High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1ß and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.

Síndrome del seno carotídeo asociado a linfoma B cervical / Carotid sinus syndrome associated to cervical B-cell lymphoma

Resumen Se describe el caso de un varón de 75 años con tumoración submaxilar derecha de 5 meses de evolución sin diagnóstico etiológico, que consultó por episodios de síncope precedidos por disnea y sudoración profusa de instalación súbita. Durante su internación se detectaron, en el monitoreo electrocardiográ fico, pausas mayores a 3 segundos luego de la lateralización cervical reproduciendo los síntomas mencionados y asociadas a sensación de pérdida inminente de la conciencia, por lo que se implantó marcapasos transitorio. Se realizó biopsia de la masa tumoral cervical, consistente con linfoma B difuso de células grandes no centro germinal, y se inició quimioterapia. Luego de dicho tratamiento quimioterápico se observó reducción significativa de la masa tumoral con abolición de los síntomas asociados a las maniobras cervicales. El diagnóstico definitivo fue síndrome del seno carotídeo maligno asociado a linfoma cervical.

Abstract We present the case of a 75-year-old male with history of 5 months of right submaxillary tumor, with no clear etiology, who consulted for episodes of syncope preceded by dyspnea and sudden onset of profuse sweating. During his stay at the hospital, electrocardiographic records showed more than 3-second-long pauses after head movements, with a sensation of imminent loss of consciousness associated. A temporary pacemaker was required. Biopsy showed a diffuse non-germinal large B-cell B lymphoma, which required chemotherapy. After the first chemotherapy session, a significant reduction of the tumoral mass was observed, with abolition of the symptoms associated to cervical movements. The definitive diagnosis was malignant carotid sinus syndrome associated with cervical lymphoma.

[Carotid sinus syndrome associated to cervical B-cell lymphoma]. / Síndrome del seno carotídeo asociado a linfoma B cervical.

We present the case of a 75-year-old male with history of 5 months of right submaxillary tumor, with no clear etiology, who consulted for episodes of syncope preceded by dyspnea and sudden onset of profuse sweating. During his stay at the hospital, electrocardiographic records showed more than 3-second-long pauses after head movements, with a sensation of imminent loss of consciousness associated. A temporary pacemaker was required. Biopsy showed a diffuse non-germinal large B-cell B lymphoma, which required chemotherapy. After the first chemotherapy session, a significant reduction of the tumoral mass was observed, with abolition of the symptoms associated to cervical movements. The definitive diagnosis was malignant carotid sinus syndrome associated with cervical lymphoma.

Se describe el caso de un varón de 75 años con tumoración submaxilar derecha de 5 meses de evolución sin diagnóstico etiológico, que consultó por episodios de síncope precedidos por disnea y sudoración profusa de instalación súbita. Durante su internación se detectaron, en el monitoreo electrocardiográfico, pausas mayores a 3 segundos luego de la lateralización cervical reproduciendo los síntomas mencionados y asociadas a sensación de pérdida inminente de la conciencia, por lo que se implantó marcapasos transitorio. Se realizó biopsia de la masa tumoral cervical, consistente con linfoma B difuso de células grandes no centrogerminal, y se inició quimioterapia. Luego de dicho tratamiento quimioterápico se observó reducción significativa de la masa tumoral con abolición de los síntomas asociados a las maniobras cervicales. El diagnóstico definitivo fue síndrome del seno carotídeo maligno asociado a linfoma cervical.