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To assess the efficacy of topical interferon alfa-2b as an adjunct therapy in the management of primary ocular surface squamous neoplasia (OSSN).: Clinically visible OSSN on slit lamp examination in 21 patients (21 tumors) was managed with topical interferon alfa-2b, 1 million IU/mL, 4times daily for a period of one month, before subjecting the patients to definitive surgery. The patients were periodically observed, over a period of 6 months. Tumor control and complications were evaluated according to American Joint Committee on Cancer classification. A significant reduction in size, was noted in smaller tumors. Final diagnosis and staging was done after histopathological examination of the surgically excised tumour, which had been excised with a 4mm margin. Bigger extensive lesion did not show appreciable response in terms of appearance or reduction of size. Tumor size was found to be reduced significantly in 19 out of 21 tumors (%) following topical interferon alfa-2b treatment for a period of 1 month, from the presentation. Of the 19 tumors, tumor surface area was reduced 44% (median). Two patients (8.3%) did not respond to the treatment.Based on American Joint Committee on Cancer classification, significant reduction was achieved in 2 of 3 Tis (67%), 17 of 20 T3 (85%), 19 of 23 N0 (83%), and 19 of 23 M0 (83%) category tumors. According to American Joint Committee on Cancer classification, significant reduction with topical interferon alfa-2b can be achieved in 67% of Tis, 85% of T3, and 83% of all OSSN.

Introduction. Recommendations cover the current state of diagnosis and treatment of mastocytosis.Aim — а consolidation of the Russian experts’ opinion on treatment for adult mastocytosis.Main findings. The recommendations have been developed taking into account foreign literature, national experience and world clinical evidence on therapy for systemic and cutaneous mastocytoses, mast cell leukaemia and other mastocytosis forms. The significance of bone marrow and peripheral blood molecular genetic testing for the presence of KITD816V gene variants is demonstrated. The treatment regimens described are based on midostaurin, imatinib, cladribine, hydroxycarbamide, interferon alfa and haematopoietic stem cell transplantation. Prognosis in different forms of mastocytosis is provided.

BACKGROUND Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma. METHODS We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 106 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, vincristine 1·4 mg/m2 maximum 2 mg intravenously on day 1, and prednisone 100 mg/m2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR aHR). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation. FINDINGS Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 53{\%} in the autologous HSCT group and 81 47{\%} in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39{\%}) of 174 patients. The median progression-free survival was 3·3 years (95{\%} CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p{\textless}0·0001; aHR 0·50 95{\%} CI 0·36-0·69). The median overall survival was 7·5 years (95{\%} CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 95{\%} CI 0·46-0·95). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab. INTERPRETATION Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma. FUNDING Deutsche Krebshilfe, the European Community, and the Bundesministerium f{\"u}r Bildung und Forschung, Kompetenznetz Maligne Lymphome.

Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.

Introduction In the 2017 World Health Organization (WHO) classification, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), is included as one of 7 distinct diagnostic entities under the major category of myeloproliferative neoplasms (MPNs).1 WHO defining criteria for CEL, NOS include: (a) peripheral blood eosinophilia >1.5×109/L; (b) evidence of clonal cytogenetic or molecular genetic abnormality, and/or (c) presence of excess myeloblasts (

Conjunctival neoplasia is one of the most frequent tumors in the eye. Actinic keratosis (AK) or solar keratosis is a precancerous lesion that is included with other epithelial tumors. This alteration does not break the basal membrane. There is enough evidence of successful outcomes to consider interferon alfa-2b (IFN alfa-2b) as the first choice of treatment for this type of tumors. In addition, side effects are mild and uncommon. We report a case in an 83-year-old woman who was referred to evaluate a leukoplakia in the tarsal conjunctiva of the lower left eyelid that measured 1 cm in diameter. Pathological study revealed AK. After the INF alfa-2b treatment, we observed conjunctival hyperemia, noninfiltrated upper nasal de-epithelization, and inferior nasal bulla. AK with presentation in conjunctiva is rarely described and in tarsal conjunctiva is exceptional. It is the first case published with only tarsal conjunctiva affectation.

Primary myelofibrosis is a myeloproliferative neoplasm that occurs de novo, characterized by clonal proliferation of stem cells, abnormal expression of cytokines, bone marrow fibrosis, hepatosplenomegaly as a result of extramedullary hematopoiesis, symptoms of tumor intoxication, cachexemia, peripheral blood leukoerythroblastosis, leukemic progression and low survival. Primary myelofibrosis is a chronic incurable disease. The aims of therapy: preventing progression, increasing overall survival, improving quality of life. The choice of therapeutic tactics is limited. Allogenic hematopoietic stem cell transplantation is the only method that gives a chance for a cure. The role of mutations in a number of genes in the early identification of candidates for allogeneic hematopoietic stem cell transplantation is being actively studied. The article describes the clinical case of the detection ofASXL1gene mutations in a patient with prefibrous primary myelofibrosis. The diagnosis was established on the basis of WHO criteria 2016. The examination revealed a mutation ofASXL1. Interferon alfa therapy is carried out, against the background of which clinico-hematological remission has been achieved. Despite the identified mutation, the patient is not a candidate for allogeneic hematopoietic stem cell transplantation. Given the unfavorable prognostic value of theASXL1mutation, the patient is subject to active dynamic observation and aggressive therapeutic tactics when signs of disease progression appear.Первичный миелофиброз (ПМФ) представляет собой миелопролиферативное новообразование, которое возникает de novo, характеризуется клональной пролиферацией стволовых клеток, аномальной экспрессией цитокинов, фиброзом костного мозга, гепатоспленомегалией как следствие экстрамедуллярного гемопоэза, симптомами опухолевой интоксикации, кахексией, лейкоэритробластозом в периферической крови, лейкемической прогрессией и невысокой выживаемостью. ПМФ является хроническим неизлечимым заболеванием. Цели терапии: предупреждение прогрессии, увеличение общей выживаемости, улучшение качества жизни. Выбор лечебной тактики ограничен. Трансплантация аллогенных гемопоэтических стволовых клеток (алло-ТГСК) единственный метод, дающий шанс на излечение. В настоящее время активно изучается роль мутаций ряда генов в раннем выявлении кандидатов для алло-ТГСК. В статье представлено описание клинического случая выявления мутации гена ASXL1 у больного префиброзным ПМФ. Диагноз установлен на основании критериев Всемирной организации здравоохранения 2016 г. При обследовании выявлена мутация ASXL1. Проводится терапия интерфероном альфа, в результате которой достигнута клинико-гематологическая ремиссия. Несмотря на выявленную мутацию, пациент не является кандидатом для алло-ТГСК. Учитывая неблагоприятное прогностическое значение мутации ASXL1, пациент подлежит активному динамическому наблюдению и агрессивной терапевтической тактике при появлении признаков прогрессирования заболевания.

Erdheim-Chester disease (ECD) is a rare entity throughout the world. This is the first case reported in Nepal. ECD is a rare aggressive, non-Langerhan's histocytosis of unknown origin with classical histological features. The patient usually presents with bone pain or skeletal symptoms along with other constitutional syndrome. Although, no definitive therapy has been approved, interferon-alfa (or Pegylated Interferon-alfa) is considered as initial therapy. In this case report, we found a patient with right-sided localized chest pain for which he was evaluated with bone scan and excisional bone biopsy and its findings support the diagnosis of ECD.

Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626

Purpose To evaluate the long-term follow-up of recurrent conjunctival and corneal intraepithelial neoplasia (CCIN) treated with combination topical interferon alfa-2b and retinoic acid (I/RA). Methods Our study represents a retrospective observational interventional series of 82 eyes from 82 patients from a single institution, reviewed for CCIN. All were administered topical interferon alfa-2b 1 million IU/mL QID and retinoic acid 0.01% every other day. Patients had been diagnosed by biopsy. A Kaplan-Meier survival analysis, Wilcoxon signed-rank test and a multivariate logistic regression were statistical tests used to correlate recurrence with patient and tumor variables. Results 79 eyes assessed for CCIN diagnoses and treated with I/RA achieved tumor resolution. The median tumor-free follow-up was ~109.1 months with a median time to resolution being ~2.8 months. Our median treatment duration was ~11.3 months. The greatest difference in the mean total residual tumor size was identified between Months 0–1 [-7.63 mm2]. The difference in mean total residual tumor size remained significant till 36-months. A statistically significant correlation with recurrence was identified for biopsy type [OR 0.138]. 6 patients experienced papillary conjunctivitis which resolved with dosage reduction. Conclusions Combination I/RA was effective in treating CCIN lesions with few transient side effects. The combination of retinoids and interferons may represent a viable topical therapeutic agent with an extended tumor-free follow-up and a large proportion of our study's patients achieving >10 year's tumor-free follow-up. Our treatment duration is long, but by cost-comparing surgical against medical interventions, topical I/RA may serve as a safe and effective alternative.

Background Tumor necrosis factor-α inhibitor (TNFi)–induced psoriasis is a paradoxic reaction characterized by the development of a psoriasiform rash that mimics idiopathic psoriasis subtypes both clinically and histologically. Few studies have investigated the histologic features of TNFi-induced psoriasis skin lesions, and most of these are limited by inclusion of few specimens. Objective We aimed to characterize histologic features of TNFi-induced psoriasis and identify histologic differences between TNFi-induced psoriasis and idiopathic psoriasis. Methods We characterized 60 biopsy specimens obtained from 47 unique patients at a single tertiary care referral center between 2004 and 2016 who developed TNFi-induced psoriasis, and we compared histologic features to those of 85 biopsy specimens from a control group of 85 patients with idiopathic psoriasis. Results The most common histologic reaction pattern in TNFi-induced psoriasis biopsy specimens was psoriasiform (80.0%). Five histologic parameters were significantly different in TNFi-induced psoriasis biopsy specimens compared with idiopathic psoriasis biopsy specimens: at least 3 dermal eosinophils per histologic section, neutrophils in the stratum corneum, neutrophils in the epidermis, papillary plate thinning, and absence of parakeratosis. Limitations Inability to exclude lesion selection bias as a potential reason for some significant histologic differences. Conclusions This study supports the idea that histologic differences exist between TNFi-induced psoriasis and idiopathic psoriasis may help distinguish between these conditions, especially for dermal eosinophil counts of 3 or greater.

Purpose To study the efficacy of interferon alfa-2b (IFN-a2b) on pigmented ocular surface squamous neoplasia (p-OSSN) and assess the resolution of the pigment to the treatment. Methods A retrospective case series of 8 tumors in 7 patients. Results The mean age at diagnosis of p-OSSN was 65 years (median, 61 years; range, 51-84 years), and all patients were men. The mean duration of symptoms was 2 months (median, 1 month; range, 1-4 months). One patient had 2 distinct lesions in the same eye. Tumor epicenter was located at the limbus (n = 5) or bulbar conjunctiva (n = 2). Complexion-associated melanosis was noted in all eyes. The mean basal dimension of the tumor was 8 mm (median, 7 mm; range, 5-12 mm). The mean % of tumor pigmentation was 47% (median, 30%; range, 10%-100%). The treatment details included topical IFN-a2b (n = 1) or a combination of topical and subconjunctival injection of IFN-a2b (n = 7). All patients with p-OSSN showed excellent response to IFN-a2b with complete tumor regression and resolution of tumor-associated pigment with a mean number of 2 subconjunctival IFN-a2b injections (median, 2; range, 0-3) and topical IFN-a2b for an average of 2 months (median, 2 months; range, 1-3 months). There was no change in the complexion-associated melanosis with IFN-a2b. Conclusions IFN-a2b is very effective in the management of p-OSSN. There is a complete resolution of the pigment along with the tumor.

This study aims to evaluate the correlation between viral clearance and blood biochemical index of 94 discharged patients with COVID-19 infection in Shenzhen Third People’s Hospital, enrolled from Jan 5 to Feb 13, 2020. The clinical and laboratory findings were extracted from the electronic medical records of the patients. The data were analysed and reviewed by a trained team of physicians. Information on clinical signs and symptoms, medical treatment, virus clearance, and laboratory parameters including interleukin 6 (IL-6) and C-reactive protein were collected. COVID-19 mRNA clearance ratio was identified significantly correlated with the decline of serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Furthermore, COVID-19 mRNA clearance time was positively correlated with the length of hospital stay in patients treated with either IFN-α + lopinavir/ritonavir or IFN-α + lopinavir/ritonavir + ribavirin. Therapeutic regimens of IFN-α + lopinavir/ritonavir and IFN-α + lopinavir/ritonavir + ribavirin might be beneficial for treatment of COVID-19. Serum LDH or CK decline may predict a favorable response to treatment of COVID-19 infection.

PURPOSE Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti–programmed death 1 use in the HDI arm versus ipi3 and ipi10 ( P ≤ .001). CONCLUSION Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

Aim To identify the most common therapeutic options for the treatment of early-stage mycosis fungoides in Spain, quantify their associated healthcare resource use and costs. Methods After reviewing the literature, a panel of 6 Spanish clinical dermatologists validated the treatments and healthcare resource use through a structured questionnaire. Individual responses were collected, analyzed and presented into a face-to-face meeting in order to reach a consensus. Cost categories considered were: drug acquisition and administration, photo/radiotherapy session and maintenance, clinical follow-up visits and laboratory tests. Costs were expressed in euros from 2018. The Spanish National Health System perspective was considered, taking into account direct health costs and time horizons of 1, 3 and 6 months. Results Costs for the skin-directed treatments (SDT) assessed at 1, 3 and 6 months, were: Topical carmustine [€6,593.36, €19,780.09 and €27,592.78]; Phototherapy with psoralens and ultraviolet A light (PUVA) [€1,098.68, €2,999.99 and €3,187.60]; Narrow-band ultraviolet B phototherapy [€1,657.47, €4,842.10 and €4,842.10]; Total skin electron beam therapy (TSEBT) [€6,796.45, €7,913.34 and €7,913.34]. Cost for topical corticosteroids, being considered an adjuvant option, were €17.16, €51.49 and €102.97. Costs for the assessed systemic treatments alone or in combination with SDT at 1, 3 and 6 months, were: Systemic retinoids [€2,026.03, €5,206.63 and €7,426.42]; Systemic retinoids + PUVA phototherapy [€3,066.50, €8,271.26 and €10,046.58]; Interferon alfa + PUVA phototherapy [€1,541.09, €5,167.57 and €6,404.55]. Conclusion According to the Spanish clinical practice, phototherapies in monotherapy were the treatments with the lowest associated costs regardless of the time horizon considered. TSEBT turned out as the treatment with the highest associated costs when considering 1 month. However, while considering 3 and 6 months the treatment with the highest associated costs was topical carmustine. The results of this analysis may provide critical information to measure the disease burden, to detect unmet medical needs and to advocate towards better treatments for this rare disease.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59–0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61–1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma. Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587

BackgroundHost factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections.MethodsWe accessed samples from Zika pregnancies, conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS newborn outcome and we characterized placenta gene expression profile at term.FindingsNewborns carrying CG/CC genotypes of rs2257167 inIFNAR1presented higher risk of developing CZS (OR=3.73; IC=1.36-10.21;Pcorrected=0.02646). No association betweenIFNLSNPs and CZS was observed. Placenta from CZS cases displayed lower levels ofIFNL2andISG15along with higherIFIT5.The rs2257167 CG/CC placentas also demonstrated high levels ofIFIT5and inflammation-related genes.InterpretationWe found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by theIFNAR1rs2257167 genotype. These findings shed light on the host-pathogen interaction focusing on the genetically regulated type I / type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections.FundingThis work was supported by the Instituto Oswaldo Cruz (Rio de Janeiro, Brazil) and by the Instituto de Tecnologia em Imunobiológicos (Rio de Janeiro, Brazil).Research in contextEvidence before this studyLevels of type I and type III interferons are genetically controlled and decisively regulate outcome of spontaneous viral infections or response to antiviral treatment. Hepatitis C virus, Yellow Fever and Zika virus belong to the Flaviviridae family and elicit similar host immune responses. Congenital Zika Syndrome presents well-known risk factors, mainly the first trimester of pregnancy as well as social and nutritional factors, however, these do not entirely explain abnormal outcomes.Added value of this studyWe conducted a case-control study to evaluate SNPs in type I and III interferon genes using samples from newborns and mothers who had zika infection during pregnancy. We have shown that newborn interferon type I background contributes to the development of abnormal CSZ. This specific genetic makeup regulates placental immunological responses and prevents an exacerbated type I, and lack of type III, interferon response in syndromic cases.Implications of all the available evidenceOur study suggests an important factor regulating the host-pathogen interaction during Zika virus (ZIKV) infections in humans. During pregnancy, genetic variations play a role in balancing tissue-specific type I and III interferons during ZIKV congenital infection influencing fetal neurological damage. Custom pharmacological interventions could be used to modulate immunity and inflammation towards protective responses.Graphical abstract

IntroductionFunctional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches.Materials and MethodsWe conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1.ResultsTwenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4–6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients’ viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-ƴ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration.DiscussionResults from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants.Clinical Trial Registration(www.ClinicalTrials.gov), identifier NCT02767193

Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.

BACKGROUND & AIMS: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive versus active chronic infection. Interferon alfa may convert HBeAg-positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. METHODS: HBs proteins were measured before and during peginterferon alfa-2a therapy in serum from 127 Asian patients with HBeAg-positive CHB. Sustained response was defined as hepatitis B e antigen (HBeAg) seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders versus nonresponders at all time points (P0.70). CONCLUSIONS: HBs proteins levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa-2a therapy in HBeAg-positive patients.

Exactly 30 years ago, hepatitis C virus was identified. Over the years, tremendous success has been achieved in the treatment of hepatitis C, which is currently considered to be an almost completely curable disease. The review presents the main stages in the development of hepatitis C antiviral therapy, the efficacy of various treatment regimens. The greatest progress in treatment was noted over the past 5 years when drugs with direct antiviral action appeared and began to be widely used, including in Russia, which ensure the elimination of the virus in 90-95% of cases.Ровно 30 лет назад был идентифицирован вирус гепатита С. За эти годы достигнут огромный успех в лечении гепатита С, который в настоящее время рассматривается как практически полностью излечимое заболевание. В обзоре представлены основные этапы становления противовирусной терапии гепатита С, эффективность различных схем лечения. Наибольший прогресс в лечении отмечен в течение последних 5 лет, когда появились и стали широко применяться, в том числе и в России, препараты с прямым противовирусным действием, которые обеспечивают элиминацию вируса в 90-95% случаев.

BACKGROUND: Erdheim Chester disease (ECD) is a rare form of non-Langerhans histiocytosis that still presents a diagnostic and clinical dilemma. CASE PRESENTATION: We present a rare case of ECD, young 31 male with atypical localisation and soft tissue presentation and no bone involvement. He started clinical investigations due to subcutaneous tumour mass in the lumbar spine that caused severe back pain. Skin biopsy revealed ECD with Immunohistochemistry CD68+, CD10+, CD11c+, vimentin+, S100A4+. Activating BRAFV600E mutation was positive from the tumour tissue. The patient was referred to the haematology department. PET CT was performed for initial disease staging. Treatment was started with corticosteroids (methylprednisolone 0.5 mg/kg per day), and after 7 days, a significant clinical improvement was noticed in terms of pain disappearance with no need for pain killers. After two weeks, treatment with interferon Alfa (IFN-α) was started in a dose of 3 million units 3 times per week. After 4 months of interim treatment PET, CT revealed a significant reduction of the tumour mass. Therapy with IFN-α was continued, and the patient is still clinically in good condition. CONCLUSION: It can be concluded that shortening the time of diagnosis of ECD is essential in treatment outcome of this disease. Still, large studies have to confirm the best treatment of this rare condition.

In 2016 the WHO Assembly defined a global strategy to combat viral hepatitis viruses, which seeks to eliminate these infections by 2030. The most important goals of this programme, adopted by 194 countries, are to reduce the incidence of viral hepatitis by 90 % and mortality rates – by 65 % as compared to the levels observed in 2016. Therefore, there is an obvious need for development of medicines for the treatment of chronic hepatitis C. The aim of the present paper was to determine basic approaches to planning pre-authorisation clinical trials for the main groups of medicines for the treatment of chronic hepatitis C. The paper summarises the current trends in the treatment of chronic hepatitis C; it lists medicines with direct antiviral effect that are currently registered in the Russian Federation, as well as interferon-free and interferon-containing regimens for the treatment of this disease. The authors examined the current requirements in force in the Russian Federation, namely: the Federal Law No. 61-FZ «On circulation of medicines» dated April 12, 2010, the Guideline on Evaluation of Medicinal Products, the Clinical Recommendations for Diagnosis and Treatment of Adult Patients with Hepatitis C, as well as recommendations of the European Medicines Agency and the Food and Drug Administration in order to analyse the planning of programmes of pre-authorisation clinical trials of interferon alfa products and direct antivirals.

Introduction. Despite the fact that the combined use of bevacizumab and interferon α -2A has been studied extensively and proved to be safe, there will always remain a group of patients for whom continuing the long-term drug treatment after a radical surgery would be unfeasible through personal reasons. This paper presents a comparison of the use of bevacizumab in combination with IFN α -2A and active monitoring in patients with metastatic kidney cancer. Materials and methods . This is a retrospective treatment outcome analysis performed on 24 patients following radical surgery. The clear cell RCC was morphologically verified following the nephrectomy in all the cases. The patients’ ages ranged from 62 to 84, averaging at 73 ± 2.2. Results. The outcomes for patients receiving treatment and those being actively monitored were then assessed for the total of 24 people counting both groups. The average length of time without progression amounted to 12.9 months and 9.8 months in the groups A and B, respectively. The median overall survival rate amounted to 22.3 and 18.7 months in the groups A and B, respectively. Discussion. The results demonstrate rather good indicators for the group of patients with metastatic kidney cancer receiving no drug therapy in comparison with the group receiving treatment in accordance with the classic immunotherapy protocol. No significant or fundamental differences have been observed when the groups studied were compared. Conclusion. A competent case-specific approach to treatment strategies for various metastatic kidney cancer patient cohorts is important both for planning satisfactory survival rate indicators and for maintaining the quality of life suited specifically for each patient.

ObjectiveBacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.MethodsNormal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.ResultsCD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection).ConclusionEntheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.

Objective: To evaluate the efficacy and safety of pegylated interferon alfa-2b (PEG IFN-α2b) along with the standard of care (SOC) in subjects with moderate COVID-19. Methods: In this phase 2, randomized, open-label study, adult subjects aged ≥18 years with RT-PCR confirmed COVID-19 with moderate symptoms were randomized in a 1:1 to receive PEG IFN-α2b plus SOC, or SOC alone. The primary endpoint was improvement in clinical status on day 15, measured by the WHO 7-point ordinal scale. Results: Forty subjects were randomized to PEG IFN-α2b plus SOC (n = 20) and SOC (n = 20). Overall, 19 (95.00%) subjects in PEG IFN-α2b plus SOC had achieved clinical improvement on day 15 compared to 13 (68.42%) subjects in SOC (p < 0.05). Overall, 80% and 95% of subjects in the PEG IFN-α2b plus SOC group had a negative RT-PCR result on day 7 and day 14, respectively, compared to 63% and 68% in the SOC group. Adverse events (AEs) were reported for eleven subjects in the PEG IFN-α2b plus SOC group and eight subjects in the SOC group. All reported AEs were mild. Conclusion: The significant improvement in clinical status on day 15 is likely due to faster viral reduction compared to SOC with the PEG IFN-α2b treated moderate COVID-19 subjects showing a difference as early as day seven and becoming significant by day 14.

This chapter summarizes the findings of one of the earliest trials of targeted therapy with a protein kinase inhibitor in patients with previously untreated, metastatic renal cell carcinoma who received either systemic sunitinib or interferon alfa. The study found better progression-free survival and overall survival in patients who received sunitinib. Diarrhea was the most common adverse event in the sunitinib group and was much more frequent compared to the interferon alfa group

Introduction: the best therapeutic option for the management of craniopharyngioma in younger children remains controversial, ranging from complete surgical resection, partial surgical resection associated with radiotherapy and application of chemotherapeutic agents such as bleomycin and interferon-alfa. Objective: to verify the response to treatment with interferon-alfa via Ommaya reservoir in a group of children under 5 years of age with diagnosis of cystic craniopharyngioma. Methods: description of a case series through consecutive review of medical records of children under 5 years of age diagnosed with cystic adamantinomatous craniopharyngioma who had an Ommaya reservoir catheter surgically implanted for intratumoral application of interferon-?. Results: seven children aged 18 to 60 months (median 46 months) with the abovementioned diagnosis and treated with interferon-alfa between 2010 and 2019, according to a pre-established protocol, were identified. A reduction in tumor volume, ranging from 88 to 100%, one year after the end of treatment was observed in the study sample. There were no complications that justified the interruption or modification of the established therapy. Conclusion: in all the cases evaluated of children less than 5 years of age with predominantly cystic adamantinomatous craniopharyngioma we observed a reduction of tumor volume on magnetic resonance imaging one year after the end of treatment with interferon-alfa.

There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir–ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19. In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion. A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81, p = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days (p = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days (p = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups. rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied.Key messagesThere are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir–ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents. There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir–ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFN alpha) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFN alpha and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

Background: Deficient interferon responses have been proposed as one of the relevant mechanisms prompting severe manifestations of COVID-19.Objective: To evaluate the interferon (IFN)-α levels in a cohort of COVID-19 patients in relation to severity, evolution of the clinical manifestations and immune/inflammatory profile.Methods: This is prospective study recruiting consecutive hospitalized patients with respiratory failure associated with SARS-COV-2 infection and matched controls. After enrollment, patients were assessed every 7 ± 2 days for additional 2 consecutive visits, for a total of 21 days. The severity of the clinical condition was ranked based on the level of respiratory support required. At each time-point blood samples were obtained to assess immune cells and mediators by multiplex immunoassay.Results: Fifty-four COVD-19 and 11 control patients matched for severity were enrolled. At recruitment, lower levels of blood IFN-α were found in COVID-19 patients compared to controls (3.8-fold difference, p < 0.01). Improvements in COVID-19 severity were paralleled by a significant increase of blood IFN-α levels. A significant increase in blood IFN-α was found over the study period in survivors (70% of the study population). A similar trend was found for blood IFN-β with IFN-β levels below the threshold of detectability in a substantial proportion of subjects. Significantly higher values of blood lymphocytes and lower levels of IL-10 were found at each time point in patients who survived compared to patients who died. In patients who clinically improved and survived during the study, we found an inverse association between IL-10 and IFN-α levels.Conclusion: The study identifies a blood immune profile defined by deficient IFN-α levels associated with increased IL-10 expression in patients progressing to severe/life threatening COVID-19 conditions, suggesting the involvement of immunological pathways that could be target of pharmacological intervention.Clinical Trial Registration:ClinicalTrials.gov identifier NCT04343053.

Virgen del Rocío Hospital COVID-19 Working Team José Miguel Cisneros, Sonsoles Salto-Alejandre, Judith Berastegui-Cabrera, Pedro Camacho-Martínez, Carmen Infante-Domínguez, Marta Carretero-Ledesma, Juan Carlos Crespo-Rivas, Eduardo Márquez, José Manuel Lomas, Claudio Bueno, Rosario Amaya, José Antonio Lepe, Jerónimo Pachón, Elisa Cordero, Javier Sánchez-Céspedes, Manuela Aguilar-Guisado, Almudena Aguilera, Clara Aguilera, Teresa Aldabo-Pallas, Verónica Alfaro-Lara, Cristina Amodeo, Javier Ampuero, María Dolores Avilés, Maribel Asensio, Bosco Barón-Franco, Lydia Barrera-Pulido, Rafael Bellido-Alba, Máximo Bernabeu-Wittel, Candela Caballero-Eraso, Macarena Cabrera, Enrique Calderón, Jesús Carbajal-Guerrero, Manuela Cid-Cumplido, Yael Corcia-Palomo, Juan Delgado, Antonio Domínguez-Petit, Alejandro Deniz, Reginal Dusseck-Brutus, Ana Escoresca-Ortega, Fátima Espinosa, Nuria Espinosa, Michelle Espinoza, Carmen Ferrándiz-Millón, Marta Ferrer, Teresa Ferrer, Ignacio Gallego-Texeira, Rosa Gámez-Mancera, Emilio García, Horacio García-Delgado, Manuel García-Gutiérrez, María Luisa Gascón-Castillo, Aurora González-Estrada, Demetrio González, Carmen Gómez-González, Rocío González-León, Carmen Grande-Cabrerizo, Sonia Gutiérrez, Carlos Hernández-Quiles, Inmaculada Concepción Herrera-Melero, Marta Herrero-Romero, Luis Jara, Carlos Jiménez-Juan, Silvia Jiménez-Jorge, Mercedes Jiménez-Sánchez, Julia Lanseros-Tenllado, Carmina López, Isabel López, Álvaro López-Barrios, Luis F. López-Cortés, Rafael Luque-Márquez, Daniel Macías-García, Guillermo Martín-Gutiérrez, Luis Martín-Villén, José Molina, Aurora Morillo, María Dolores Navarro-Amuedo, Dolores Nieto-Martín, Francisco Ortega, María Paniagua-García, Amelia Peña-Rodríguez, Esther Pérez, Manuel Poyato, Julia Praena-Segovia, Rafaela Ríos, Cristina Roca-Oporto, Jesús F. Rodríguez, María Jesús Rodríguez-Hernández, Santiago Rodríguez-Suárez, Ángel Rodríguez-Villodres, Nieves Romero-Rodríguez, Ricardo Ruiz, Zida Ruiz de Azua, Celia Salamanca, Sonia Sánchez, Víctor Manuel Sánchez-Montagut, César Sotomayor, Alejandro Suárez Benjumea & Javier Toral, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19., This work was supported by Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades Junta de Andalucia (research Project CV20-85418), Consejeria de salud Junta de Andalucia (Research Contract RH-0037-2020 to JV) the Instituto de Salud Carlos III (CP19/00159 to AGV, FI17/00186 to MRJL, FI19/00083 to MCGC, CM20/00243 to APG, and COV20/00698 to support COHVID-GS) and the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020 and RD16/0025/0026), which is included in the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, 2008 to 2011 and 2013 to 2016, Instituto de Salud Carlos III, Fondos FEDER. ERM was supported by the Spanish Research Council (CSIC).

BACKGROUND: Only a few recent phase III trials with targeted therapies or immune checkpoint inhibitors (ICIs) in metastatic clear-cell renal cell carcinoma (m-ccRCC) demonstrated an overall survival (OS) benefit compared to standard of care. We aimed to study the evolution of OS since the start of systemic therapy from 2000 to 2020. PATIENTS AND METHODS: Retrospective study on all consecutively treated m-ccRCC patients in three Belgian hospitals starting with systemic therapy. The study outcome was OS since the start of systemic therapy. We used a univariable Cox model for OS with year of the start of therapy as a predictor, and a multivariable analysis including known prognostic factors. Linear and non-linear trends of time were tested. RESULTS: Five hundred patients were included. In a linear model, the HR for OS depending on the year of the start of therapy was 0.95 (95%CI 0.93-0.97; p

Renal cell carcinoma (RCC) is a malignancy that has been found to be responsive to various immune therapies and immunomodulation. Historic agents such as interleukin-2 and interferon alfa demonstrated some benefit in select patients with advanced disease; however, their use has become limited due to the introduction of targeted novel immunomodulators, such as the checkpoint inhibitors. This chapter reviews the historical development and indications of immune therapies for advanced RCC. Early agents such as interleukin and interferon will be discussed, as well as the newer contemporary checkpoint inhibitors, which are becoming first-line therapies for this patient population.

Interferon alfa (IFN#945;) has been used in the treatment of myeloproliferative disorders for more than 30 years. IFN#945; has been shown to induce clinical, hematological, molecular, and histopathological remission, but its toxicity has remained a limitation of its more widespread use. The development of pegylated forms with a better tolerance has brought new options for patients. Phase III clinical trials, ropeginterferon#945; versus hydroxyurea: PROUD-PV and CONTINUATION-PV, have shown long-term superiority in the efficacy and safety when comparing ropeginterferon alfa-2 b with hydroxyurea. Therapeutic use of interferons is a necessary part of the treatment regimen in younger at-risk patients in the first line, but until now, no SPC of a non-pegylated or pegylated interferon included treatment of patients with polycythemia vera. Ropeginterferon alfa-2 b (Besremi®) is the first and only one to have obtained registration and is available in the European Union as well as the Czech Republic for the treatment of patients with polycythemia vera without symptomatic splenomegaly.

A prospective observational study was conducted for assessing the therapeutic efficacy of interferon (IFN)-α2b in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first month after the coronavirus disease 2019 (COVID-19) outbreak began in Cuba. From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba. Seven hundred sixty-one (93.4%) were treated with a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-α2b (Heberon

Interferon alfa was first used in the treatment of myeloproliferative neoplasms (MPNs) over 30 years ago. However, its initial use was hampered by its side effect profile and lack of official regulatory approval for MPN treatment. Recently, there has been renewed interest in the use of interferon in MPNs, given its potential disease-modifying effects, with associated molecular and histopathological responses. The development of pegylated formulations and, more recently, ropeginterferon alfa-2b has resulted in improved tolerability and further expansion of interferon’s use. We review the evolving clinical use of interferon in essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). We discuss interferon’s place in MPN treatment in the context of the most recent clinical trial results evaluating interferon and its pegylated formulations, and its role in special populations such as young and pregnant MPN patients. Interferon has re-emerged as an important option in MPN patients, with future studies seeking to re-establish its place in the existing treatment algorithm for MPN, and potentially expanding its use for novel indications and combination therapies.

A 54-year-old patient presented with a large, fleshy conjunctival lesion in the right eye that had been previously surgically removed in another centre. Diagnosis of Conjunctival intraepithelial neoplasia (CIN) was confirmed by conjunctival impression cytology. The tumor was treated with topical IFN-α-2β (1,000,000 IU/ (ml) adjuvant to surgery for chemoreduction purposes. One month after treatment, the lesion showed almost complete involution, therefore the treatment was continued up to 6 months, and the lesion showed full regression. The patient is currently under periodical follow-up by conjunctival impression cytology. We consider that topical IFN-α-2β can be used in CIN for chemoreduction and/ or curative purposes. We believe that conjunctival impression cytology is a useful and non-invasive method for diagnosis and follow-up in this condition.

Our aim was to study the effect of cycloferon on in vitro susceptibility of peripheral blood leukocytes to interferon-α2 in children with infectious mononucleosis in acute phase caused by Epstein-Barr virus (EBV). Materials and methods were as follows: the study included 23 children 4 to 6 years of age admitted in acute period of infectious mononucleosis. The control group consisted of 15 healthy children of the same age group. In vitro susceptibility of peripheral blood leukocytes to interferon-α2 was determined by the method of L.M. Kurtasova (2007).Four types of in vitro response of peripheral blood leukocytes to interferon-α2 upon induction by cycloferon have been revealed in both healthy children and patients with EBV-positive infectious mononucleosis. Differences in occurrence rates of these 4 types of reactions have been found among patients with EBVinfection, in comparison with the group of healthy children. There was no regular dose-dependent changes in susceptibility of peripheral blood leukocytes to interferon-α2 in vitro after cycloferon induction in the group of children with EBV-infection. depending on the dose, which have been revealed in healthy children.

Background Mucosal melanoma of the head and neck is a rare malignant tumor associated with a poor prognosis. Surgery, chemotherapy, radiotherapy, and biotherapy are common strategies for treating mucosal melanoma of the head and neck. Episcleritis is an idiopathic, immune-mediated disease, and is classified into two types: simple episcleritis and nodular episcleritis. Case presentation In this case report we describe ocular changes involving simple episcleritis in a 65-year-old Chinese man with mucosal melanoma of the head and neck after treatment with interferon alfa-2b and radiotherapy. On the third day of interferon alfa-2b treatment, he began to develop simple episcleritis in his left eye. Moreover, the percentage of CD3+ T cells in lymphocytes from blood was increased after interferon alfa-2b treatment. After approximately 6 days, the symptoms of eye pain, hyperemia, and edema disappeared gradually. Then, after radiotherapy was performed three times, he again developed episcleritis in his left eye. The same symptoms of hyperemia and edema occurred again; CD3+ T cell frequency was also at a higher level. After approximately a week, all the symptoms disappeared completely. Simple treatment involving topical ofloxacin and phenylephrine was administered during the two periods of episcleritis. Conclusion Episcleritis in this patient might have been due to the treatment with interferon alfa-2b and radiotherapy, leading to an increase in the level of CD3+ T cells and activation of immune system cells, which provides the guide for clinical clinicians.

Background. Even 100 years after the first attempts to introduce the chemotherapeutic approaches (in 1918) and despite the completely formed notions of myeloproliferative diseases as a group of malignant neoplasms, in the majority of patients with Ph-negative myeloproliferative neoplasms (MPN), a symptomatic, in fact, therapy approach – the impact on peripheral blood indices and nonspecific thromboprophylaxis – is allowed. The limitations of classical cytoreduction and current targeted therapy, as well as the conviction of most specialists in the impossibility of adequately containment of disease progression, continue to be the main factors that keep physicians from the early start of pathogenetic therapy. Objective: to study the efficacy and safety of cepeginterferon alpha-2b (cePEG-IFN alpha-2b) in early (non-risk-adjusted) therapy of classical Ph-negative myeloproliferative neoplasms in initial use and after therapy with other pegylated interferons (PEG-IFN). Materials and methods. Twenty seven patients with polycythemia vera or essential thrombocythemia, without considering risk, received cePEG-IFN alpha-2b: initially, or after 6 or 12 months of other pegylated interferon therapy, in a dosage of 200 μg per week, with a decrease to 100 μg per week if 2 degree hematological toxicity developed. Hematological and molecular responses were assessed. Follow-up – from 20 to 46 months. Results. In all groups, a hematologic response comparable in depth and dynamics, as well as a molecular response as a steady decrease in the JAK2V617F allelic load, was achieved. There was no effect on the results of change to therapy with cePEG-IFN alpha-2b. CePEGIFN alpha-2b showed less dose-limiting toxicity for neutropenia and better pharmacoeconomic feasibility. Discussion . New data about mechanisms of antiproliferative effects of interferon alfa preparations are given. The pharmacological advantages of cePEG-IFN alpha-2b are discussed: superiority in pharmacokinetic parameters, the presence of one position isomer purity of the drug substance, the convenience of self-application. Conclusion . Early administration of an effective pathogenic therapy is an independent preventive measure to prevent the MPN progression and complications development. The use of cePEG-IFN alpha-2b may help to improve the care of MPN patients.

To evaluate in vivo confocal microscopy (IVCM) findings of ocular surface squamous neoplasia (OSSN) during treatment with topical interferon alfa-2b (IFN alfa-2b).In this prospective interventional case series, 20 eyes from 20 patients with OSSN were treated with topical IFN alfa-2b 3 million IU/mL four times a day. Treatment was continued for 2 or 3 months after clinical resolution. IVCM was done at baseline, on a monthly basis, and at the end of treatment. Confocal images were evaluated in conjunction with clinical findings during treatment. Limbal dendritic cell (DC) density within the involved areas was calculated manually in confocal images.Topical therapy resulted in clinical resolution of neoplasia in 80% of eyes. Main features of OSSN on IVCM were hyper-reflectivity of epithelium, demarcation line between neoplastic and normal epithelium, and pleomorphic cells. These findings became less prominent in response to IFN alfa-2b therapy. However, some degree of residual epithelial hyper-reflectivity could be detected in 9 (56.2%) subjects who responded to therapy at time of treatment cessation. Limbal DCs density within involved areas was significantly increased at month 1 follow-up compared to baseline only in responders (P .0001). There was a trend toward higher limbal DCs density in responders to topical IFN alfa-2b than non-responders (208.6 ± 53.5 vs. 153.1 ± 48.2 cell/mmIVCM is proposed as an adjunctive tool for monitoring OSSN during topical treatment. IVCM documents epithelial cell response as well as limbal DC density increase during topical IFN therapy.

BACKGROUND AND AIM Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6. METHODS Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naive, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (

Several countries have used pegylation technology to improve the pharmacokinetic properties of essential drugs. Recently, a novel interferon alfa-2b protein conjugated to four-branched 12 kDa polyethylene glycol molecules was developed jointly between Cuba and Brazil. The aim of this study was to compare the pharmacokinetic properties of BIP48 (pegylated interferon alfa-2b from Bio-Manguinhos/Fiocruz, Brazil) to those of PEGASYS® (commercially available pegylated interferon alfa-2a from Roche Pharmaceutical). This phase I, single-centre, randomized, double-blind crossover trial enrolled 31 healthy male volunteers aged 19 to 35 who were allocated to two stages, either side of a 5-week wash-out period, with each arm lasting 14 consecutive days after subcutaneous administration of 180 μg of one formulation or the other (study or comparator). The main outcome variable was serum pegylated interferon concentrations in 15 samples collected during the course of the study and tested using an enzyme immunoassay. There were no differences between formulations in terms of magnitude or absorption parameters. Analysis of time parameters revealed that BIP48 remained in the body significantly longer than PEGASYS® (Tmax: 73 vs. 54 h [p = 0.0010]; MRT: 133 vs. 115 h [p = 0.0324]; ke: 0.011 vs. 0.013 h(−1) [p = 0.0153]; t1/2: 192 vs. 108 h [p = 0.0218]). BIP48 showed the expected pharmacokinetic profile for a pegylated product with a branched molecular structure. Compared to PEGASYS®, the magnitude absorption was similar, but time parameters were consistent with slower elimination. Further studies should be conducted to evaluate the clinical implications of these findings. A phase II-III repeated-dose clinical trial is ongoing to study these findings in patients with chronic hepatitis C virus infection. This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 ). This trial was retrospectively registered in June 2013.

Mycosis fungoides with large-cell transformation is historically associated with a poor prognosis. Pediatric cases of mycosis fungoides with large-cell transformation are rare, with only three other cases reported in the literature. We present the first case of a child with almost complete remission of his mycosis fungoides with large-cell transformation shortly after administration of psoralen plus ultraviolet A, interferon-alfa, and localized radiation.

Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment.

BACKGROUND Although recombinant interferon-α (rIFNα) effectively treats patients with early myelofibrosis, the effect of driver and high molecular risk (HMR) mutations has not been considered. In this phase 2 study, for the first time, the authors correlate response to rIFNα treatment with driver and HMR mutations. METHODS Patients were diagnosed using World Health Organization or International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Only patients who had low or intermediate-1 Dynamic International Prognostic Scoring System scores with ≥15% hematopoietic bone marrow foci were included. History, symptom assessment, physical examination, and blood and bone marrow studies were performed. Genomic DNA was extracted from frozen cells, and next-generation targeted sequencing of 45 genes was performed. Either rIFNα-2b (0.5 million units subcutaneously 3 times weekly) or pegylated rIFNα-2a (45 μg weekly) with escalation was initiated. All patients were followed at the authors' institution, and regular bone marrow biopsies were encouraged. International Working Group for Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet treatment response criteria were used. RESULTS Of 30 patients (16 women and 14 men; median age, 58 years), 22 were classified as low risk, and 8 were classified as intermediate-1 risk. Two patients achieved complete remission, 9 achieved partial remission, 4 had clinical improvement, 7 had stable disease; 3 had progressive disease, 1 relapsed, and 4 died. There were 22 patients with JAK mutations, 6 with CALR mutations, and 2 with MPL mutations. Seventy-three percent of patients improved or remained stable with acceptable toxicity, including 37% who achieved complete or partial remission. There was no correlation between treatment response and baseline driver mutations or Dynamic International Prognostic Scoring System scores. Of 8 poor responders, 3 had ASXL1 or SRSF2 mutations. CONCLUSIONS Early treatment with rIFNα in patients without HMR mutations may prevent the development of marked splenomegaly, anemia, and florid myelofibrosis. Molecular profiling at the time of diagnosis may predict prognosis and treatment response. Cancer 2017;123:2680-87. © 2017 American Cancer Society.