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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 (

Background & Aims Despite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino acid polymorphisms (A150V and K206E) in the polymerase (NS5B) of G3 HCV reduce response to sofosbuvir. We now demonstrate that these polymorphisms alter the response to interferon alpha. Methods Quantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons. Results We show the presence of the A150V polymorphism markedly reduces the response to IFN alpha (IC50 of S52_WT = 1.162 IU/mL and IC50 of S52_A150V = 14.45 IU/mL, 12.4-fold difference). The induction of IFN-stimulated genes in A150V replicon cells is unaffected, but nuclear localization of active protein kinase R (PKR) is reduced. Blockade of PKR activity reduced the antiviral effect of IFN on wild-type replicons, whereas augmented PKR activation promoted the antiviral effect of IFN on A150V replicons. Furthermore, we show that impaired activation of PKR in A150V replicon cells diminishes cellular apoptosis. Conclusions These results demonstrate that polymorphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.

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.

Hepatitis E virus (HEV) can cause chronic infections in immunosuppressed patients with adverse clinical outcomes. Intervention strategies are limited with ribavirin (RBV) being the only main therapeutic option as off-label drug. Recent reports on RBV monotherapy failures show a coherence with the presence of certain single nucleotide variants (SNVs) and in-frame insertions in the hypervariable region of open reading frame 1 in the HEV genome. Importantly, some of the alterations were present in the viral population as minor variant before RBV administration. Individualized infection medicine by early detection of emerging viral variants in patients could improve treatment outcome and prognosis.

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.

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.

Hepatitis C virus infection is associated with many extrahepatic manifestations, including rheumatic disorders such as arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.The treatment of hepatitis C virus infection has long been based on interferon alfa, which was contraindicated in many autoimmune/inflammatory disorders.The emergence of new oral interferon-free combinations now offers an opportunity for patients infected with hepatitis C virus with extrahepatic manifestations, including autoimmune/inflammatory disorders, to be cured with a short treatment duration and a low risk of side effects.

The enzyme 2′-5′ oligoadenylate synthase (OAS) is one of the key interferon-induced antiviral factors that act through inhibition of viral replication. In chickens, there is a single well-characterized OAS gene, oligoadenylate synthase-like (OASL) that has been shown to be upregulated after infection with various viruses. However, a deeper understanding of how chicken OASL acts against viral infection is still necessary. In this study, we tested the hypothesis that OASL short interfering RNA (siRNA)–mediated knockdown would decrease the host gene expression response to the Newcastle disease virus (NDV) by impacting antiviral pathways. To assess our hypothesis, a chicken fibroblast cell line (DF-1) was infected with the NDV (LaSota strain) and OASL expression was knocked down using a specific siRNA. The level of NDV viral RNA in the cells and the expression of interferon response- and apoptosis-related genes were evaluated by quantitative PCR at 4, 8, and 24 h postinfection (hpi). Knockdown of OASL increased the level of NDV viral RNA at 4, 8, and 24 hpi (P 0.05). The lack of differential expression suggests that knockdown of OASL resulted in a decreased response to NDV infection. Within NDV-infected cells, OASL knockdown reduced expression of signal transducer and activator of transcription 1, interferon alfa receptor subunit 1, eukaryotic translation initiation factor 2 alpha kinase 2, ribonuclease L, caspase 8 (CASP8) and caspase 9 (CASP9) at 4 hpi, CASP9 at 8 hpi, and caspase 3, CASP8, and CASP9 at 24 hpi (P

Purpose To document long-term outcomes using a standardized treatment protocol of enucleation with preservation of vital structures and adjuvant subcutaneous interferon for aggressive giant cell lesions (GCLs) of the jaws. Materials and Methods A retrospective cohort study was designed. We evaluated all patients treated at Massachusetts General Hospital from April 1995 through September 2015 by enucleation with preservation of vital structures and adjuvant daily subcutaneous interferon for aggressive GCLs. The sample included patients with complete medical records consisting of clinical, radiographic, histopathologic, and follow-up data. The exclusion criteria included patients with incomplete records, contraindications to interferon therapy, non-aggressive GCLs, and GCLs associated with syndromes or with hyperparathyroidism. The primary outcome variable was long-term progression-free survival (PFS). The secondary outcome variables were adverse effects and laboratory abnormalities classified by type, frequency, and severity. Predictor variables for recurrence or failure included age, gender, location and features of lesion, type of procedure, duration of interferon treatment, amount of bone fill at end of treatment, and adverse effects. Descriptive statistics, Kaplan-Meier survival analysis, and Cox proportional hazards regression analysis were computed. Results Of a total of 77 patients, 45 (mean age, 18.8 ± 12.5 years; 29 female patients; 36 in whom the mandible was affected) met the inclusion criteria. The mean duration of interferon therapy was 7.9 ± 2.3 months. After follow-up of 4.8 ± 3.9 years, 6 patients showed progression of the lesion, considered recurrence (13.3% failure rate, 82.6% PFS rate). Most patients had mild (n = 42; 93.3%) and/or moderate (n = 31; 68.8%) side effects, which were readily managed. Adverse effects required stoppage of interferon in 7 patients, whereas no patients had long-term toxicity. No variable was significantly associated with PFS. Conclusions The results of this study indicate that enucleation with preservation of vital structures in combination with adjuvant interferon alfa is a reliable treatment for aggressive GCLs of the jaws associated with a low recurrence rate.

Sarcoidosis is an uncommon systemic granulomatous disease of unknown origin affecting lung, skin, liver, and other tissues. Noncaseating granulomas in the involved organs are the hallmark of this disease. An exaggerated immune response to an unknown antigenic stimulus could play a role in sarcoidosis development. Lung is one of the most frequently involved organs.1 Manifestations range from alveolitis to granulomatous infiltration of alveoli, bronchi, and blood vessels. The end stage of lung sarcoidosis is development of interstitial fibrosis with “honeycombing” of lung parenchyma. Interferon alfa in association with ribavirin is the treatment of choice for hepatitis C. Early treatment of acute hepatitis C with interferon alfa-2b will prevent the development of hepatic cirrhosis, but adverse effects are frequent and often can result in discontinuation of treatment.2 Most frequent adverse effects related to interferon are malaise, fever, arthralgia, and cough. Pulmonary events such as bronchial asthma, bronchiolitis obliterans, and interstitial pneumonitis have been reported. Interferon alfa is also used in the treatment of malignant melanoma, multiple myeloma, hairy-cell leukemia and HIV-associated Kaposi's sarcoma.3 Some cases of sarcoidosis after treatment with interferon alfa have been reported in the literature.4, 5, 6 Improvement of sarcoidosis has been reported with discontinuation of treatment, but in other cases an independent course of disease has been proposed, raising the belief that interferon discontinuation is unnecessary in mild-to-moderate cases of interferon-related sarcoidosis.7 We present the case of a patient with hepatitis C treated with interferon in whom pulmonary sarcoidosis developed. The sarcoidosis was initially believed to be a pulmonary neoplasm, but skin lesions developed that indicated the diagnosis of systemic sarcoidosis. The sarcoidosis finally resolved without discontinuation of interferon alfa.

There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and β (IFNα/β). Treatment with IFN-α or IFN-β at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC50 of IFN-α and IFN-β treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.

Chronic hepatitis C virus (HCV) infection is associated with several extra-hepatic manifestations. Patients with HCV may develop mixed cryoglobulinemia and its sequelae, ranging from cutaneous and visceral vasculitis to glomerulonephritis and B cell non-Hodgkin’s lymphoma. HCV-infected patients have increased rates of insulin resistance, diabetes and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality. Neurologic manifestations of HCV infection include fatigue and cognitive impairment. The mechanisms causing the extra-hepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extra-hepatic cells, or a heightened immune reaction with systemic effects. Successful eradication of HCV with interferon alpha and ribavirin was shown to improve some of these extra-hepatic effects: sustained virologic response is associated with resolution of complications of cryoglobulinemia, reduced levels of insulin resistance, reduced incidence of diabetes and stroke, and improved fatigue and cognitive functioning. The availability of new interferon-free, well-tolerated anti-HCV treatment regimens is broadening the spectrum of patients available for therapy, including those in whom interferon was contraindicated, and will likely result in greater improvements in the extra-hepatic manifestations of HCV. If these regimens are shown to confer significant benefit in the metabolic, cardiovascular, or neuropsychiatric conditions associated with HCV infection, extra-hepatic manifestations of HCV may become a major indication for treatment even in the absence of liver disease.

Interferons are polypeptides that naturally occur in the human body as a part of the innate immune response. By harnessing these immunomodulatory functions, synthetic interferons have shown efficacy in combating various diseases including cutaneous T-cell lymphoma. This article closely examines the qualities of interferon alfa and interferon gamma and the evidence behind their use in the 2 most common types of cutaneous T-cell lymphomas, namely, mycosis fungoides and Sezary syndrome.

Bone marrow (BM) morphologic features remain the cornerstone of diagnosis in both essential thrombocythemia (ET) and polycythemia vera (PV). In addition, recently discovered mutations, such as JAK2, CALR, and MPL, have proven useful in facilitating the diagnostic process. A JAK2 mutation is expected in PV, and its absence makes the diagnosis unlikely. However, JAK2 mutations also occur in about 60% of patients with ET, which underlines the need for BM examination in distinguishing JAK2-mutated ET from PV when the hemoglobin/hematocrit level is diagnostically equivocal (ie, as in "masked" PV). Most patients with JAK2-unmutated ET express CALR or MPL mutations, with respective estimated incidences of 22% and 3%, while approxmately 15% are wild-type for all 3 mutations (ie, they are triple-negative). As such, CALR first, followed by MPL if CALR is absent, mutation screening is appropriate in the diagnostic work-up of JAK2-unmutated ET but does not replace the need for BM morphologic examination in (1) confirming the diagnosis in triple-negative ET and (2) distinguishing ET from other myeloproliferative neoplasms that share the same mutations, including masked PV and early/prefibrotic myelofibrosis. Young patients (aged < 60 years) with ET or PV and no history of thrombosis are conventionally regarded as having "low-risk" disease. First-line treatment in low-risk PV is phlebotomy to achieve a hematocrit target of 45% and low-dose aspirin, and first-line treatment in ET is observation alone in the absence of additional risk factors for arterial thrombosis (ie, JAK2 mutation and cardiovascular risk factors) or low-dose aspirin therapy, once or twice daily, in the presence of one or both of these risk factors, respectively. Cytoreductive therapy is indicated in high-risk (patients aged ≥ 60 years or a history of thrombosis) PV or ET in the form of hydroxyurea as first-line and interferon alfa or busulfan as second-line drugs of choice. We do not use ruxolitinib in patients with PV unless they have severe pruritus or symptomatic splenomegaly that is proved to be refractory to hydroxyurea, interferon alfa, and busulfan.

Overall prevalence of HCV infection in India has been estimated to be approximately 1.3% in the general population. Recent introduction of sofosbuvir in India at a relatively affordable price has led to great optimism about prospects of cure for these patients. This drug is likely to form the backbone of current and future treatment regimes for HCV infection, displacing pegylated interferon. Availability of directly acting antiviral drugs (DAAs) has necessitated revision of INASL guidelines for the treatment of HCV published in 2014, as has happened across the world. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. Since only one DAA, sofosbuvir, is available in India, only two sofosbuvir-based regimes are possible: either dual drug therapy in combination with ribavirin alone for 6 months or triple drug therapy in combination with ribavirin and pegylated interferon for 3 months. The utility of these regimes in various situations has been discussed. Availability of a few other newer DAAs, expected in 2016, is expected to lead to more widespread use of these agents. Current guidance will be updated once newer DAAs, newer evidence with DAAs and ‘real-life experience’ with use of DAAs accumulate in India.

Background & Aims Interferon alfa–based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. Methods In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. Results Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%−82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. Conclusions Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.

The estimated prevalence of hepatitis C virus (HCV) infection in India is between 0.5 and 1.5% with hotspots showing much higher prevalence in some areas of northeast India, in some tribal populations and in certain parts of Punjab. Genotype 3 is the most prevalent type of infection. Recent years have seen development of a large number of new molecules that are revolutionizing the treatment of hepatitis C. Some of the new directly acting agents (DAAs) like sofosbuvir have been called game-changers because they offer the prospect of interferon-free regimens for the treatment of HCV infection. These new drugs have not yet been approved in India and their cost and availability is uncertain at present. Till these drugs become available at an affordable cost, the treatment that was standard of care for the whole world before these newer drugs were approved should continue to be recommended. For India, cheaper options, which are as effective as the standard-of-care (SOC) in carefully selected patients, are also explored to bring treatment within reach of poorer patients. It may be prudent to withhold treatment at present for selected patients with genotype 1 or 4 infection and low levels of fibrosis (F1 or F2), and for patients who are non-responders to initial therapy, interferon intolerant, those with decompensated liver disease, and patients in special populations such as stable patients after liver and kidney transplantation, HIV co-infected patients and those with cirrhosis of liver.

Clinical case A patient with chronic, painless, bilateral loss of vision, after significant intake of interferon (IFNα) and ribavirina due to liver transplant. Ocular fundus is normal. A suspected retrobulbar optic neuropathy is confirmed by a prolongation of the latency of the patient's visual evoked potential. There being no prior record of risk factors and with the patient's systemic analysis giving normal results, the clinical improvement and the electro-physiological tests conducted after the drug was withdrawn point to interferon as negatively affecting the bilateral optic nerve. Discussion Interferon-α is used in the treatment of viral and neoplastic illnesses. Currently the drug is formulated as Interferon alfa pegilado (IFNα-p) in order to reduce toxicity and increase tolerance. The most common secondary effects are flu symptoms, asthenia and weigh loss. Affected ocular tissue is rare and optic neuropathy is also an infrequent complication: retinopathy at the beginning of treatment is, however, more frequent. The most widely accepted hypothesis as to the cause of toxicity is the presence of circulating immune complexes. It is, therefore, essential for ophthalmologists to be aware of the toxicity of this drug in order to be able to withdraw it in good time, thus preventing potentially irreversible sight loss.

Background Interferon-alfa is used in the treatment of primary cutaneous B-cell lymphoma (PCBCL). Therapy with interferon-alfa has thus far been reported solely in case reports and small case series, mostly describing intralesional use. Objective We sought to evaluate efficacy, response rate, time to response, duration of response, and safety of subcutaneously administered interferon-alfa for the treatment of cutaneous B-cell lymphoma. Methods We conducted a retrospective chart analysis of patients given the diagnosis of PCBCL and treated with interferon-alfa subcutaneously at a tertiary referral center. Results Fifteen patients with indolent subtypes of PCBCL were identified. The overall response rate was 66.7%; all responding patients went into complete remission. Response was not significantly associated with the maximum tolerated dose. Within the median follow-up time of 40 months, 90% of the responders experienced a relapse; median duration of response was 15.5 months. Adverse events were predominantly mild and in no case led to cessation of therapy. Limitations Retrospective nature of the analysis and small number of patients because of scarcity of the disease are limitations. Conclusion Treatment of indolent PCBCL with subcutaneously injected interferon-alfa demonstrated good response rates and tolerability. Response was not dose dependent. Relapses were observed in nearly all responding patients raising the question of interferon-alfa maintenance therapy in PCBCL.

Appropriate protocol for the sequential treatment of metastatic renal cell carcinoma (mRCC) has not been established yet. Some mRCC cases with favorable risk were reported to achieve complete remission and durable response using interferon alfa (IFNα) + low dose interleukin-2 (IL-2). Cytokine therapies may be suitable for some patients with mRCC as first-line therapy. The present study is a phase III, investigator-initiated, multicenter, prospective randomized controlled trial investigating patients with low and intermediate risk mRCC classified by Memorial Sloan-Kettering Cancer Center risk criteria to evaluate the efficacy and safety of sequential treatment with cytokine (IFNα + IL-2) as first-line and axitinib as second-line therapy versus sequential treatment with sunitinib as first-line and axitinib as second-line therapy, which is the current standard treatment for patients with favorable risk. The target sample size was set at 72 patients per group (total 144 cases). The study duration is 7 years, and the duration for recruitment is 4 years. Our expectation of this trial is to clarify first- and second-line sequential treatment for mRCC better, especially in patients with favorable risk and some with intermediate risk. The results of this trial will certainly contribute to new information for the strategy of first- and second-line sequential treatment for mRCC. Trial registration: University hospital Medical Information Network (UMIN) Center identifier UMIN 000012522. Keywords: Cytokine, Interferon alfa, Interleukin-2, Sunitinib, Axitinib, Metastatic renal cell carcinoma

Background The prognosis in advanced hepatocellular carcinoma (HCC) with multiple intrahepatic metastases is extremely poor. Combination therapy with subcutaneous interferon (IFN) alfa and intraarterial 5-fluorouracil was reported to be effective against such advanced HCC. We describe results of debulking surgery followed by combination therapy with IFN alfa and 5-FU for massive HCC with multiple intrahepatic metastases. Methods In 27 HCC patients with massive tumors and multiple intrahepatic metastases, we performed combination therapy with IFN alfa and 5-FU after maximal liver tumor resection. Results Mean patient age was 63.3 years. Including intrahepatic metastases, tumors numbered 5 or more in 17 patients (63%). Portal or hepatic vein branches were invaded in 22 (81%). The mean maximum tumor diameter was 102 mm. Among 24 patients whose results were analyzed, an objective response by residual intrahepatic metastases was observed in 13 (54%; complete response in 12, and partial response in 1). Overall 1-, 3-, and 5-year survival was 73.2%, 38.7%, and 38.7%, respectively; 1-, 3-, and 5-year progression-free rates were 38.2%, 22.3%, and 22.3%. Conclusions Debulking surgery followed by IFN alfa and 5-FU combination chemotherapy offers possibility of long-term survival despite massive HCC with multiple intrahepatic metastases.

Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity.60 treatment-naïve patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24h and the maximal increase from baseline during that time (ΔTmax) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs - CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped.Temperatures rose by 1.2±0.8°C, peaking after 12.5h. ΔTmax was strongly associated with 1st phase virological decline (r=0.59, p0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12979860CC genotype (r = 0.65, p0.0001) but not in CT/TT (r = 0.13, p = 0.53) and patients with CC genotype had a higher DTmax (1.4 ± 0.8 C vs. 0.8 ± 0.6 +C, p = 0.001). DTmax was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12979860CC [corrected].ΔTmax weakly predicted early virological response (AUC=0.68, CI 0.49-0.88).Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness.

Introduction Renal cell carcinoma (RCC) is the most common malignancy of the kidney, with about 4% of patients having sarcomatoid dedifferentiation. Sarcomatoid features can develop in conjunction with all subtypes of RCC, including clear cell renal carcinoma (8%), papillary renal carcinoma (3%), chromophobe renal carcinoma (9%), and collecting duct carcinoma (29%). As a morphologic diagnosis, saromatoid renal cell carcinoma (SRCC) is defined by the spindled orphologic features of cells, resembling a sarcoma, among a backround of the primary histologic renal carcinoma type. Despite the pindled appearance, SRCC does not routinely express mesenchymal arkers, so epithelial-mesenchymal transition has been proposed as a mechanism for SRCC evolution. Regardless of the percentage of arcomatoid cells present in the tumor, sarcomatoid dedifferentiaion has been associated with a significantly worse prognosis inde

The treatment of interferon alfa (IFN-α) and ribavirin for chronic hepatitis C virus (HCV) infection achieves limited sustained virological response (SVR). We conducted a systematic review and meta-analysis to explore the efficacy of adding statins to IFN-α and ribavirin therapy for chronic hepatitis C. Studies with data pertinent to the effect of statins on chronic hepatitis C were reviewed, and randomized controlled trials (RCTs) evaluating the efficacy of the addition of statins to IFN-α and ribavirin were included in meta-analysis. The primary outcome measure was SVR. Secondary outcome measures were rapid virological response (RVR) and early virological response (EVR). The literature was systematically searched through October 2012. After screening of the 1724 non-duplicated entries, 54 potentially relevant studies were fully reviewed. Of those, 18 studies were relevant and 5 RCTs met the inclusion criteria for meta-analysis. In comparison with IFN-α and ribavirin therapy, the addition of statins significantly increased SVR (OR=2.02, 95% CI: 1.38-2.94), RVR (OR=3.51, 95% CI: 1.08-11.42) and EVR (OR=1.89, 95% CI: 1.20-2.98). The SVR increase remained significant for HCV genotype 1 (OR=2.11, 95% CI: 1.40-3.18). There were no significant increases in adverse events and withdrawals with the addition of statins. In conclusion, the addition of statins to IFN-α and ribavirin improves SVR, RVR, and EVR without additional adverse events and thus may be considered as adjuvant to IFN-α and ribavirin for chronic hepatitis C. Statins might also be used for HCV genotypes other than genotype 1, or in patients in whom the use of protease inhibitors is contraindicated or not indicated.

THE CHALLENGE A39-year-old man was referred by his dermatologist to an oral and maxillofacial pathologist (C.A.) for evaluation of multiple papillary lesions involving the facial and lingual surfaces of the maxillary and mandibular attached gingiva. The patient had been aware of multiple oral lesions for approximately one year and stated that they appeared initially at the angles of his mouth, affecting primarily the skin. He was unsure of the exact diagnosis for his condition, but he had been told it was “not cancer.” He reported that he had initially been treated by means of cryotherapy, followed by a seven-month course of imiquimod (applied topically every other night), which seemed to control the problem until he subsequently developed intraoral lesions. Recently, the patient had noted rapid growth of these lesions with occasional episodes of hemorrhage. The patient’s medical history was significant for chronic active hepatitis B, for which he recently had finished a four-month course of interferon alfa (5,000 units administered subcutaneously six days per week). Interestingly, the patient reported that his oral lesions seemed to regress during the interferon treatment and

SUMMARY Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor’s adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harm- ful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor’s growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents.

Aim Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN. Patients and methods Patients with resected melanoma ⩾1.5 mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3–4. Results Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73–1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80–1.32) and OS (HR 1.09, 95% CI 0.82–1.45). Peg-IFN was associated with higher rates of grade 3–4 AEs (47.3% versus 25.2%; p Conclusion This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702 .

Background Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. Methods Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. Results Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. Conclusions Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer–specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.

Objective To evaluate the long-term recurrence rate of conjunctival and corneal intraepithelial neoplasia (CIN) treated with retinoic acid and topical interferon alfa-2b. Design Retrospective, noncomparative, interventional case series. Participants A total of 89 eyes of 89 patients from 1 institution who were treated between September 2003 and February 2010 for CIN lesions used topical interferon alfa 1 million IU/ml drops 4 times daily and retinoic acid 0.01% once every second day. Methods Diagnosis was made by biopsy and impression cytology. Patients' notes and clinical photographs were reviewed, and data were analyzed. All eyes were monitored for the possibility of recurrence with a minimum of 1 year of follow-up from the time of documented clinical resolution. Main Outcome Measures All eyes were monitored for the possibility of recurrence with a minimum of 1 year of follow-up from the time of documented clinical resolution. Results Complete clinical resolution of the CIN lesions was achieved in 87 of the 89 eyes treated (97.75%). Two of the 89 eyes treated (2.25%) had only a partial response to treatment; of these 2 patients, 1 was taking cyclosporine for keratitis sicca. For the 87 eyes with complete response, resolution occurred after a mean of 1.69 months (range, 19 days to 6.5 months). Mean follow-up after clinical resolution (tumor-free period) was 51.5 months (range, 11–84 months). Four of the 87 patients with complete response developed a mild allergic papillary conjunctivitis that settled on halving the interferon dose to 0.5 million IU drops and reducing the frequency to 3 times daily. Side effects were limited to 1 case of epithelial microcysts and 1 case of marginal keratitis. Conclusions In this group of patients observed with CIN lesions, combination treatment of topical retinoic acid and interferon alfa-2b was effective in treating lesions with minimal self-limited side effects with faster and greater resolution and a longer tumor-free period compared with studies using interferon alfa-2b alone. We hypothesize that topical all-trans retinoic acid and interferon alfa-2b may act synergistically. We believe that combination treatment of interferon alfa-2b and retinoic acid may offer a superior alternative to interferon alfa-2b alone in treating CIN. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Background The purpose of this study was to assess the outcome in patients treated by immunotherapy using interferon-alpha (IFN-α) and to evaluate the significance of the neutrophil count after IFN-α immunotherapy as a predictive marker for metastatic renal cell carcinoma (RCC). Patients and Methods We identified 84 patients with metastatic RCC who underwent immunotherapy with IFN-α between 1998 and 2006. The predictive values of the neutrophil count before and after IFN-α treatment as well as other clinical and laboratory parameters were assessed retrospectively. Results On univariate analysis, the significant correlation with overall survival (OS) was recognized in the Eastern Cooperative Oncology Group (ECOG) performance score (PS), lactate dehydrogenase (LDH) levels, corrected calcium levels, interval from diagnosis to treatment, and the ratio of neutrophil number before and after treatment with INF-α. Multivariate analysis showed that ECOG PS, corrected calcium levels, interval from diagnosis to treatment and neutrophil number after IFN-α treatment were independent factors for OS. Using the number of neutrophils after IFN-α treatment, subgroups were identified using the Memorial Sloan-Kettering Cancer Center (MSKCC) model. The 1-year survival rate was 93% vs. 63% in the intermediate-risk group and 34% vs. 8% in the poor-risk group. In the favorable-risk group, all patients had a good decrease in neutrophil number after treatment with IFN-α. Conclusion Neutrophil number after IFN-α treatment can be a good predictive marker for OS in metastatic RCC. By combining MSKCC score with neutrophil number after treatment with IFN-α, we can subdivide each group.

Considerable evidence suggests that iron could be a comorbid factor for liver injury in chronic hepatitis C (CHC). Elevated iron indices are frequently described in CHC and may impact negatively on the course of liver disease and on the response to interferon alfa therapy. The aim of this study was to evaluate the frequency of hemochromatosis gene mutations in Sardinian CHC patients, the association with iron overload and the impact on response to therapy.Sixty-nine CHC patients were enrolled. Iron indices, hepatic and viral parameters were detected. C282Y, H63D and S65C mutations were identified through a PCR. Liver biopsy was performed for hepatic fibrosis evaluation. All patients were treated for 6 months (viral genotype 2/3) or 12 months (viral genotype 1/4) with pegylated-interferon 180 mcg once weekly and ribavirin 1000-1200 mg/daily. Sustained virological response (SVR) was defined as undetectable HCV RNA 24 weeks after the end of treatment.HFE gene mutation was detected in 29 patients (42%). The presence of HFE mutations was significantly associated with elevated transferrin saturation (P 0.01). Hepatic fibrosis was more advanced in HFE mutation carriers (χ (2), P = 0.04). Among mutation carriers 27.5% achieved responses at the end of treatment compared with 60% of non-carriers (P = 0.005). Patients with HFE wildtype produced significant SVR compared with patients with HFE mutations (P = 0.03).The literature shows discordant results about the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C. Our findings shows that HFE gene mutations could favor, synergically with CHC and other genetic or acquired factors, the development of liver damage and could influence the outcome of interferon treatment with higher rate of non-response.

Interferon-α2b (IFN-α2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-α2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-α2b responses in human melanoma cells. Shp2 knockdown increased IFN-α2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-α2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-α2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-α2b.

In humans, chikungunya virus (CHIKV) infection causes fever, rash, and acute and persisting polyarthralgia/arthritis associated with joint swelling. We report a new CHIKV disease model in adult mice that distinguishes the wild-type CHIKV-LR strain from the live-attenuated vaccine strain (CHIKV-181/25). Although eight-week old normal mice inoculated in the hind footpad developed no hind limb swelling with either virus, CHIKV-LR replicated in musculoskeletal tissues and caused detectable inflammation. In mice deficient in STAT1-dependent interferon (IFN) responses, CHIKV-LR caused significant swelling of the inoculated and contralateral limbs and dramatic inflammatory lesions, while CHIKV-181/25 vaccine and another arthritogenic alphavirus, Sindbis, failed to induce swelling. IFN responses suppressed CHIKV-LR and CHIKV-181/25 replication equally in dendritic cells in vitro whereas macrophages were refractory to infection independently of STAT1-mediated IFN responses. Glycosaminoglycan (GAG) binding may be a CHIKV vaccine attenuation mechanism as CHIKV-LR infectivity was not dependent upon GAG, while CHIKV-181/25 was highly dependent.

Background and Aim: Pegylated-interferon-alfa (PEG-IFN-a) with ribavirin is an established treatment in chronic hepatitis due to hepatitis C virus (HCV) (CH-C). Such treatment is expensive and in resource-poor countries such as India, alternative less expensive therapy is needed. Methods: Multicenter randomized controlled trial comparing two treatment regimens (interferon-alfa-2b [IFN-a-2b] 3 million unit/day [MU/day] and ribavirin 1000 mg/day [I + R] vs IFN-a-2b 3 MU/day and glycyrrhizin 250 mg [I + G]) in CH-C. Viral, host characteristics and therapeutic responses were assessed (ICMR—6 months trial for chronic hepatitis—CTRI/2008/091/000105). Results: One hundred and thirty-one patients meeting the inclusion criteria were randomized to I + G (n = 64) or I + R (n = 67) during the period February 2002 to May 2005. About 85% (I + G = 53, I + R = 58) completed 6 months of treatment and 89% of them (I + G = 46, I + R = 53) completed 6 months of follow-up after completion of treatment. Hepatitis C virus genotype 3 was the major type detected (71% patients). The mean log10 viral load (copies/mL), histological activity index, and fibrosis stage for all patients were 5.1 ± 0.98, 5 ± 2, and 2 ± 1.5, respectively. Sustained viral response (SVR) was significantly higher in I + R group than in I + G group (65.7% vs 46.9%, OR = 2.2, P = 0.03). Treatment with I + G was associated with significantly lower frequencies of leukopenia (2% vs 17%, P < 0.01) and anemia (8% vs 40%, P < 0.001) as compared to treatment with I + R. Conclusion: Genotype 3 HCV infection with low viral load is prevalent in India. Daily IFN with ribavirin showed significantly better responses. Leukopenia and anemia were significantly more in ribavirin group. Responses observed with IFN + ribavirin were similar to the reported response rates with PEG-IFN suggesting that this modality may be considered as a cheaper alternative of treatment for chronic hepatitis C. ( J CLIN EXP HEPATOL 2012;2:10–18)

Background: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-a (IFN-a) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study. Methods: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes. Results: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased. Conclusions: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.

Resumen Introduccion Los perfiles de expresion genica (PEG) en las primeras semanas de tratamiento de pacientes con hepatitis C cronica pueden servir para evaluar la eficacia de la terapia basada en interferon. El objetivo de este trabajo fue estudiar los PEG de pacientes respondedores y no respondedores precoces antes y tras 12 semanas de tratamiento con peginterferon alfa y ribavirina. Metodos Estudio observacional donde se analizaron los PEG de 12 pacientes con hepatitis C cronica candidatos a recibir tratamiento con peginterferon alfa y ribavirina. Resultados De los 12 pacientes estudiados, seis mostraron una respuesta virologica precoz completa, mientras que seis no lograron controlar la viremia. En respondedores precoces, el tratamiento con peginterferon y ribavirina indujo un aumento de la expresion de un mayor numero de genes de respuesta al interferon (ISG15, IFI6, IFI44L, IFI27, MX1, OASL, IRF7, IFIT3, IFITM1, EIF2AK2, HERC5 y APOBEC3A) que en no respondedores (ISG15, IFI44L, IFI27, IRF7, USP18) (p Conclusiones Los PEG descritos en este trabajo pueden ayudar a comprender mejor la patogenesis de la infeccion, asi como las bases fisiologicas de la respuesta al tratamiento. Asi, el mayor efecto del tratamiento sobre la expresion de genes de respuesta al interferon observado en respondedores podria explicar su mejor control de la carga viral.

Interferon (IFN)-α, a type-I IFN, is widely used to treat chronic hepatitis C virus (HCV) infection, but the broad expression of IFN-α receptors often leads to adverse reactions in many organs. Here, we examine IFN-λ, a type-III IFN, as a therapeutic alternative to IFN-α. Like IFN-α, IFN-λ also induces antiviral activity in hepatocytes, but may induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virologic response (SVR) to therapy with pegylated IFN-α plus ribavirin in patients with chronic hepatitis C.

Summary Background Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. Methods TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov, number NCT00619268. Findings Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29·5% (26 of 88 patients, 95% CI 20·0–39·1) in group A, 35·7% (15 of 42, 21·2–50·2) in group B, and 61·0% (25 of 41, 46·0–75·9) in group C. Median PFS was 8·2 months (95% CI 7·0–9·6) in group A, 8·2 months (5·5–11·7) in group B, and 16·8 months (6·0–26·0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. Interpretation The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. Funding French Ministry of Health and Wyeth Pharmaceuticals.

Background High-dose Interferon-α-2b (HD-IFN) is an adjuvant treatment for melanoma. However, clinical trials for HD-IFN have not been reported in acral melanoma (AM), the predominant subtype of cutaneous melanoma in Asian population. Methods Patients with resected high-risk (stage IIb–IIIc) AM were randomly assigned to a regimen of 4-week (arm A: 15 × 106 U/m2 d1–5/w × 4w) or 1-year adjuvant HD-IFN (arm B: 15 × 106 U/m2 d1–5/w × 4w + 9 × 106 U tiw × 48w), respectively. The endpoints were relapse-free survival (RFS), overall survival (OS) and toxicities. Results A total of 158 patients were enrolled in this study and 147 patients were eligible for survival analysis. With a median follow-up of 36.1 months, median RFS for arm A and arm B were 17.9 months and 22.5 months, respectively (P = 0.72). Stratified analysis showed that RFS curves of patients in stage IIIb–IIIc were statistically different between arm A and arm B (P = 0.02). The median RFS of patients with more nodal metastases (n ⩾ 3) was shorter (P = 0.004) in arm A (3.3 months) than that in arm B (11.9 months). Grade 1/2 adverse effects were observed in both groups. However, patients in arm B showed higher incidence of reversible Grade 3/4 hepatotoxicity (P = 0.03). Conclusions The induction dose of 15 × 106 U/m2 and the maintenance dose of 9 × 106 U were tolerable, which may be the optional dose intensity for adjuvant IFN-α-2b therapy in Chinese high risk AM population. No statistical significance was detected in RFS between the 4-week and 1-year regimen while a 1-year regimen may show clinical benefits in patients with stage IIIb–IIIc AM or with ⩾3 nodal metastases.

Background & Aims Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC) 3 program. Methods Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. Results There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880–2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130–2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls ( P = .016). There were no new safety observations. Conclusions Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Amongst HIV patients with successful virological responses to antiretroviral therapy (ART), poor CD4+ T-cell recovery is associated with low nadir CD4+ T-cell counts and persistent immune activation. These factors might be influenced by dendritic cell (DC) function. Interferon-α-producing plasmacytoid DC and IL-12-producing myeloid DC were quantified by flow cytometry after stimulation with agonists to TLR7/8 (CL075) or TLR9 (CpG-ODN). These were compared between patients who achieved CD4+ T-cell counts above or below 200 cells/μL after 6 months on ART (High vs. Low groups). High Group patients had more DC producing interferon-α or IL-12 at Weeks 6 and 12 on ART than Low Group patients. The frequencies of cytokine-producing DC at Week 12 were directly correlated with CD4+ T-cell counts at baseline and at Week 12. Patients with good recovery of CD4+ T-cells had robust TLR-mediated interferon-α responses by plasmacytoid DC and IL-12 responses by myeloid DC during early ART (1–3 months).

This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C).A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65 years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age.The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%).Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for Peg-IFN plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1.

Patients with complete IFN-γR deficiency are unable to respond to IFN-γ and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-α and IFN-γ share signalling pathways, treatment with IFN-α has been proposed in complete IFN-γR deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-γR1 with IFN-α and IFN-γ, to establish whether IFN-α would substitute for IFN-γ effects. IFN-α induced STAT1 phosphorylation in monocytes of the IFN-γR1­/­ patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-α inhibited the priming effect of IFN-γ on LPS-induced pro-inflammatory cytokine release. Finally, IFN-γ but not IFN-α induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-α in IFN-γR-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-α may even adversely affect host defence against Mycobacteria.

To evaluate the role of host single nucleotide polymorphisms (SNPs) of 2′,5′-oligoadenylate synthetase (OAS) in predicting IFN response in patients with HBV infection, OAS gene and four SNPs were examined in 363 patients with chronic HBV infection (including 41 patients with HBsAg seroconversion) and 57 healthy controls. One SNP and three haplotypes were identified after adjustment for age, sex, HBV DNA. The frequency of OAS3T/C heterozygotes is 52.2% in responders (R) and 38.2% in non-responders (NR), with an odds ratio (OR) of 1.511 (P = 0.018). For complete responders (CR) and NR, the OR reached 2.323(P = 0.023). Haplotype analyses revealed significant association between three OAS haplotypes and response to IFN-α treatment. Genotype combination and interaction between gene–gene analyses disclosed that there was a positive interaction between OAS2/OAS3 and OAS3/OASL, and the rate of OR was 2.46 (likelihood test, P = 0.004) and 4.46 (likelihood test, P = 0.004), respectively. Our results suggest that OAS gene variations may play an important role in response to IFN-α and provide a novel strategy for the resolution of HBV infection.

Resume Le virus de l’hepatite E (HEV) est endemique dans de nombreux pays en developpement ou la transmission s’effectue par l’eau contaminee. Dans les pays industrialises, l’infection etait consideree comme rare et importee. On sait a present que la transmission autochtone a partir d’un reservoir animal (porc, sanglier, cervides) est preponderante et relativement frequente dans certaines regions. Des hepatites fulminantes ont ete decrites chez les patients presentant une hepatopathie sous-jacente ou durant la grossesse. L’infection peut evoluer vers une hepatite chronique chez les sujets immunodeprimes. Plusieurs approches permettent d’obtenir une eradication virale dans cette situation : reduction des doses d’immunosuppresseur chez le transplante, traitement par interferon-α pegyle, traitement par ribavirine. En consequence, meme en l’absence de notion de voyage, les patients presentant une hepatite inexpliquee doivent beneficier d’un depistage du HEV fonde sur la mise en evidence des IgM et de l’ARN viral dans le sang et les selles.

Background: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. Patients and methods: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m2 i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m2/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m2/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. Results: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0–20.1 months) and 25.4 months (95% CI 23.4–34.1 months), respectively. Conclusions: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.