung tissue. The purified peptide had antibacterial activity in vitro against Escherichia coli, Staphylococcus aureus, Klebsiella pneumonia, and Pseudomonas aeruginosa. In addition, the peptide was active against Candida albicans, indicating a broad spectrum of activity. This peptide appears to be, based on structure and activity, a member of a group of cysteine-rich, cationic, antimicrobial peptides found in animals, insects, and plants. The isolation of TAP from the mammalian respiratory mucosa may provide insight into our understanding of host defense of this vital tissue.

A comparison of the inhibition of blastospore viability and germ-tube development in Candida albicans by histidine peptides and ketoconazole.

Synthetic homologous peptides of L-histidine, ranging in length from 3 to 64 amino-acid residues, suppressed blastospore viability. Killing activity was dependent upon the peptide molecular size and concentration, and the time of cell exposure to the agent, but was independent of cell concentration in the range 10(5)-10(7) colony-forming units (c.f.u.) per ml. A 25 amino-acid residue polypeptide, similar to the human parotid salivary histidine-rich peptide (HRP-5), also affected yeast viability. Its killing effect was dependent upon the number of c.f.u. in the assay, as well as contact time with the blastospores and the final peptide concentration. HRP-5 inhibition increased with rising pH in the range 5-7.4, in contrast to poly-L-histidine and ketoconazole, which had optimal candidacidal activity at about pH 6. Poly-L-histidine, HRP-5, and ketoconazole each prevented conversion of blastospores to germ tubes, but their rank order of effectiveness varied with the assay selected. In N-acetylglucosamine-supplemented fetal calf serum, poly-L-histidine and HRP-5 were more effective inhibitors than ketoconazole, but the reverse was true in amino-acid-supplemented glucose beef-extract medium. Reduction of both germ-tube numbers and germ-tube size by HRP-5 was concentration-dependent.

Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients.

Renal failure (RF) occurring in the course of multiple myeloma is often judged irreversible and generally considered an ominous complication. The aim of the present study was to re-evaluate the outcome, triggering conditions and prognostic factors of severe RF in a series of 34 patients, 33 to 90 years old. RF was totally reversible in 7 patients and partially reversible in 9 although 6 of them had to be temporarily dialyzed. However, the improvement in renal function was often very slow as indicated by an average recovery time of 115 days. The high rate of RF reversibility was associated with markedly lengthened survival. Review of triggering events confirmed the leading role of dehydration and hypercalcemia, but further suggested that intake of nonsteroidal anti-inflammatory drugs and renal infection might play a part in the development of RF. Systematic statistical analysis of potential prognostic factors showed that the outcome was significantly more severe in females, but age, myeloma characteristics including tumor mass, calcemia, and triggering events had no predictive value. The most reliable prognostic indicators were provided by analysis of kidney biopsy performed in 30 patients. Complete recovery from RF was observed only in the absence of global tubular atrophy and interstitial damage. In contrast, cast-induced tubular obstruction detected by the presence of Tamm-Horsfall protein in urinary space of glomeruli did not seem to influence the outcome of RF. Finally, we analyzed the prognostic value of immunochemical properties of light chains (LC). Lambda LC were unexpectedly detected in 2 of 3 patients, as compared to a ratio of 1 to 3 in the population of normal and monoclonal Ig, but LC type did not correlate with the course of RF. Isoelectric points of LC measured in 32 patients were dispersed from 5.2 to 8.9 and bore only weak prognostic significance. These results underline the value of kidney biopsy and justify aggressive treatment including dialysis and chemotherapy.

Metabolic implications during a 20-km run after heart transplantation.

The aim of the present study was to evaluate a heart transplanted patient who ran a 20-km race 9 months after surgery. Thirty-six healthy male subjects were studied during the same run and served as control group. Biochemical variables were determined in blood and urine samples collected before and after the race. Post-exercise blood urea increased by 23% (P less than 0.05) in the control group but remained unchanged in the patient. Blood lactate increased far more in the transplanted patient (7.07 mmol/L) than in the control subjects (2.53 mmol/L). The exercise induced a 5.46- and 0.67-fold increase in creatine phosphokinase activity in the transplanted patient and control group, respectively. The creatinine and urea urinary excretion and clearance decreased by 40%-60% after exercise for all subjects. It may be concluded that the heart transplanted patient responded for most registered variables in the same way as normal subjects, but some differences occurred on the renal side due to the use of an immunosuppressive drug.

ACTH, cortisol and growth hormone 24-hour profiles in major depressive illness.

Circadian rhythms of ACTH, cortisol and growth hormone have been studied in eighteen major depressives (eight unipolar and ten bipolar) as well as in eight normal controls. Both unipolar and bipolar depressed patients secreted more growth hormone than normal men. This hypersecretion occurred during waking hours rather than during sleep. An early sleep GH increase was found in all but one of the normal men, but was absent in seven of the eight unipolar depressed patients, who had instead a presleep increase. No consistent disturbance of the temporal association between sleep onset and GH secretion was found in bipolar depressed patients. Both unipolar and bipolar depressed patients had higher 24 h mean cortisol levels than normal men, but no significant difference was found for 24 h ACTH levels. An early timing of the nadir of ACTH-cortisol secretion which was observed in our depressed patients also suggest that disorders of circadian time keeping may characterize major endogenous depression.