Dramatic Clinical Improvements Research Articles

Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity.

Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

Effects of highly effective modulator therapy on the dynamics of the respiratory mucosal environment and inflammatory response in cystic fibrosis.

While the widespread initiation of elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic clinical improvements among persons with cystic fibrosis (pwCF), little is known about how ETI affects the respiratory mucosal inflammatory and physiochemical environment, or how these changes relate to lung function. We performed a prospective, longitudinal study of adults with CF and chronic rhinosinusitis (CF-CRS) followed at our CF center (n = 18). Endoscopic upper respiratory tract (paranasal sinus) aspirates from multiple visit dates, both pre- and post-ETI initiation, were collected and tested for cytokines, metals, pH, and lactate levels. Generalized estimating equations were used to identify relationships between ETI and upper respiratory tract (URT) biomarker levels, and between URT biomarkers and lung function or clinical sinus parameters. ETI was associated with decreased upper respiratory mucosal cytokines B-cell activating factor (BAFF), IL-12p40, IL-32, IL-8, IL-22 and soluble tumor necrosis factor-1 (sTNFR1), and an increase in a proliferation-inducing ligand (APRIL) and IL-19. ETI was also associated with decreased URT levels of copper, manganese, and zinc. In turn, lower URT levels of BAFF, IL-8, lactate, and potassium were each associated with ~1.5% to 4.3% improved forced expiratory volume in 1 s (FEV1), while higher levels of IFNγ, iron, and selenium were associated with ~2% to 10% higher FEV1. Our observations suggest a dampening of inflammatory signals and restriction in microbial nutrients in the upper respiratory tract with ETI. These findings improve our understanding of how ETI impacts the mucosal environment in the respiratory tract, and may give insight into the improved infectious and inflammatory status and the resulting clinical improvements seen in pwCF.

Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis

BackgroundThere have been dramatic clinical improvements in people with cystic fibrosis (PwCF) commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in PwCF. MethodsSputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry. ResultsPost-ETI, mean FEV1 % increased by 13.7 % (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged. ConclusionsSputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.

WHAT IS THE COMPLIANCE REGARDING THROMBOPROPHYLAXIS IN POSTOPERATIVE ARTHROPLASTY PATIENTS IN A TERTIARY HOSPITAL IN SOUTH AFRICA?

Total Joint Arthroplasty (TJA) is a successful orthopaedic procedure allowing dramatic clinical and functional improvements. Globally, there's been an increase in demand and performed cases associated with an increase in complications. Subsequently, focus on the prevention of complications has become important worldwide. The incidence of venous-thrombolic events (VTE) despite great attention has not diminished despite much investigation. A balance between efficacy and safety from the available agents is essential. Low molecular weight heparin (LMWH) has been commonly used, but oral anti-coagulants have become more popular. The aim of this study was to assess the adherence LMWH and the effectiveness and safety of preventing VTE in post-operative arthroplasty patients in a South African setting.We conducted a prospective cohort study that included hip and knee, primary and revision, arthroplasty patients who received thromboprophylaxis with one daily injection of LMWH for 14 days post discharge. Patients who omitted 1 or more doses during the follow up period were classified as “non adherent”. A questionnaire was used at follow up visits at least 6 weeks post-operatively.100 consecutive patients were followed up. The mean age of patients was 63.45 years. There were 68 % female patients. There was a 92% compliance rate. 60 % of patients had the injection administered by a family member, 38 % administered it themselves and 2 % had the injection administered by health professionals. Venous thromboembolic events were confirmed in 5 % at 7.86 days after surgery. Three patients had persistent wound drainage after surgery, however, none required reoperation or readmission.Compliance with LMWH is high and is comparable with oral agents. It is effective in preventing VTE and safe with regards to bleeding and wound complications in a South African setting. Patient education regarding medications may improve compliance of the medication.

Isolated Aldosterone Deficiency Due to an Aldosterone Synthase Mutation: A Rare Cause of Life-Threatening Salt Wasting in Infancy

Purpose: Isolated hypoaldosteronism is a rare cause of salt wasting in infancy caused by the loss of activity of aldosterone synthase (AS), which is encoded by the CYP11B2 gene. This condition may be life-threatening, especially in newborns. Methods: We are reporting the case of a newborn male born to consanguineous parents, who presented at the age of 1 month with severe dehydration, vomiting, and hypotonia. Results: Lab studies showed severe hyponatremia, hyperkalemia, and metabolic acidosis. Hormonal assessment confirmed a normal corticotrope axis with severe deficiency in aldosterone. Genetic analysis revealed a novel mutation in the CYP11B2 gene in the highly conserved donor splice site of exon 3 and confirmed the isolated aldosterone deficiency. The patient was subsequently treated with fludrocortisone and sodium only, without hydrocortisone. Conclusion: AS deficiency is a rare inherited disease. There should be a high index of suspicion of cases with life-threatening salt-wasting in infancy as dramatic clinical improvements and good long-term prognosis can be achieved with timely replacement treatment.

Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions.

IntroductionPancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC.MethodsA literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications.ResultsOver 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed.ConclusionsThe potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward.

Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.

Clinical Features, Therapeutic Trends, and Outcome of Giant Prolactinomas: A Single-Center Experience Over a 12-Year Period.

Background:Management of giant prolactinomas presents a different challenge than the management of traditional prolactinomas.Objective:The aim of this study was to report the largest long-term single-center study of giant prolactinomas to analyze their clinical features; define epidemiological characteristics, comorbidities, complications, treatment outcomes; and to demonstrate our experience with long-term cabergoline (CAB) treatment of these giant tumors.Methods:A retrospective case study and clinical review of patients presenting with giant prolactinomas in the pituitary clinic at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia, in the period between 2006 and 2018 were included in the study. Of the charts reviewed, 33 patients (24 men; 9 women) with age of diagnosis between 18 and 63 years (mean = 37.21 years) met the selection criteria for giant prolactinomas.Result:The most common presenting features include headache (87.8%), visual defects (69.7%), and hypogonadism (51.5%). The baseline means serum prolactin (PRL) level was extremely high for both sexes (95 615.03 nmol/L), which eventually decreased by as much as 95.4% after CAB treatment. Serum PRL concentrations completely normalized in 11 patients and significantly reduced in 22 patients. The mean tumor volume at baseline was 42.87 cm3, whereas the mean posttreatment tumor volume was 3.42 cm3 (no residual tumor in 2 patients, while in others, it ranged from 0.11 to 16.7 cm3) at the last follow-up visit. The mean change in tumor volume was 88.84%. Tumor volume decreased by an average of 92% for men and 80.4% for women. One patient had no tumor size change with CAB (3.5 mg thrice a week) or radiotherapy and required surgery. The response rate (remission after medical therapy alone) in this series was 84.84%.Conclusions:Findings reinforce results from our previous study that CAB provides dramatic clinical improvements with an excellent safety profile. The CAB should, therefore, be considered as the primary therapy for giant prolactinomas.

SU93. Targeted Treatment of a Genetic Mutation in Glycine Decarboxylase With d-Cycloserine in Psychotic Disorders

Abstract Background: The identification of mutations in specific genes could enable personalized, “medically actionable” treatment interventions. We identified a potentially informative mutation, a rare structural rearrangement that includes a triplication of the glycine decarboxylase gene (GLDC). GLDC is the enzyme that catabolizes glycine, a precursor of d-serine, both of which are coagonists at the NMDA receptor (NMDAR). Four copies of GLDC would be expected to increase the degradation of glycine, resulting in low levels of brain glycine and NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of psychotic disorders. Carriers of this mutation may especially benefit from augmentation of psychotropic drug treatment with NMDAR coagonists. Methods: We carried out a double-blind placebo-controlled clinical trial (6 weeks per arm) of d-cycloserine (DCS), a partial agonist at the NMDAR glycine site, followed by 24 weeks of open-label DCS, in 2 related individuals who are carriers of the GLDC mutation, one with a diagnosis of bipolar disorder with psychotic features and the other with a diagnosis of schizo-affective disorder. Clinical assessments were carried out every 2 weeks using the PANSS, BPRS, YMRS, HAM-D, and CGI. The same individuals previously completed trials of acute and chronic glycine augmentation, which produced significant symptom improvement but caused problematic GI side effects. Results: Full trial results are still pending as the blind has not yet been broken. However, blinded analyses show significant changes in severity of clinical symptoms, indicating that DCS either produced dramatic clinical improvements or worsened symptom severity. Complete, unblinded results will be available and presented at the meeting. Conclusion: DCS may be an effective augmentation in psychotic individuals selected for being carriers of duplications or triplications of GLDC, or who are carriers of other genetic variants resulting in NMDAR hypofunction. If DCS reduced symptom severity, it is a preferable alternative to glycine as a targeted treatment in light of its clinical efficacy, ease of administration, and favorable side effect profile.

Giant prolactinomas: clinical manifestations and outcomes of 16 Arab cases.

The management of giant prolactinomas remains a major challenge, despite dopamine agonists being the first line of treatment, owing to its efficacy to normalize prolactin levels and reduce tumor volume. The aim of this study is to characterize the therapeutic aspects, manifestations and outcomes of 16 cases of giant prolactinomas admitted at a single tertiary center in Riyadh, Saudi Arabia. Retrospective data collection involving 16 Saudi patients diagnosed with giant prolactinoma at the Pituitary Clinic in King Fahad Medical City, Riyadh, Saudi Arabia between January 2006 and July 2012. A total of 16 patients (ten males; six females) with age of diagnosis between 21 and 55 years (mean 34.9 years) were included in the analysis. The most common presenting features include headache, visual defects and sexual dysfunction. Baseline mean serum prolactin level were extremely high for both sexes which eventually decreased by as much as 97% after cabergoline treatment. Serum prolactin concentrations completely normalized in six patients and significantly decreased in five patients 3-5 times that of normal range. Tumor volume also decreased by an average of 86% for males and 87% for females. Two patients had no tumor size change with cabergoline and required surgery. Findings indicate that cabergoline provides dramatic clinical improvements with excellent safety profile. Cabergoline should therefore be considered as the primary therapy for giant prolactinomas.

Anti-neutral glycolipid antibodies in encephalomyeloradiculoneuropathy

The aim of this study was to review 4 patients with encephalomyeloradiculoneuropathy (EMRN) and assess for autoantibodies against neutral glycolipids. We studied the progression of clinical, radiologic, neurophysiologic, and CSF findings, as well as anti-neutral glycolipid antibodies in sera. All patients developed acute or subacute motor weakness and impaired consciousness. Their CSF showed pleocytosis and high immunoglobulin G concentrations. MRI revealed lesions in the brain and spinal cord. Neurophysiologic examinations indicated dysfunction of the spinal cord, nerve roots, and peripheral nerves. Steroid pulsed immunotherapy and/or high dose of IV immunoglobulin replacement therapy resulted in clear and often dramatic clinical improvements. Reactivity to anti-neutral glycolipid antibodies was positive in all patients with acute EMRN but not in the recovery phase. Forty-seven age-matched patients with other neurologic disorders and 28 age-matched healthy volunteers tested negative for reactivity to anti-neutral glycolipid antibodies. The resolution of radiologic and neurologic abnormalities and altered autoantibody titers against neutral glycolipids after immunotherapy suggest that EMRN is caused by an immune-mediated mechanism. These autoantibodies may be useful biomarkers for EMRN.

High Response Rates and Prolonged Survival in Patients With Corticotroph Pituitary Tumors and Refractory Cushing Disease From Capecitabine and Temozolomide (CAPTEM)

Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors. We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM. This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.

Interventional immunotherapy in breast cancer

257 ISSN 1758-1923 10.2217/BMT.12.44 © 2012 Future Medicine Ltd Breast Cancer Manage. (2012) 1(4), 257–260 Breast cancer remains a global public health burden with more than 1 million new cases diagnosed worldwide each year [101]. Furthermore, despite notable diagnostic and therapeutic innovations over the last several decades, approximately a third of women with early-stage breast cancer ultimately develop distant metastases and die of related complications [101,102]. Until all women are cured of this disease, additional therapeutic strategies are needed. However, because each individual patient is unique and their tumors are similarly heterogeneous, it is likely that successful future treatment innovations will harness and, perhaps, exploit these unique features if truly personalized medicine is to be delivered. One such promising strategy combines tumor ablation with immune stimulation. The overarching hypothesis behind this strategy is that ablation of a tumor mass generates tumor fragments that are potentially readily digested by the immune system. If the immune system is further potentiated, a robust response to an individual’s tumor may be achieved. It is hoped that by exploiting the biology of an individual’s tumor and harnessing an individual’s immune system, life-long immunity to one’s tumor and, thus, cure may be achieved. Some of the most notable recent therapeutic innovations in breast cancer reflect improvements in the ability to recognize biologically distinct breast cancer subtypes and, ultimately, to tailor treatment recommendations to these features. Currently, outside of clinical trials, biologic subsets are primarily defined by two biologic features: hormone receptor and HER2 status. In fact, the recognition of HER2 status and the subsequent successful development of HER2-targeted therapies represents one of the most notable innovations in breast cancer therapy within the last several decades and has translated into dramatic clinical improvements for women with HER2-positive disease [1,2]. However, breast cancer subtyping not only confers advances (better targeted therapies and improved patient selection) but also presents significant clinical challenges (ever

Lung Cancer: New Therapeutic Targets, New Definitions

Lung Cancer: New Therapeutic Targets, New Definitions

PTU-020 Rifaxamin is a highly efficacious treatment for the parkinsonian phenotype of hepatic encephalopathy (HE)

IntroductionPatients who develop Parkinsonian symptoms on a background of cirrhosis and portosystemic shunting (PSS) form a unique subset of so-called acquired hepatocerebral degeneration. The syndrome is entirely different from acute...

Novel Immunotherapeutic Agents and Small Molecule Antagonists of Signalling Kinases for the Treatment of Metastatic Melanoma

Melanoma incidence is increasing annually and over 40,000 die of this disease each year worldwide. In this review, we discuss the rationale and recent trial results of several novel immunotherapeutic approaches and small molecule inhibitors of signalling kinases. Ipilimumab is a humanized anti-CTLA4 antibody that has been proven to increase the median overall survival of large cohorts of patients with unresectable melanoma in two phase III trials. OncoVEX(GM-CSF) is an oncolytic herpes simplex virus-1 recombined with granulocyte-macrophage colony-stimulating factor that has demonstrated durable objective responses in a phase II trial. Tumour-infiltrating lymphocytes given after lymphocyte depletion and followed by high-dose interleukin (IL)-2 yield durable complete responses in a significant percentage of melanoma patients. Lastly, denileukin diftitox, a fusion of IL-2 and diphtheria toxin, was recently observed to deplete regulatory T cells and cause durable partial responses, particularly in chemo/immune-naïve patients. These agents are enabling the rational design of novel combination trials to simultaneously increase antigen presentation, deplete regulatory T cells and block immune check-points in order to activate melanoma antigen-specific immunity. Although melanoma metastases have been found to contain thousands of mutations, the V600E BRAF mutation is clearly a driver of the neoplastic phenotype and is present in 40-60% of melanomas. Two separate small molecule antagonists of B-Raf have been found to yield very high partial response rates in metastatic melanoma, and the B-Raf inhibitor, vemurafenib (PLX4032), was recently observed to increase median overall survival in an interim analysis. However, B-Raf inhibitor resistance through up-regulation or activating mutations of alternative oncogenic signalling receptors and enzymes is proving to be a major challenge. Inhibitors of c-Kit and mitogen-activated protein kinase (MEK) have also been found to have activity against melanomas and MEK inhibitors are now being examined as a strategy to overcome B-Raf inhibitor resistance. In summary, these studies reveal that, for the first time, several immunotherapeutic and targeted agents are yielding dramatic clinical responses and improvements in overall survival in patients with unresectable stage III and IV melanoma.

Abstract 3165: Anti-tumor activity of the eIF4E-targeted drug ribavirin in breast cancer cells

Abstract In this study, we explored the potential of targeting the eukaryotic translation initiation factor (eIF4E) with ribavirin as a novel anti-tumor agent in breast cancer. eIF4E is an oncogene that facilitates nuclear export and translation of specific, growth-stimulatory mRNAs, including cyclins, c-myc, survivin, VEGF and others, thereby promoting cell survival. Overexpression of eIF4E also leads indirectly to activation of Akt, providing a positive feed-back loop for eIF4E activation and Akt signaling effects. Ribavirin is an antiviral drug that has been shown to inhibit oncogenic transformation mediated by eIF4E and reduce the clonogenic potential of cancer cells with high eIF4E levels. Ribavirin specifically inhibits translation and/or nuclear export of eIF4E targets in cells both in vitro and in patients, as shown in a recent phase I/II proof-of-principle trial in patients with AML. In this trial, dramatic clinical improvements were observed and reductions in eIF4E levels and activity correlated with clinical response. Importantly, ribavirin is largely non-toxic even at high doses, possibly due to an eIF4E oncogene addiction specific to tumor cells. eIF4E is overexpressed in more than 50% of breast cancers, and high levels are associated with increased angiogenesis, clinical progression and poor prognosis. Targeting eIF4E with ribavirin may therefore be an attractive therapeutic strategy for this malignancy. We studied the effects of ribavirin in a panel of breast cancer cells, representing luminal and basal-type tumors with various ER, PR and Her2 status. Western blot analysis showed that eIF4E was overexpressed compared to normal breast tissue and predominantly cytoplasmic in all of the cell lines. In addition, we examined eIF4E levels in metastatic skin lesions of three breast cancer patients and found highly elevated levels compared to normal skin. Ribavirin anti-proliferative activity was assessed using a cell viability assay and clonogenic assays were performed to examine changes in both anchorage dependent and -independent growth. At clinically relevant concentrations, the majority of the cell lines responded to ribavirin, with varying sensitivity. Inhibition of cell growth was associated with decreased protein levels of eIF4E targets such as cyclin D1 and survivin, and a reduction in phosphorylation of Akt as well as eIF4E binding protein 1 (4E-BP1) were observed. Cell cycle analysis showed that ribavirin caused a significant S-phase arrest in sensitive cells, while apoptosis was only observed at elevated concentrations of the drug. This data encourages further study of ribavirin as a breast cancer therapeutic and identification of potential combination regimens. A clinical trial of single agent ribavirin in patients with advanced metastatic breast cancer is planned in the near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3165.

Magnetic resonance spectroscopy findings in a case of hyperglycaemic hemianopia

Patients with nonketotic hyperglycaemia may present with neurological manifestations, including hemianopia. Thus far, the pathophysiology of such neurological events remains unknown, although the findings on magnetic resonance imaging (MRI) may help to elucidate the underlying mechanisms. This report describes a patient who had an episode of homonymous hemianopia, which coincided with a state of nonketotic hyperglycaemia. Initial MRI showed hypointense areas on T2-weighted and FLAIR sequences, involving the internal portion of the right occipital cortex and adjacent white matter, with mild hyperintensity on diffusion-weighted imaging. Magnetic resonance spectroscopy revealed significant increases in cerebral metabolites. Dramatic clinical and neuroimaging improvements were progressively observed over 3 weeks, following rehydration and normalization of blood glucose levels with insulin therapy. In this patient, magnetic resonance spectroscopy was used in combination with other neuroimaging methods and clinical evidence to suggest that hyperosmolality leading to intracellular dehydration in localized brain regions should be considered a potential underlying mechanism responsible for reversible neurological symptoms in nonketotic hyperglycaemia.

A Message from the New Editor-in-Chief

Cancer Research is the flagship publication of one of the largest scientific societies in the field and its most frequently cited journal. This exceptional resource has a long history of communicating studies of broad interest and high impact in basic, translational, and clinical aspects of oncology. Building on the outstanding leadership of the previous Editor-in-Chief and his team, the new editorial team seeks to continue to expand the breadth, influence, and quality of the journal, which is well situated to extend its stature as the field's leading scientific society journal.A key strength of Cancer Research is the interest of its content to the field as a whole, which encompasses a broad and diverse readership. Looking to the future, the incoming editorial team will continue to focus on publishing studies with the highest impact and broadest significance. We will also offer other content and editorial improvements to assist readers in gaining a cross-disciplinary grasp of diverse areas of the field. We will deepen the general core excellence in pathobiology, particularly in the exciting and rapidly growing areas of tumor microenvironment and immunology, capturing the most seminal work. Overall, the editorial team will work to continue the tradition of Cancer Research as the cancer community's most vital publication, strengthening its focus on broad-reaching, high-impact studies that inform solutions to the personal, clinical, and societal problems posed by cancer.The new editorial team has been expanded and rebalanced to reflect priorities for the journal as well as areas of expertise where submissions are received and distributed. Changes have been made in the categories for submission and in the number of editors in each category to improve editorial efficiencies. In particular, the number and balance in expertise of the Senior Editors and Editorial Board members who handle manuscripts has been matched more closely to the category in which manuscripts are received. By reducing the workload in high submission categories, this change should help enhance review efficiency. The roles and responsibilities for the different editors of the journal are as follows:Cancer Research has matured to become a highly translational enterprise. It is exciting to behold the field as it enters what may be a golden age of applications of modern concepts to create dramatic clinical improvements in cancer diagnosis, prognosis, and treatment. For those who seek the elimination of the scourge of disease, Cancer Research will continue to serve as the leading venue for publishing high-impact findings of the broadest significance to the field, along with other content to enlighten and integrate the field's efforts to change the fate of those suffering from cancer.

Access to highly active antiretroviral therapy for injection drug users: adherence, resistance, and death

Injection drug users (IDUs) continue to comprise a major risk group for HIV infection throughout the world and represent the focal population for HIV epidemics in Asia and Eastern Europe/Russia. HIV prevention programs have ranged from HIV testing and counseling, education, behavioral and network interventions, drug abuse treatment, bleach disinfection of needles, needle exchange and expanded syringe access, as well as reducing transition to injection and primary substance abuse prevention. With the advent of highly active antiretroviral therapy (HAART) in 1996, dramatic clinical improvements have been seen. In addition, the treatment's impact on reducing HIV viral load (and therefore transmission by all routes) provides a stronger rationale for an expansion of the focus on prevention to emphasize early identification and treatment of HIV infected individuals. However, treatment of IDUs has many challenges including adherence, resistance and relapse to high risk behaviors, all of which impact issues of access and ultimately effectiveness of potent antiretroviral treatment. A major current challenge in addressing the HIV epidemic revolves around an appropriate approach to HIV treatment for IDUs.