Neuromuscular and cardiac adverse events associated with immune checkpoint inhibitors: pooled analysis of individual cases from multiple institutions and literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.

Influence of DNA acidification on DNA premelting and template properties.

Acidification of a T7 DNA sample was found to be partly irreversible as ultraviolet difference spectra measured at various sub-melting temperatures were different from those observed for a 'normal' DNA sample. This implies some subtle conformational change which is not reversed by return to neutral pH. In the same conditions, only poly(purine)-poly(pyrimidine) polymers behaved in a different manner, during premelting, according to whether they were previously acidified or not. The properties of acidified and reneutralized T7 DNA were also investigated for Escherichia coli RNA polymerase binding and transcription. An inhibition of RNA synthesis and chain initiation was observed. The results suggest that the binding of the enzyme is affected. RNA synthesized is specific but there is a decrease in the number and in the stability of the RNA-polymerase-DNA complexes.

Protonated polynucleotide structures, 20. Interaction between poly(dG)-poly(dC) and poly(rC).1.

A study of the interaction between poly(dG)-poly(dC) and poly(rC) demonstrates that, at neutral pH and high ionic strength, there is replacement of the dC strand by poly(rC). At acid pH, formation of a triple-stranded complex which equally may involve the replacement phenomenon is observed. There is no evidence for interaction at neutral pH between poly(dG)-poly(dC) and oligo(rC), while a three-stranded complex is formed at acid pH. These data are consistent with the studies of comparative stabilities of double stranded deoxy or ribo polymers and deoxy-ribo hybrids.

Protonated polynucleotide structures : 14. Poly(dG). poly(dC) and its metastable form.

The circular dichroism spectra of poly(dG). poly(dC) have been studied as a function of pH in 0.15 M NaCl solution. Acid titration to pH 2.5 showed two transitions, one around pH 5, the second below pH 3. These transitions are disproportionation reactions and are not due to the dissociation of the complexes. Alkaline back titration to neutrality showed only one step above pH 7, without appearance of the intermediate form. The hysteresis loop observed gave rise to a metastable (probably protonated) form at pH 7 which reverted to the neutral form upon heating or alkali treatment. In order to obtain again the metastable hysteretic form, a whole titration cycle to pH 2.5 had to be performed.

Protonated polynucleotide structures : 15. Metastable protonated polydeoxyribonucleotides.

The CD spectra of three polydeoxyribonucleotide complexes, poly(dG-C). poly(dG-C), poly(dA-G). poly(dT-C) and poly(dA-C). poly(dT-G) have been studied as a function of pH at 25°C. Only poly(dA-G). poly(dT-C) showed large hysteresis, analogous to that observed for poly(dG). poly(dC), while the alternating pur-p-pyr containing polymers reversible titration curves exhibited. The hysteretic form R of poly(dA-G). poly(dT-C) is metastable at neutrality and reverts spontaneously and irreversibly to the neutral from N upon heating to about 60°. A whole titration cycle to pH 2.5 and back to neutrality has to be performed in order to obtain the metastable form R again.