An immunological signature to predict outcome in patients with triple-negative breast cancer with residual disease after neoadjuvant chemotherapy.

BACKGROUND: When triple-negative breast cancer (TNBC) patients have residual disease after neoadjuvant chemotherapy (NACT), they have a high risk of metastatic relapse. With immune infiltrate in TNBC being prognostic and predictive of response to treatment, our aim was to develop an immunologic transcriptomic signature using post-NACT samples to predict relapse. MATERIALS AND METHODS: We identified 115 samples of residual tumors from post-NACT TNBC patients. We profiled the expression of 770 genes related to cancer microenvironment using the NanoString PanCancer IO360 panel to develop a prognostic transcriptomic signature, and we describe the immune microenvironments of the residual tumors. RESULTS: Thirty-eight (33%) patients experienced metastatic relapse. Hierarchical clustering separated patients into five clusters with distinct prognosis based on pathways linked to immune activation, epithelial-to-mesenchymal transition and cell cycle. The immune microenvironment of the residual disease was significantly different between patients who experienced relapse compared to those who did not, the latter having significantly more effector antitumoral immune cells, with significant differences in lymphoid subpopulations. We selected eight genes linked to immunity (BLK, GZMM, CXCR6, LILRA1, SPIB, CCL4, CXCR4, SLAMF7) to develop a transcriptomic signature which could predict relapse in our cohort. This signature was validated in two external cohorts (KMplot and METABRIC). CONCLUSIONS: Lack of immune activation after NACT is associated with a high risk of distant relapse. We propose a prognostic signature based on immune infiltrate that could lead to targeted therapeutic strategies to improve patient prognosis.

Coadministration of atropine, NBQX and TCP against soman-induced seizures.

The ability of relatively low doses of atropine, NBQX and TCP administered in combination to prevent or stop seizures induced by soman, was studied in rats. While these drugs injected together early after soman prevented the onset of seizures, their delayed concomitant administration after 5 or 30 min of epileptic activity only mildly attenuated the intensity of seizures. Conversely, a total arrest of epileptic activity was observed in 80 to 100% of animals when NBQX and TCP were given together after 5 to 50 min of seizures to atropine pretreated rats. The large time-window for antiepileptic effectiveness of this 'three drug treatment', provided that atropine is administered early after soman, is discussed in relation to reciprocal potentiations of the antiepileptic effects of atropine, NBQX and TCP in combination.

Anticonvulsant and antilethal effects of the phencyclidine derivative TCP in soman poisoning.

The protection afforded by TCP (thienylcylohexylpiperidine), a non-competitive blocker of N-methyl-D-aspartate (NMDA) receptors, against the seizures and lethality produced by 2 x LD50 of soman (62 micrograms/kg, sc), an irreversible inhibitor of cholinesterase, was studied in guinea-pigs. In the presence of additional anticholinergic medication (pyridostigmine: 0.2 mg/kg, sc, 30min prior to soman; atropine sulphate: 5mg/kg, im, 1 min post-soman), TCP pretreatment (2.5mg/kg, im, 30 or 15 min prior to soman) did not generally prevent the appearance of soman-induced status epilepticus but did arrest it after 30-40 min in 80% (TCP-30min) or 100% (TCP-15min) of the convulsing subjects. Moreover, in all subjects treated curatively, TCP was able to interrupt ongoing status epilepticus in approximately 20, 10 or 8 min when it was administered 5, 30 or 60min respectively after the onset of epileptiform tracings on EEG. All of these curatively administered animals survived and recovered remarkably well. On every criteria examined (latency-to-seizure arrest, 24hr-survival rate, clinical recovery), injection of 2.5mg/kg TCP after 90min of seizures appeared slightly less efficient compared to earlier curative administration. Therefore, our study (a) establishes that the previously reported capacity of MK-801 (dibenzocyclohepneimine) to counteract soman toxicity is not unique and could be extended to other non-competitive inhibitors of NMDA receptors; (b) shows that TCP could easily prevent and, above all, interrupt soman-induced seizures; furthermore, TCP appears the first compound ever tested on soman poisoning that still displays satisfactory anticonvulsant activity after such a long duration of initial status epilepticus (90min); therefore, TCP might be of special value for the delayed therapy for soman poisoning; (c) confirms that NMDA receptors are involved in the maintenance of seizures and play an important role in other processes implicated in the overall toxicity (including the lethal respiratory effects) of soman poisoning.

Antiepileptic effects of NBQX against soman-induced seizures.

The ability of NBQX, a potent antagonist of AMPA glutamatergic receptors, to prevent or stop seizures induced by the organophosphate soman, an irreversible inhibitor of AChE, was studied in rats. NBQX administered concomitantly with soman prevents the onset of seizures (ED50: 29.2 mg kg-1, i.p.). Administered 5 min after the onset of seizures, NBQX greatly reduces the intensity of the epileptic activity. The same decrease of epileptic activity is observed, in the presence of atropine, when the administration of NBQX is delayed 15 min after the onset of seizures. NBQX thus appears as a promising antiepileptic candidate against soman-induced seizures. The roles of AMPA and muscarinic receptors in the onset and propagation of soman-induced epileptic activity are discussed.

Effects of paraldehyde on the convulsions induced by administration of soman in rats.

The ability of paraldehyde, a potent central nervous system depressant, to prevent the convulsions induced by the organophosphate soman, an irreversible inhibitor of acetylcholinesterase, was studied in rats. Paraldehyde (0.1-500 mg/kg, im) administered 10 min before soman (100 micrograms/kg, sc) did not protect against seizures. Co-administered with atropine sulfate (10 mg/kg, im), paraldehyde produced a clear dose-dependent anticonvulsant response. Although this pre-treatment could delay the occurrence of death, it did not produce any change in the soman-induced 24 h mortality rate. Thus, co-administration of paraldehyde and atropine sulfate might constitute a valuable tool to be used against the convulsant consequences of soman poisoning. However, supplementary pre-medication, in addition to paraldehyde and atropine sulfate, remains necessary to improve the antilethal capacity of the pre-treatment.