Hepatitis C virus (HCV) is known for its oncogenic potential and has been found to be associated with hepatocellular carcinoma (HCC) and non-Hodgkin lymphoma. It has also been postulated that HCV may play a role in the development of other extrahepatic solid tumors of other organs of the body since it has been isolated from the vessel wall, kidney, and oral mucosa. In this article, we have reviewed epidemiological studies that have been done to look into the relationship of HCV with nonliver solid cancers of the pancreas, thyroid, renal, oral cavity, breast, and lung and nonpancreatic gastrointestinal cancers. Based on this review, HCV might be associated with an increased risk of renal cell and lung cancers.

Prostate cancer can transform from androgen-responsive to an androgen-independent phenotype. The mechanism responsible for the transformation remains unclear. We studied the effects of an epigenetic modulator, phenethyl isothiocyanate (PEITC), on the androgen-responsive LNCaP cells. After treatment with PEITC, floating spheres were formed with characteristics of prostate cancer stem cells (PCSC). These spheres were capable of self-renewal in media with and without androgen. They have been maintained in both types of media as long term cultures. Upon androgen deprivation, the adherent spheres differentiated to neuroendocrine cells (NEC) with decreased proliferation, expression of androgen receptor, and PSA. NEC reverse differentiated to spheres when androgen was replenished. The sphere cells expressed surface marker CD44 and had enhanced histone H3K4 acetylation, DNMT1 down-regulation and GSTP1 activation. We hypothesize that PEITC-mediated alteration in epigenomics of LNCaP cells may give rise to sphere cells, whereas reversible androgenomic alterations govern the shuttling between sphere PCSC and progeny NEC. Our findings identify unrecognized properties of prostate cancer sphere cells with multi-potential plasticity. This system will facilitate development of novel therapeutic agents and allow further exploration into epigenomics and androgenomics governing the transformation to hormone refractory prostate cancer.

INTRODUCTION: Riociguat is approved for the treatment of adults with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). It is marketed with a warning against co-administration with nitric oxide donors in any form due to a risk of hypotension, although the supporting data is limited. CASE PRESENTATION: A 33-year-old female with idiopathic PAH on subcutaneous treprostinil 50 ng/kg/min and macitentan 10 mg daily presented with worsening dyspnea and syncope. Suspecting absorption failure, treprostinil was changed to intravenous route. Right heart catheterization showed right atrial pressure of 2 mmHg, severely elevated pulmonary artery (PA) pressure of 97/38 mmHg, mean PA pressure (mPAP) of 59 mmHg, pulmonary capillary wedge pressure of 4 mmHg, Fick cardiac output of 3.83 L/min, and pulmonary vascular resistance(PVR) of 14.36 Wood units. During the procedure she responded favorably to 40 ppm inhaled nitric oxide (iNO), with a decrease in mPAP to 44 mmHg and PVR to 8.79 Wood units. In the setting of clinical right heart failure, iNO was continued at 40 ppm. PDE5 inhibitors could not be used as she had a prior allergic reaction to tadalafil. Riociguat 0.5mg was started and iNO stopped simultaneously. However, mPAP increased to 65 mmHg and iNO was restarted. Over the next 4 days, riociguat was titrated up to 2.5mg every 8 hours, iNO was gradually weaned off based on mPAP, and treprostinil increased to 60 ng/kg/min. During this period, hemodynamics improved considerably with the lowest recorded mPAP of 35 mmHg. By day 4, improvement was noted in mPAP to 43 mmHg, Fick cardiac output to 6.46 L/min, and PVR to 9 Wood units. Mean arterial pressure remained stable around her baseline of 70 mmHg without any hypotensive episodes. Her symptoms improved significantly and she was weaned off nasal oxygen. DISCUSSION: Riociguat, iNO, and PDE5 inhibitors act via potentiation of the soluble guanylate cyclase pathway. Coadministration of these drugs is contraindicated due to a risk of hypotension, although the supporting data is limited. The safe and additive effect of iNO and sildenafil on postoperative hemodynamics in cardiac surgery patients with severe pulmonary hypertension was previously described. In this case of severe PAH, short term iNO was safely and successfully used in combination with riociguat with favorable synergistic effects on PA pressure and PVR without systemic hypotension. CONCLUSIONS: To our best knowledge, this is the first reported case of safe co-administration of riociguat with iNO. Utility of riociguat added to short term iNO therapy in decompensated patients with severe PAH and in post-operative pulmonary thromboendarterectomy patients with CTEPH needs to be validated in larger trials. Reference #1: Matamis D et al. Inhaled NO and sildenafil combination in cardiac surgery patients with out-of-proportion pulmonary hypertension: acute effects on postoperative gas exchange and hemodynamics.