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Background: The Phase 3 CT-P6 3.2 study demonstrated equivalent efficacy and comparable safety between CT-P6 and reference trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer after up to 3 years' follow-up. Objective: To investigate long-term survival with CT-P6 and reference trastuzumab. Methods: In the CT-P6 3.2 study, patients with HER2-positive early breast cancer were randomised to neoadjuvant chemotherapy with CT-P6 or reference trastuzumab, surgery, and adjuvant CT-P6 or reference trastuzumab before a 3-year post-treatment follow-up. Patients who completed the study could enter a 3-year extension (CT-P6 4.2 study). Data were collected every 6 months to assess overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Results: Of 549 patients enrolled in the CT-P6 3.2 study, 216 (39.3%) patients continued in the CT-P6 4.2 study (CT-P6, 107; reference trastuzumab, 109) (intention-to-treat extension set). Median follow-up was 76.4 months for both groups. Medians were not reached for time-to-event parameters; estimated hazard ratios (95% confidence intervals) for CT-P6 versus reference trastuzumab were 0.59 (0.17–2.02) for OS, 1.07 (0.50–2.32) for DFS, and 1.08 (0.50–2.34) for PFS. Corresponding 6-year survival rates in the CT-P6 and reference trastuzumab groups, respectively, were 0.96 (0.90–0.99) and 0.94 (0.87–0.97), 0.87 (0.78–0.92) and 0.89 (0.81–0.94), and 0.87 (0.78–0.92) and 0.89 (0.82–0.94). Conclusions: Data from this extended follow-up of the CT-P6 3.2 study demonstrate the comparable long-term efficacy of CT-P6 and reference trastuzumab up to 6 years. EudraCT number: 2019-003518-15 (retrospectively registered 10 March 2020). [ABSTRACT FROM AUTHOR]

Simple Summary: Nanoparticle radiosensitizers can be used to increase the efficacy of radiotherapy. In this work a multiscale computational model has been developed to assess the distribution of nanoparticles during and after intratumoural injection into a realistic tumour. The aim of the study is to assess how particle surface charge and injection location can affect the distribution of nanoparticles within the tumour, with the optimal result being a uniform concentration across the tumour. This work aims to aid the development of radiosensitizers and guide clinical trials. Radiosensitizers have proven to be an effective method of improving radiotherapy outcomes, with the distribution of particles being a crucial element to delivering optimal treatment outcomes due to the short range of effect of these particles. Here we present a computational model for the transport of nanoparticles within the tumour, whereby the fluid velocity and particle deposition are obtained and used as input into the convection-diffusion equation to calculate the spatio-temporal concentration of the nanoparticles. The effect of particle surface charge and injection locations on the distribution of nanoparticle concentration within the interstitial fluid and deposited onto cell surfaces is assessed. The computational results demonstrate that negatively charged particles can achieve a more uniform distribution throughout the tumour as compared to uncharged or positively charged particles, with particle volume within the fluid being 100% of tumour volume and deposited particle volume 44.5%. In addition, varying the injection location from the end to the middle of the tumour caused a reduction in particle volume of almost 20% for negatively charged particles. In conclusion, radiosensitizing particles should be negatively charged to maximise their spread and penetration within the tumour. Choosing an appropriate injection location can further improve the distribution of these particles. [ABSTRACT FROM AUTHOR]

Radio-sensitizing nanoparticles are a potential method to increase the damage caused to cancerous cells during the course of radiotherapy. The distribution of these particles in a given targeted tumour is a relevant factor in determining the efficacy of nanoparticle-enhanced treatment. In this study, a three-part mathematical model is shown to predict the distribution of nanoparticles after direct injection into a tumour. In contrast with previous studies, here, a higher value of diffusivity for charged particles was used and the concentration profile of deposited particles was studied. Simulation results for particle concentrations both in the interstitial fluid and deposited onto cells are compared for different values of particle surface charges during and after injection. Our results show that particles with a negative surface charge can spread farther from the injection location as compared to uncharged particles with charged particles occupying 100% of the tumour volume compared to 8.8% for uncharged particles. This has implications for the future development of radiosensitizers and any associated trials. [ABSTRACT FROM AUTHOR]

The article presents research report on Janus kinase inhibitors (JAK) inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Topics include mortality benefit in patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse event; and cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

The article focuses on most persons who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are asymptomatic or have only mild-to-moderate symptoms, whereas others have progression to severe disease, characterized by acute respiratory distress encompassing pulmonary hyper inflammation and endothelial and broad multisystem dysfunction. Topics include the number of drugs have been developed or repurposed to prevent clinical deterioration.

Purpose: Access to trastuzumab, a valuable anti-cancer treatment, can be limited by cost. The primary aim of this study was to evaluate and compare the PK profiles of CT-P6, a biosimilar of trastuzumab, and US-licensed reference trastuzumab (Herceptin®) in healthy subjects. Secondary study aims included comparison of the safety and immunogenicity of CT-P6 and reference trastuzumab in these subjects.Methods: We performed a single-dose, randomised, double-blind, parallel group study (NCT02665637) comparing CT-P6 with reference trastuzumab (6 mg/kg, 90 min intravenous infusion) in 70 healthy adult males. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks post-dose. Primary endpoints were area under the serum concentration-time curve (AUC) from time 0 to infinity (AUCinf); AUC from time 0 to last quantifiable concentration (AUClast); and observed maximum serum concentration (Cmax). The pre-determined equivalence criterion was a 90% confidence interval of 80-125% for ratios of geometric least squares (LS) means.Results: Equivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference trastuzumab) of geometric LS means (90% confidence interval) were: AUCinf 99.05 (93.00, 105.51); AUClast 99.30 (92.85, 106.20); Cmax 96.58 (90.93, 102.59). Safety profiles were similar; treatment-emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive for anti-drug antibodies.Conclusions: These data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of CT-P6-in which equivalent neoadjuvant efficacy to reference trastuzumab has been demonstrated-is ongoing. [ABSTRACT FROM AUTHOR]

Background. Targeted treatments have been incorporated into oncology protocols, often with more traditional therapies, and are not totally free of adverse reactions, some of which affect the orofacial region. Methods. The authors searched PubMed, the Cochrane Library, and the US Food and Drug Administration Approved Drug Products database to identify reported adverse effects of targeted agents in the orofacial region as well as other implications in oral health care. Their principal focus was the relatively newer category of molecularly targeted drugs which are called small molecules (SMs). Results. The authors identified several categories of SMs and biological agents (for example, monoclonal antibodies) with adverse effects in the orofacial region. The oral and perioral regions are also fields for which there are therapeutic applications for targeted therapies, particularly to treat malignant neoplasms such as head and neck cancers. Conclusions. SMs are the most rapidly growing group of targeted cancer treatments. Patients receiving SMs and other targeted antineoplastic agents may require oral medicine advice and special-care dentistry. Practical Implications. In this narrative review, the authors focus mainly on the orofacial adverse effects of targeted cancer therapies and outline many of the agents that are in use so the dentally focused reader can familiarize themselves with these adverse effects and agents. [ABSTRACT FROM AUTHOR]

Background: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.Methods: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.Findings: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).Interpretation: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.Funding: Celltrion Inc. [ABSTRACT FROM AUTHOR]

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma.Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected.Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01).Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study. [ABSTRACT FROM AUTHOR]

Summary: The characterisation of CTCs (circulating tumour cells) and cfDNA (circulating free DNA) by Salvianti et al. highlight critical aspects of these approaches' relative strengths, weaknesses, and interdependencies in this study. [ABSTRACT FROM AUTHOR]

The characterisation of CTCs (circulating tumour cells) and cfDNA (circulating free DNA) by Salvianti et al. highlight critical aspects of these approaches' relative strengths, weaknesses, and interdependencies in this study. [ABSTRACT FROM AUTHOR]

BACKGROUND Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-of-care therapeutics available is small. The rarity of this tumor, combined with the wide range of subtypes, leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with a variety of common solid tumors who received treatment with drug regimens that were first tested in patient-derived xenografts using a proprietary method ('TumorGrafts'). METHODS Tumors resected from 29 patients with sarcoma were implanted into immunodeficient mice to identify drug targets and drugs for clinical use. The results of drug sensitivity testing in the TumorGrafts were used to personalize cancer treatment. RESULTS Of 29 implanted tumors, 22 (76%) successfully engrafted, permitting the identification of treatment regimens for these patients. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 13 of 16 (81%) of the remaining individuals. No patients progressed during the TumorGraft-predicted therapy. CONCLUSIONS The current data support the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors such as sarcomas. A randomized phase 3 trial versus physician's choice is warranted. Cancer 2014;120:2006-2015. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. [ABSTRACT FROM AUTHOR]

Genes involved in the carcinogenetic mechanisms underlying malignant pleural mesothelioma (MPM) are still poorly characterized. So far, mesothelin (MSLN) has aroused the most interest. It encodes for a membrane glycoprotein, frequently over-expressed in various malignancies such as MPM, and ovarian and pancreatic cancers. It has been proposed as a diagnostic and immunotherapeutic target with promising results. However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity. To date, such a gene-level inhibition has been attempted in two studies only, both on pancreatic and ovarian carcinoma cell lines, with the use of silencing RNA approaches. With regard to MPM, only one cell line (H2373) has been employed to study the effects of MSLN depletion. Indeed, the knowledge on the role of MSLN in MPM needs expanding. Accordingly, we investigated the expression of MSLN in a panel of three MPM cell lines, i.e. NCI-H28, Mero-14, and IstMes2; one non-MPM cell line was used as reference (Met5A). MSLN knock-down experiments on MSLN-overexpressing cells were also performed through silencing RNA (siRNA) to verify whether previous findings could be generalized to a different set of cell cultures. In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells. Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin. In summary, our findings confirm that MSLN should be considered a key molecular target for novel gene-based targeted therapies of cancer. [ABSTRACT FROM AUTHOR]

Background: Analysis of circulating tumor cells (CTCs) provides real-time measures of cancer sub-populations with potential for CTC-directed therapeutics. We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR-positive pool of CTCs, which may in turn lead to clinical benefits. Patients and Methods: Patients with metastatic breast cancer and HER2 non-amplified primary tumors with EGFR-positive CTCs were recruited and lapatinib 1500 mg daily was administered, in a standard two step phase 2 trial. Results: There were no responses leading to termination at the first analysis with 16 patients recruited out of 43 screened. In 6 out of 14 (43%) individuals eligible for the efficacy analysis, a decrease in CTCs was observed with most of these having a greater decrease in their EGFR-positive CTC pool. Conclusions: This is one of the first studies of CTC-directed therapeutics and suggests that lapatinib monotherapy is not having any demonstrable clinical effects by reducing the EGFR-positive pool of CTCs in HER2 non-amplified primary tumors. Our attempt to expand the pool of patients eligible for a targeted therapy was unsuccessful; the role of clonal populations in cancer biology and therapeutic strategies to control them will require extensive evaluation in years to come. Trial Registration: Clinical trials.gov NCT00820924 [ABSTRACT FROM AUTHOR]

Background & Aims: Outcome prediction is uniquely different in hepatocellular carcinoma (HCC) as the progressive functional impairment of the liver impacts patient survival independently of tumour stage. As chronic inflammation is associated with the pathogenesis of HCC, we explored the prognostic impact of a panel of inflammatory based scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in independent cohorts. Methods: Inflammatory markers, Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) scores were studied in a training set of 112 patients with predominantly unresectable HCC (75%). Independent predictors of survival identified in multivariate analysis were validated in an independent cohort of 466 patients with an overall lower tumour burden (BCLC-A, 56%). Results: In both training and validation sets, mGPS and CLIP scores emerged as independent predictors of overall survival. The predictive accuracy of the combined mGPS and CLIP score (c score 0.7, 95% CI 0.6–0.8) appeared superior to that of the CLIP score alone (c score 0.6, 95% CI 0.5–0.7). Conclusions: Systemic inflammation as measured by the mGPS, independently predicts overall survival in HCC. We have validated a novel, easy to use inflammatory score that can be used to stratify individuals. These data enable formulation of a new prognostic system, the inflammation based index in HCC (IBI). Further validation of the IBI considering treatment allocation and survival is warranted in an independent patient cohort. [ABSTRACT FROM AUTHOR]

The prevalence of breast cancer is increasing as more women are living with the disease. Outcomes have improved as a result of progress in all major aspects of multidisciplinary care. These include surgery, radiotherapy, hormonal therapy, chemotherapy and newer targeted drugs. Two aspects merit particular attention here. First, there is an understanding now that cancer is a heterogenous disease and a 'one-size-fits-all' approach is becoming redundant, albeit slowly. Second, basic science and an appreciation of cellular molecular targets in those different types of breast cancer is being translated into the clinic and has led to the development of exciting new drugs for both triple negative and HER2-positive relapsed disease. An improved understanding of endocrine resistance remains an unmet need in drug development and here, it appears worthwhile to adopt less conventional approaches. Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effectiveness. [ABSTRACT FROM AUTHOR]

HIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals. [ABSTRACT FROM AUTHOR]

The article discusses a study on the prognostic significance of a combined dexamethasone and diethylstilbestrol (DS) therapy by measuring the prostate-specific antigen (PSA) level before and after a month of DS therapy. An assessment of the prognostic patients factors was done 30 days after the start of DS therapy. The study indicates that the prognostic index developed showed the possibility of identifying patients with castrate-resistant prostate cancer (CRPC) who had a good prognosis within a month of DS therapy.

The article presents a study on the characteristics, treatment and clinical outcomes of HIV-infected patients with primary epithelial neoplasms of the esophagus. The study examined data obtained from various cases of primary esophageal malignant neoplasms in HIV-infected persons, and recognized 19 patients with squamous cell carcinoma and adenocarcinoma in the esophagus. The study showed that moderate immunosuppression and lifestyle habits are associated with HIV-related esophageal carcinoma.

Summary: Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30mg/m2 for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3–11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM. [Copyright &y& Elsevier]

In this article, the authors discuss three potential regulatory solutions to better enable the development and commercialization of therapeutic cancer vaccines. The solutions include a proposed cost-recovery program from the U.S. Food and Drug Administration, conditional marketing authorization and a development paradigm. According to the authors, the solutions aim to balance a complex equation of biologic rationale, weight of the evidence for efficacy and safety, regulatory expectations, and cost and timeline of clinical development.

A letter to the editor is presented in response to the article "High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors," by L.H. Einhorn, S.D. Williams and colleagues in the July 26, 2007 issue.

Generally physicians have a legal and ethical obligation of keeping confidentiality regarding their communication with patients and it is clear that we all have rights. The application of rights theorem, which usually refers to the recognition of individual human rights, to the deceased offers possible answers to the problematic question of patient confidentiality after death. Philosophical considerations broadly support utilitarian ideals concerning the `common good'. However, it may be possible to rank rights according to a hierarchy of need and thus preserve individual rights where they do not impinge upon the publics' right to protection from harm and the physician's right to tell the truth. This has broad implications for confidentiality, anonymity and health care information in general for patients, their families and healthcare workers. We discuss these issues, with specific reference to an individual case. [ABSTRACT FROM AUTHOR]

Summary: Background: AIDS-associated Kaposi's sarcoma remains common in individuals with HIV-1 infection in the era of highly active antiretroviral therapy (HAART). We developed a simple model for predicting mortality on the basis of clinical characteristics present at the time of diagnosis of Kaposi's sarcoma. Methods: Of 5,873 individuals with HIV-1 infection, 326 (6%) developed Kaposi's sarcoma; for 262 (80%) this was their first AIDS-defining illness. We did univariate and multivariate Cox regression analyses to identify covariates predictive of overall survival and validated our model with an independent data set of 446 patients with Kaposi's sarcoma. Results: In the primary model, we developed a prognostic score from 0 to 15 starting at 10. Having Kaposi's sarcoma as the AIDS-defining illness (-3 points) and increasing CD4 count (-1 point for every complete 100 cells per mm) improved prognosis; age of 50 years or older (2 points) and having another AIDS-associated illness at the same time (3 points) conveyed a poorer prognosis. In individuals with prognostic scores of 0, 5, 10, and 15, probability of survival at 1-year was 0·993, 0·967, 0·834, and 0·378, and at 5 years was 0·984, 0·918, 0·631, and 0·084, respectively. Increasing prognostic score by 1 increased 1-year death hazard ratio by 40% (95% CI 28-53%; bootstrapped hazard ratio 1·39, 1·25-1·51). The index had concordance of 76·8% (71·7-82·3). Interpretation: We identified four prognostic factors that can be used to obtain an accurate prognostic index at diagnosis of AIDS-associated Kaposi's sarcoma. This index is widely applicable and can be used to guide therapeutic options. [ABSTRACT FROM AUTHOR]

Summary: Few genetic markers are used routinely to predict clinical effectiveness and toxic effects despite the fact that physicians and their patients are consistently confronted with this balance. Because one of the goals of pharmacogenomics is to identify individuals and target populations that might have adverse outcomes, pharmaceutical companies have been reluctant to use a strategy that might identify patients who are not eligible for a particular treatment. This view is changing because drug-discovery programmes and treatments that target specific pathways, are showing improvements in surrogate and survival endpoints. HIV and cancer are now regarded as chronic diseases, which commonly need life-long systemic treatment from the time of diagnosis. HIV and cancer medicine have used pharmacogenomics to some extent in clinical care. Common and classic features of pharmacogenomics that are related to both antiretroviral treatment and to cytotoxic treatment are discussed in this review, providing a framework for individual treatment of these diseases. [Copyright &y& Elsevier]

Human immunodeficiency virus type 1 (HIV-1) appears to adversely affect hepatitis C, but whether hepatitis C virus (HCV) has a reciprocal effect on HIV-1 infection remains a point of controversy. In a multivariate analysis of a cohort of 5832 individuals, we found that individuals coinfected with HCV and HIV-1 (prevalence of coinfection, 5.8%) had a CD4+ cell count that decreased at a rate similar to that for individuals infected with HIV-1 alone. However, coinfection was associated with a statistically significant increased likelihood of onset of an acquired immunodeficiency syndrome- defining illness or developing a CD4+ cell count of <200 cells/ mm³, compared with infection with HIV-1 alone (hazard ratio, 1.52; 95% confidence interval, 1.07-2.17). Patients who were naive to highly active antiretroviral therapy were significantly less likely to progress to either end point, because of their higher CD4+ cell counts. In conclusion, there was an increased number of adverse events in coinfected individuals, compared with individuals infected with HIV-1 alone. [ABSTRACT FROM AUTHOR]

Abstract: Cell adhesion molecules are involved in a diverse array of cellular processes. Recent data suggests that human immunodeficiency virus (HIV-1) co-opts their functions, in particular the properties of the intercellular cell adhesion molecules (ICAMs), to enhance viral infection and transmission. To investigate mechanisms that may underlie the non-progression that occurs in immunodeficiency virus-infected chimpanzees, we amplified the protein coding regions of multiple non-human primate ICAMs 1–5 and two ICAM ligands, leukocyte function-associated antigen-1 (LFA-1) and macrophage antigen 1 (Mac-1). We then employed a phylogenetic tree-based approach to comparative genomics, in order to screen for the presence of adaptive changes. Strong Darwinian positive selection in chimpanzee ICAMs 1, 2 and 3 was observed, most markedly in domains that are critical for the integrity and maintenance of ICAM-1 dimerization. As binding of ligands, including the attachment of virions, is influenced by the state of ICAM 1 dimerization, chimpanzee ICAMs may have evolved to modulate their own dimerization. In concert with previous evidence suggesting an ancient retroviral pandemic as a prominent selective force in chimpanzee evolution, adaptation of chimpanzee ICAMs may have effected a mechanism that explains the lack of immunosuppression observed following HIV-1 or simian immunodeficiency virus (SIVcpz) infection. [Copyright &y& Elsevier]

Investigates the incidence and risk of renal dysfunction in individuals receiving tenofovir disiproxil fumarate (DF) and compares this with other antiretrovirals. Finding of an alternative etiology of renal dysfunction in 90 percent of the individuals; Conclusion that tenofovir DF is not associated with renal dysfunction more frequently than other antiretroviral drugs and that the occurrence of renal dysfunction in this context is attributable to other causes.

Physicians have, for over a century, attempted to harness the potential therapeutic power of the immune system to treat patients with cancer. The discovery that cancer regression can be achieved by immune rejection of tumour antigens theoretically allows the eradication of neoplastic cells without toxicity to normal tissues. An understanding of the mode of presentation of tumour antigens, including those complexed to heat shock proteins by major histocompatibility complex (MHC) class I and class II molecules, and their recognition by CD8+ and CD4+ T cells, respectively, has further delineated the potential cancer rejection pathways involved. This also enables the sustained induction and expansion of specific anti-tumour T cells with cytolytic activity. [Copyright &y& Elsevier]

Developments in HIV-related medicine have significant implications for the practice of oncology. Although HIV is a relatively new discipline within medicine, the identification and therapeutic targeting of HIV has been rapid. Furthermore, political lobbying has sculpted scientific research and patient care. Rational drug design has reduced morbidity and mortality to such an extent that the development of predictive surrogate endpoints has been necessary to enable randomised assessments of new protocols to continue. These studies now include the routine detection of resistance to tailor specific therapies to the patient. The involvement of affected communities in dynamically modelled studies have shown the efficacy of new, preventive strategies and debates about such approaches have improved the standard of care. In this review, we discuss what oncologists can learn from the HIV epidemic. [Copyright &y& Elsevier]

Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of Kaposi's sarcoma (KS) and certain lymphoproliferations particularly in the context of human immunodeficiency virus (HIV) type 1-induced immunosuppression. The introduction of effective therapies to treat HIV has led to a decline in the incidence of KS, suggesting that immune responses may play a role in controlling KSHV infection and pathogenesis. Cytotoxic-T-lymphocyte (CTL) activity against KSHV proteins has been demonstrated; however, the identification of KSHV CTL epitopes remains elusive and problematic. Although the herpesvirus genomic layout is generally conserved, KSHV encodes a unique hypervariable protein, K1, with intense biological selection pressure at specific amino acid sites. To investigate whether this variability is partly driven by cellular immunity, we designed K1 peptides that match only the unique viral sequence for every individual studied here (autologous peptides). We identified functional CTL epitopes within K1's most variable areas, and we show that a given individual responds only to autologous peptides and not to peptides from other individuals. Furthermore, these epitopes are highly conserved sequences within KSHV isolates from a specific strain but are not conserved between different strains. We conclude that CTL recognition contributes to K1, and therefore to KSHV, evolution. [ABSTRACT FROM AUTHOR]

Classical activating alterations including exon 19 deletions and exon 21 L858R point mutations comprise the majority of epidermal growth factor receptor (EGFR) changes in non-small cell lung cancer. Patients with these exhibit excellent clinical responses to EGFR tyrosine kinase inhibitors (TKIs). However, rare alterations including point mutations, deletions, and insertions occur and are associated with poorer responses to EGFR TKIs. Herein, we report an unusual case of a patient with lung adenocarcinoma with an EGFR L747P mutation (c. 2239_2240TT>CC, p.L747P) that was initially misdiagnosed as EGFR exon 19 deletion by amplification refractory mutation system PCR, leading to gefitinib as first-line therapy. However, both the primary tumor, mediastinal lymph node, and brain metastasis progressed after 1 month. A re-examination of gene mutation status by next generation sequencing revealed an EGFR exon 19 L747P, and this case then responded to second-line chemotherapy and third-line afatinib. [ABSTRACT FROM AUTHOR]

The author reflects on the role of cell free deoxyribonucleic acid (DNA) in detecting the malignancy. He informs about the Epstein-Barr virus (EBV) which is a viral nuclear antigen and acts as an anticancer agent in the myelodysplastic syndrome. He further discusses the Kaposi sarcoma herpesvirus (KSHV) in which the proposed viral oncogenic porducts are lytic genes.

The epidermal growth factor receptor (EGFR) is a therapeutic target in a number of settings in solid malignancies, but its role in breast cancer has remained unclear and controversial. In 810 primary breast cancers derived from patients suitable for cytotoxic chemotherapy, EGFR was prospectively measured and interactions with tumour and clinical correlates were tested to observe whether postulated cross-talk mechanisms are likely to modulate breast cancer metastasis and proliferation. A minority (79 tumours, 9.8%) were EGFR positive; in a multivariate analysis the likelihood of being EGFR positive was significantly increased for patients with grade 3 disease, compared with grade 1 (OR 15.6; 95% CI 2 to 122, p=0.0001), and for oestrogen receptor-negative status compared with positive (OR 24.1; 95% CI 12.7 to 46.00, p=0.0001). EGFR expression may play a role in breast cancer proliferation, but appears unlikely to modify tumour pathology via postulated mechanisms of oestrogen receptor/EGFR-mediated cross-talk. [ABSTRACT FROM AUTHOR]

Abstract: Therapy for infection with HIV-2 remains limited. We report an HIV-2-infected patient in whom genotyping demonstrated PI, NRTI and NNRTI resistance, with a subsequent response to raltegravir- and maraviroc-based therapy. Further studies are required to assess the clinical efficacy of maraviroc in HIV-2 infection. [Copyright &y& Elsevier]

The article discusses the drug therapy for colorectal cancer in Great Britain. It notes that Bevacizumab (Avastin) is a monoclonal antibody which targets vascular endothelial growth factor receptor for treating colon cancer, kidney cancer, and gliomas. Moreover, it highlights the drug cetuximab (Erbitux) which is a monoclonal antibody targeted against human epidermal growth factor receptor.

A letter to the editor is presented which discusses the association between antiretroviral therapy and cryptogenic liver disease.

The article focuses on the importance of the host control of lytic and latent infection in human herpesvirus-8 (HHV-8). Poorly controlled and lytic HHV-8 infection, as assessed by the detection of antibodies to the lytic K8.1 antigen, and latent HHV-8 infection, as assessed by the detection of antibodies to latent nuclear antigen, were associated with an overrepresentation of a 3 locus haplotype, interleukin-4, and the functional promoter variant of interleukin-6, as well as interleukin-12A, respectively.

Temozolomide (TMZ) represents the cornerstone of therapy for glioblastoma (GBM). However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under‐investigated proteins yet to be characterized. Here, following a kinome‐wide RNAi screen, pantothenate kinase 4 (PANK4) isuncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ‐resistant GBM cell models, patient‐derived GBM cell lines, tissue samples, as well as in vivo studies, corroborates the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. Furthermore, a Tandem Mass Tag (TMT)‐based quantitative proteomic approach, reveals that PANK4 abrogation leads to a significant downregulation of a host of proteins with central roles in cellular detoxification and cellular response to oxidative stress. More specifically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. Collectively, a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM is unveiled. [ABSTRACT FROM AUTHOR]

Background: The interplay between exosomes and the tumor microenvironment (TME) remains unclear. We investigated the influence of exosomes on the TME in hepatocellular carcinoma (HCC), focusing on their mRNA expression profile. Methods: mRNA expression profiles of exosomes were obtained from exoRBase. RNA sequencing data from HCC patients’ tumors were acquired from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). An exosome mRNA-related risk score model of prognostic value was established. The patients in the two databases were divided into high- and low-risk groups based on the median risk score value, and used to validate one another. Functional enrichment analysis was performed based on a differential gene prognosis model (DGPM). CIBERSORT was used to assess the abundance of immune cells in the TME. The correlation between the expression levels of immune checkpoint-related genes and DGPM was analyzed alongside the prediction value to drug sensitivity. Results: A prognostic exosome mRNA-related 4-gene signature (DYNC1H1, PRKDC, CCDC88A, and ADAMTS5) was constructed and validated. A prognostic nomogram had prognostic ability for HCC. The genes for this model are involved in extracellular matrix, extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway. Expression of genes here had a positive correlation with immune cell infiltration in the TME. Conclusions: Our study results demonstrate that an exosome mRNA-related risk model can be established in HCC, highlighting the functional significance of the molecules in prognosis and risk stratification. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and anti-programmed death cell protein 1 (anti-PD1) have extended patient survival benefit and revolutionized cancer treatment. As ICIs rely on immune regeneration to eliminate tumor cells, they can also lead to an imbalance of immune reactions often called immune-related adverse events (irAEs). Rare irAEs such as ocular or cardiac toxicity or vasculitis are seen in less than 1% of patients receiving ICIs. Immune-related cystitis remains a rare occurrence. Herein, we describe a patient with extensive-stage small cell lung cancer (SCLC) and a history of syphilis with a complete response to second-line treatment using nivolumab plus paclitaxel who complained of urinary irritation symptoms. At biopsy, we found infiltration of CD3+ and CD8+ lymphocytes in the urothelium. Although there are reports describing immune-related cystitis in cancer patients, our case has comprehensive pathological confirmation and a differentiation diagnosis. In this report, we review other cases to elucidate clinical characteristics and discuss suitable management of this rare irAE. [ABSTRACT FROM AUTHOR]

Differentiating between pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) is crucial for the appropriate course of treatment, especially with advancements in the role of neoadjuvant chemotherapies for PDAC, compared to CCA. Furthermore, benign pancreaticobiliary diseases can mimic malignant disease, and indeterminate lesions may require repeated investigations to achieve a diagnosis. As bile flows in close proximity to these lesions, we aimed to establish a bile-based microRNA (miRNA) signature to discriminate between malignant and benign pancreaticobiliary diseases. We performed miRNA discovery by global profiling of 800 miRNAs using the NanoString nCounter platform in prospectively collected bile samples from malignant (n = 43) and benign (n = 14) pancreaticobiliary disease. Differentially expressed miRNAs were validated by RT-qPCR and further assessed in an independent validation cohort of bile from malignant (n = 37) and benign (n = 38) pancreaticobiliary disease. MiR-148a-3p was identified as a discriminatory marker that effectively distinguished malignant from benign pancreaticobiliary disease in the discovery cohort (AUC = 0.797 [95% CI 0.68–0.92]), the validation cohort (AUC = 0.772 [95% CI 0.66–0.88]), and in the combined cohorts (AUC = 0.752 [95% CI 0.67–0.84]). We also established a two-miRNA signature (miR-125b-5p and miR-194-5p) that distinguished PDAC from CCA (validation: AUC = 0.815 [95% CI 0.67–0.96]; and combined cohorts: AUC = 0.814 [95% CI 0.70–0.93]). Our research stands as the largest, multicentric, global profiling study of miRNAs in the bile from patients with pancreaticobiliary disease. We demonstrated their potential as clinically useful diagnostic tools for the detection and differentiation of malignant pancreaticobiliary disease. These bile miRNA biomarkers could be developed to complement current approaches for diagnosing pancreaticobiliary cancers. [ABSTRACT FROM AUTHOR]