Pathophysiology of HCV-Related cryoglobulinemic vasculitis: molecular, immunological and clinical analysis

ABSTRACT INTRODUZIONE: L’infezione da virus dell’epatite C (HCV) rappresenta la principale causa di malattia cronica del fegato, che può evolvere in cirrosi e carcinoma epatocellulare (HCC). L’infezione cronica da HCV è inoltre caratterizzata dall’insorgenza di diverse manifestazioni extraepatiche, la più comune delle quali è la crioglobulinemia mista (MC). Si tratta di una vasculite mediata da immunocomplessi che coinvolge vasi sanguigni di piccolo calibro, caratterizzata da una proliferazione B-cellulare con possibile evoluzione in linfoma non-Hodgkin a cellule B. Il caratteristico tropismo dell’HCV per il tessuto linfoide è stato ampiamente dimostrato. La persistenza dell’HCV può rappresentare uno stimolo continuo per il sistema immunitario dell’ospite. Questo potrebbe sostenere proliferazioni oligo/monoclonali B-cellulari con l’espansione di un singolo clone dominante da cui deriva, ad esempio, la sintesi di IgM monoclonali con attività di fattore reumatoide nella crioglobulinemia mista. D’altro canto, la proliferazione linfocitaria può essere promossa in maniera diretta dall’infezione e dalla replicazione dell’HCV all’interno delle cellule B. Su queste basi, l’approccio terapeutico della MC HCV-associata è attualmente basato sulla terapia antivirale, in presenza o assenza di deplezione B-cellulare con rituximab. Tra i fattori dell’ospite che influenzano la risposta virologica ai regimi terapeutici antivirali basati sull’uso di interferone-α peghilato e ribavirina, i polimorfismi del gene dell’IL28B sono stati identificati mediante studi di associazione genomewide come fattori predittivi attendibili dell’esito della terapia antivirale. Lo scopo dello studio consiste nella valutazione della possibile associazione tra i polimorfismi del singolo nucleotide (SNPs) rs12979860/ rs8099917 a livello del gene IL28B e la risposta terapeutica in pazienti con MC HCV-correlata. È stata anche considerata la possibile associazione dei polimorfismi con le manifestazioni cliniche specifiche della MC nonché il loro possibile ruolo nella valutazione della risposta completa (intesa come virologica, molecolare ed immunologica) alla terapia. METODI: Sono stati reclutati 159 pazienti infetti da HCV con MC e 172 pazienti infetti da HCV senza MC, trattati con terapia antivirale basata su interferone-α peghilato e ribavirina. È stata effettuata la genotipizzazione degli SNPs rs12979860/ rs8099917 in tutti i pazienti. In 106 (66.6%) pazienti affetti da crioglobulinemia mista è stato determinato il profilo clonale delle cellule B circolanti. RISULTATI: Il genotipo T/T IL28B rs12979860 è risultato più frequente nei pazienti con MC piuttosto che nei pazienti senza MC (17% vs 8.1%, p=0.02). Il genotipo C/C è risultato associato con un maggior tasso di risposte complete alla terapia (52.6% vs 39.2%, p=0.13). È stata inoltre riscontrata una maggior frequenza di espansioni clonali B-cellulari in circolo (84.2% vs 55.9%, p=0.005), coinvolgimento renale (21% vs 2.9%, p=0.003) e linfomi non-Hodgkin a cellule B (17.5% vs 6.8%, p=0.048). L’analisi del polimorfismo rs8099917 ha fornito risultati sostanzialmente sovrapponibili. CONCLUSIONI: Nei pazienti HCV-positivi affetti da MC, il genotipo C/C rs12979860 del gene IL28B è caratterizzato biologicamente da una maggior frequenza di restrizione clonale nella risposta B-cellulare e clinicamente da un maggior rischio di nefropatia crioglobulinemica e neoplasie B-cellulari; è, inoltre, un fattore predittivo indipendente di risposta virologica sostenuta alla terapia antivirale. Nei pazienti con vasculite crioglobulinemica si è riscontrato una maggior prevalenza della variante T/T rs12979860 del gene IL28B. ABSTRACT INTRODUCTION: Hepatitis C virus (HCV) infection represents the leading cause of chronic liver damage evolving into cirrhosis and hepatocellular carcinoma (HCC). HCV chronic infection is also characterized by the emergence of several extrahepatic manifestations, the most common of which is represented by mixed cryoglobulinemia (MC). It is an immune complex-mediated vasculitis involving small vessels, characterized by an underlying B cell proliferation with potential evolution into B-cell non- Hodgkin lymphoma. The peculiar tropism of HCV for the lymphoid tissue has been clearly demonstrated. HCV persistence could represent a continuous stimulus to host immune system. It should lead to B cells oligo/monoclonal expansions with the emergence of a single dominant clone whose expression may be represented by monoclonal IgM RF production in MC. On the other hand, lymphocyte proliferation may be promoted by HCV direct infection and replication into B cells. On these bases the therapeutic approach of HCV-associated MC is currently based on antiviral therapy with or without B-cell depletion with rituximab. Among host factors influencing virological response to pegylated interferon- ibavirin-based antiviral therapeutic regimens, IL28B gene polymorphisms have been identified by genome wide association studies, as highly reliable predictors of the outcome after antiviral therapy. Aim of the study was to assess the possible association between IL28B single nucleotide polymorphism (SNPs) rs12979860/ rs8099917 and therapeutic response in patients with HCV-related MC. We also searched for their association with peculiar clinical manifestations of MC and the potential influence on the complete response (virological, molecular, and immunological) to the therapy. METHODS: Study cohort included 159 and 172 HCV infected patients with or without MC treated with pegylated interferon- -based antiviral therapy. We performed SNP rs12979860/ rs8099917 genotyping in all patients. In 106 (66.6%) patients with MC, the profile of circulating B cell clonalities was determined. RESULTS: The T/T IL-28B rs12979860 was more common in patients with MC than in those without (17% vs 8.1%, p = 0.02). C/C genotype was associated with a higher rate of complete response (52.6% vs 39.2%, p = 0.13). A higher frequency of expanded B cell clonalities in the circulation (84.2% vs 55.9%; p = 0.005), kidney involvement (21% vs 2.9%; p = 0.003), and B cell non-Hodgkin lymphoma (17.5% vs 6.8%; p = 0.048) were also observed. No additional results derived from the analysis of IL28B rs8099917 polymorphisms. CONCLUSIONS: In HCV-positive patients with MC, the IL-28B rs12979860 C/C genotype is distinguished biologically by a higher frequency of restriction of B cell response and clinically by a higher risk of cryoglobulinemic nephropathy and B cell malignancies, while acting as an independent predictor of a sustained virological response to antiviral therapy. In addition, we found that IL-28B rs12979860 T/T variant was more prevalent in patients with CV than in those without

REPLY TO THE LETTER TO THE EDITOR "ANDROGEN DEPRIVATION THERAPY AND RISK OF RHEUMATOID ARTHRITIS IN PATIENTS WITH LOCALIZED PROSTATE CANCER" by YANG et al.

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Hepatitis C Virus Infection and Mixed Cryoglobulinemia

Hepatitis C virus (HCV) chronic infection is recognized as the major cause of mixed cryoglobulinemia (MC). Its persistence represents a continuous stimulus for host immune system with production of circulating immune complexes (ICs), one-third of them with cryoprecipitate property. Several factors contribute to the biological activities of ICs, many of which are not completely known. Among them, complement factors play a crucial role in the cold-insoluble ICs-mediated vasculitis, involving primarily small blood vessels in different tissues including skin, kidney, peripheral, and central nervous system. Liver represents the major target of HCV infection with inflammatory infiltrates, resembling secondary lymphoid follicles. Cytokine like CXCL13 contribute to B-cell homing in intraportal lymphoid aggregates, in which B-cell clonal selection may arise. B-cell clonal expansion starts as an antigen-driven event and expands towards indolent and malignant B-cell proliferation. Occurrence of intrahepatic B-cell clonalities correlates with extrahepatic clinical manifestations of HCV infection. In this context, cryoglobulinemic patients should be considered a peculiar HCV-infected population that needs a clinical multidisciplinary approach and more articulated therapeutic measures

Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer

Càncer de pròstata; Receptor d'andrògens; DocetaxelCáncer de próstata; Receptor de andrógenos; DocetaxelProstate cancer; Androgen receptor; DocetaxelPlasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.Funding/Support and role of the sponsor: V. Conteduca was funded by a European Society of Medical Oncology Translational Clinical Research Fellowship. A. Jayaram is supported by a grant from the Medical Research Council (MR/P002072/1). G. Attard is supported by a Cancer Research UK Advanced Clinician Scientist Grant (A22744). This work was funded in part by Prostate Cancer UK (PG12-49), the “Instituto de Salud Carlos III” (ISCII) PI16/01565 grant. E. Gonzalez-Billalabeitia was funded by a grant from the “Instituto de Salud Carlos III” (ISCIII) PI15/01499. N. RomeroLaorden was funded by a grant from the “Instituto de Salud Carlos III” (CM14-00200). E. Castro is supported by a Prostate Cancer Foundation Young Investigator Award (2017). E. Castro and D. Olmos are supported by grants from the Ministerio de Economía, Industria y Competitividad (JCI-2014-19129 to E.C., RYC-2015-18625 to D.O.). B. Mellado and M. Marin-Aguilera work were supported by the Instituto de Salud Carlos IIISubdirección General de Evaluación y Fomento de la Investigación (PI12/ 01226 and PI15/676) and co-funded by the European Regional Development Fund. Funding from CERCA Programme/Generalitat de Catalunya is gratefully acknowledged. During the conduct of the study, E. Castro was supported by a grant from the Ministerio de Educación, Cultura y Deportes (CAS17/00182). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all data and had the final responsibility for the decision to submit for publication

Persistent neutrophil to lymphocyte ratio >3 during treatment with enzalutamide and clinical outcome in patients with castration-resistant prostate cancer

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (&gt;3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline &gt;50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR &#62;3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p &#60; 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR &gt;3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p &#60; 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR &#62;3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients

Persistent neutrophil to lymphocyte ratio &gt;3 during treatment with enzalutamide and clinical outcome in patients with castration-resistant prostate cancer

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (&gt;3 vs ?3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline &gt;50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8-90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7-4.2) in patients with baseline NLR &gt;3 and 7.4 months (95% CI = 5.5-9.7) in those with NLR ?3, p &lt; 0.0001. The median OS was 10.4 months (95% CI = 6.5-14.9) in patients with baseline NLR &gt;3 and 16.9 months (95% CI = 11.2-20.9) in those with baseline NLR ?3, p &lt; 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07-1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10-1.51, p = 0.001. A persistent NLR &gt;3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib.

Background: In this retrospective analysis, we explored the prognostic and predictive value of the systemic immune-inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, at baseline and changes at week 6 during first-line sunitinib in patients with metastatic renal cell cancer (RCC).Results: Patients were stratified into high SII (? 730) and low SII (&lt; 730) groups. SII was associated with objective response, p &lt; 0.0001. The median PFS was 6.3 months (95% CI 5.5–8.9) in patients with SII ? 730 and 18.7 months (95% CI 14.7–22.8) in those with SII &lt; 730, p &lt; 0.0001. The median OS was 43.6 months (95% CI 35.3–52.1) in patients with SII &lt; 730, and 13.5 months (95% CI 9.8–18.5) in those with SII ? 730, p &lt; 0.0001. In multivariate analysis, performance status, IMDC score and SII were able to predict OS (HR = 3.29, HR = 1.71 and HR = 1.79, respectively).Materials and Methods: We included 335 consecutive RCC patients treated with first-line sunitinib. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion at week 6 of treatment on PFS and OS was evaluated by Cox regression analyses.Conclusions: The SII and its changes during treatment represent a powerful prognostic indicator of clinical outcome in patients with metastatic RCC

Psychosocial Issues in Long-Term Survivors of Testicular Cancer

Testicular cancer is the most frequent tumor in young males aged 15–39 years. As cure rates are currently around 90%, the prevalence of survivors is increasing. However, a disease-free condition does not necessarily correspond to a life free of physical and psychosocial health problems. The aim of this review was to explore psychosocial morbidity among testicular cancer survivors. A literature search was conducted in three electronic databases (PubMed, Medline, and Embase). The results of the search on cancer survivors were then combined with those of the search on psychosocial concerns and work performance. Eighty-four publications met the inclusion criteria. Physical, psychological, work-related problems and changing perspectives about work and life in general influenced life and career decisions among testicular cancer survivors. Individual health, sexual relationships and work problems, affect several important aspects of survival and significantly influence the QoL of long-term survivors

The Geriatric G8 Score Is Associated with Survival Outcomes in Older Patients with Advanced Prostate Cancer in the ADHERE Prospective Study of the Meet-URO Network

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p &lt; 0.001 and p = 0.004) and PSA decline ≥50% (p &lt; 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p &lt; 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care