Precision QALYs, Precisely Unjust.

Warwick Heale has recently defended the notion of individualized and personalized Quality-Adjusted Life Years (QALYs) in connection with health care resource allocation decisions. Ordinarily, QALYs are used to make allocation decisions at the population level. If a health care intervention costs £100,000 and generally yields only two years of survival, the cost per QALY gained will be £50,000, far in excess of the £30,000 limit per QALY judged an acceptable use of resources within the National Health Service in the United Kingdom. However, if we know with medical certainty that a patient will gain four extra years of life from that intervention, the cost per QALY will be £25,000. Heale argues fairness and social utility require such a patient to receive that treatment, even though all others in the cohort of that patient might be denied that treatment (and lose two years of potential life). Likewise, Heale argues that personal commitments of an individual (religious or otherwise), that determine how they value a life-year with some medical intervention, ought to be used to determine the value of a QALY for them. I argue that if Heale's proposals were put into practice, the result would often be greater injustice. In brief, requirements for the just allocation of health care resources are more complex than pure cost-effectiveness analysis would allow.

Controlling Healthcare Costs: Just Cost Effectiveness or "Just" Cost Effectiveness?

Meeting healthcare needs is a matter of social justice. Healthcare needs are virtually limitless; however, resources, such as money, for meeting those needs, are limited. How then should we (just and caring citizens and policymakers in such a society) decide which needs must be met as a matter of justice with those limited resources? One reasonable response would be that we should use cost effectiveness as our primary criterion for making those choices. This article argues instead that cost-effectiveness considerations must be constrained by considerations of healthcare justice. The goal of this article will be to provide a preliminary account of how we might distinguish just from unjust or insufficiently just applications of cost-effectiveness analysis to some healthcare rationing problems; specifically, problems related to extraordinarily expensive targeted cancer therapies. Unconstrained compassionate appeals for resources for the medically least well-off cancer patients will be neither just nor cost effective.

Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited.

Inhibitors of poly(ADP-ribose) polymerases actualized the biological concept of synthetic lethality in the clinical practice, yielding a paradigmatic example of translational medicine. The profound sensitivity of tumors with germline BRCA mutations to PARP1/2 blockade owes to inherent defects of the BRCA-dependent homologous recombination machinery, which are unleashed by interruption of PARP DNA repair activity and lead to DNA damage overload and cell death. Conversely, aspirant BRCA-like tumors harboring somatic DNA repair dysfunctions (a vast entity of genetic and epigenetic defects known as "BRCAness") not always align with the familial counterpart and appear not to be equally sensitive to PARP inhibition. The acquisition of secondary resistance in initially responsive patients and the lack of standardized biomarkers to identify "BRCAness" pose serious threats to the clinical advance of PARP inhibitors; a feeling is also emerging that a BRCA-centered perspective might have missed the influence of additional, not negligible and DNA repair-independent PARP contributions onto therapy outcome. While regulatory approval for PARP1/2 inhibitors is still pending, novel therapeutic opportunities are sprouting from different branches of the PARP family, although they remain immature for clinical extrapolation. This review is an endeavor to provide a comprehensive appraisal of the multifaceted biology of PARPs and their evolving impact on cancer therapeutics.

Oral targeted therapy for cancer.

Oral targeted therapies are increasingly being used to treat cancer. They work by interfering with specific molecules or pathways involved in tumour growth. It is essential that health professionals managing patients taking these drugs have appropriate training and skills. They should be aware of potential adverse effects and drug interactions, and be able to manage toxicities when they occur. Despite the selectivity of these targeted therapies, they still have serious adverse effects including skin reactions, diarrhoea and altered organ function.

Hydrogen-bonded cytosine-endowed supramolecular polymeric nanogels: Highly efficient cancer cell targeting and enhanced therapeutic efficacy.

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy-and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.

CD147: an integral and potential molecule to abrogate hallmarks of cancer.

CD147 also known as EMMPRIN, basigin, and HAb18G, is a single-chain type I transmembrane protein shown to be overexpressed in aggressive human cancers of CNS, head and neck, breasts, lungs, gastrointestinal, genitourinary, skin, hematological, and musculoskeletal. In these malignancies, the molecule is integral to the diverse but complimentary hallmarks of cancer: it is pivotal in cancerous proliferative signaling, growth propagation, cellular survival, replicative immortality, angiogenesis, metabolic reprogramming, immune evasion, invasion, and metastasis. CD147 also has regulatory functions in cancer-enabling characteristics such as DNA damage response (DDR) and immune evasion. These neoplastic functions of CD147 are executed through numerous and sometimes overlapping molecular pathways: it transduces signals from upstream molecules or ligands such as cyclophilin A (CyPA), CD98, and S100A9; activates a repertoire of downstream molecules and pathways including matrix metalloproteinases (MMPs)-2,3,9, hypoxia-inducible factors (HIF)-1/2α, PI3K/Akt/mTOR/HIF-1α, and ATM/ATR/p53; and also functions as an indispensable chaperone or regulator to monocarboxylate, fatty acid, and amino acid transporters. Interestingly, induced loss of functions to CD147 prevents and reverses the acquired hallmarks of cancer in neoplastic diseases. Silencing of Cd147 also alleviates known resistance to chemoradiotherapy exhibited by malignant tumors like carcinomas of the breast, lung, pancreas, liver, gastric, colon, ovary, cervix, prostate, urinary bladder, glioblastoma, and melanoma. Targeting CD147 antigen in chimeric and induced-chimeric antigen T cell or antibody therapies is also shown to be safer and more effective. Moreover, incorporating anti-CD147 monoclonal antibodies in chemoradiotherapy, oncolytic viral therapy, and oncolytic virus-based-gene therapies increases effectiveness and reduces on and off-target toxicity. This study advocates the expedition and expansion by further exploiting the evidence acquired from the experimental studies that modulate CD147 functions in hallmarks of cancer and cancer-enabling features and strive to translate them into clinical practice to alleviate the emergency and propagation of cancer, as well as the associated clinical and social consequences.

Targeted Cancer Therapies Causing Elevations in Serum Creatinine Through Tubular Secretion Inhibition: A Case Report and Review of the Literature.

Rationale: Targeted cancer therapies have revolutionized the field of oncology by selecting for specific molecular pathways, thus improving overall clinical prognosis. However, many of these targeted treatments have been reported to have adverse kidney effects, including acute kidney injury, interstitial nephritis, and glomerular disease. Furthermore, some of these targeted therapies have also been found to cause an asymptomatic rise in serum creatinine levels through inhibition of active tubular secretion. Presenting concerns: A 79-year-old woman was being followed for stage 4 A2 chronic kidney disease secondary to type 2 diabetes and longstanding hypertension. She was diagnosed with invasive mammary carcinoma and was initiated on letrozole, an aromatase inhibitor, and palbociclib, a selective cyclin-dependent kinase inhibitor, was subsequently added. Prior to the initiation of her treatments, her baseline estimated glomerular filtration rate (eGFR) fluctuated between 25 and 28 mL/min/1.73 m2 over the previous year. After initiating palbociclib, her serum creatinine progressively increased, despite having well-controlled blood pressure and diabetes. In addition, there was no history of pre-renal events nor any sonographic evidence of obstruction. Within 7 months, her eGFR based on serum creatinine had decreased down to 12 mL/min/1.73 m2. Interventions: Given that there were no clinical or other biochemical changes suggestive of worsening renal function, a serum cystatin C was measured using an immunoturbidimetric assay, which was 1.71 mg/L and correlated with an eGFR of 33 mL/min/1.73 m2 based on the chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C equation (2012). This value was consistent with her previous baseline. Based on these findings, the significant decrease in eGFR measured by serum creatinine was attributed to the inhibitory effects of palbociclib on tubular creatinine secretion, rather than representing true kidney damage. Thus, a kidney biopsy was not performed in this context. Outcomes: Seven months later, a repeat serum cystatin C was repeated to assess for any worsening of the patient's kidney function and revealed an eGFR of 35 mL/min/1.73 m2 based on the CKD-EPI cystatin C equation (2012), thus revealing stable kidney function and reinforcing the inhibitory effects of palbociclib on tubular creatinine secretion through its direct effects on kidney transporters. Teaching points: This case report and literature review acknowledges the importance of using alternative methods of assessing kidney function when patients are undergoing targeted cancer therapies known to affect tubular creatinine secretion, which include cyclin-dependent kinase 4/6 inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, tyrosine kinase inhibitors, and mesenchymal-epithelial transition inhibitors. The use of non-creatinine-based markers of glomerular filtration rate (GFR), such as cystatin C and nuclear renal scans, will allow for more accurate estimation of kidney function in the appropriate setting, thus avoiding invasive diagnostic tests and unnecessary adjustments of treatment plans. However, certain targeted cancer therapies have also been proven to cause true kidney injury; therefore, physicians must still maintain a high degree of suspicion and consider invasive investigations and/or cessation or reduction of treatments when alternative measurements of kidney function do not suggest an underestimation of GFR via serum creatinine.

Contexte: Les thérapies ciblées contre le cancer ont révolutionné le domaine de l'oncologie en sélectionnant des voies moléculaires spécifiques, ce qui améliore le pronostic clinique global. Il a toutefois été rapporté que plusieurs de ces traitements ciblés entraînent des effets indésirables sur les reins, notamment l'insuffisance rénale aiguë, la néphrite interstitielle et la glomérulonéphrite. Qui plus est, certains de ces traitements provoquent aussi une augmentation asymptomatique des taux de créatinine sérique en inhibant la sécrétion tubulaire active. Présentation du cas: Une femme de 79 ans était suivie pour une insuffisance rénale chronique de stade 4 A2 secondaire à un diabète de type 2 et à une hypertension de longue date. La patiente été diagnostiquée avec un carcinome mammaire invasif et a reçu du létrozole, un inhibiteur de l'aromatase. Un traitement au palbociclib, un inhibiteur sélectif de la kinase dépendante de la cycline, a été ajouté par la suite. Avant le début du traitement, le DFGe initial de la patiente avait fluctué de 25 à 28 ml/min/1,73 m2 lors de l'année précédente. Après avoir commencé le palbociclib, son taux de créatinine sérique a augmenté progressivement, malgré une pression artérielle et un diabète bien contrôlés. La patiente n'avait aucun antécédent d'événements pré-rénaux ni de preuves échographiques d'obstruction. En sept mois, son DFGe basé sur la créatinine sérique était passé à 12 ml/min/1,73 m2. Intervention: En absence de changements cliniques ou biochimiques suggérant une aggravation de la fonction rénale, la cystatine C sérique a été mesurée par dosage immunoturbidimétrique. Son taux (1,71 mg/L) correspondait à un DFGe de 33 ml/min/1,73 m2 obtenu par l'équation CKD-EPI (2012) pour la cystatine C; une valeur comparable à sa référence précédente. À la lumière de ces résultats, la chute significative du DFGe mesurée par la créatinine sérique a été attribuée aux effets inhibiteurs du palbociclib sur la sécrétion tubulaire de créatinine, plutôt qu'à une véritable atteinte rénale. C'est pourquoi une biopsie rénale n'a pas été effectuée. Résultats: Après sept mois, la mesure de la cystatine C sérique a été répétée pour évaluer une potentielle aggravation de la fonction rénale. Cette nouvelle mesure a révélé un DFGe de 35 ml/min/1,73 m2 obtenu avec l'équation CKD-EPI (2012) de la cystatine C, ce qui indique une fonction rénale stable et renforce le diagnostic retenu d'un effet inhibiteur du palbociclib sur la sécrétion tubulaire de créatinine dû à ses effets directs sur les transporteurs rénaux. Enseignements tirés: Ce rapport de cas et la revue de la littérature soulignent l'importance d'utiliser d'autres méthodes d'évaluation de la fonction rénale lorsque les patients suivent des traitements ciblés contre le cancer connus pour affecter la sécrétion tubulaire de créatinine, notamment les inhibiteurs de la kinase dépendante de la cycline (CDK4/6), les inhibiteurs de la polymérase poly-adénosine diphosphate ribose (PARP), les inhibiteurs de la tyrosine kinase (TK) et les inhibiteurs de la transition mésenchymateuse-épithéliale (TEM). L'utilisation de marqueurs du DFG autres que la créatinine, tels que la cystatine C et la scintigraphie rénale nucléaire, permettra une estimation plus précise de la fonction rénale dans le contexte approprié, évitant ainsi des tests diagnostiques invasifs et des ajustements inutiles des plans de traitement. On sait toutefois que certains traitements ciblés contre le cancer sont à l'origine de véritables lésions rénales. Par conséquent, les médecins doivent maintenir un haut degré de suspicion et envisager des examens invasifs et/ou l'arrêt ou la réduction des traitements lorsque d'autres mesures de la fonction rénale ne suggèrent pas une sous-estimation du DFG par la créatinine sérique.

Digital Holographic Imaging as a Method for Quantitative, Live Cell Imaging of Drug Response to Novel Targeted Cancer Therapies.

Digital holographic imaging (DHI) is a noninvasive, live cell imaging technique that enables long-term quantitative visualization of cells in culture. DHI uses phase-shift imaging to monitor and quantify cellular events such as cell division, cell death, cell migration, and drug responses. In recent years, the application of DHI has expanded from its use in the laboratory to the clinical setting, and currently it is being developed for use in theranostics. Here, we describe the use of the DHI platform HoloMonitorM4 to evaluate the effects of novel, targeted cancer therapies on cell viability and proliferation using the HeLa cancer cell line as a model. We present single cell tracking and population-wide analysis of multiple cell morphology parameters.

Regarding the Yin and Yang of Precision Cancer- Screening and Treatment: Are We Creating a Neglected Majority?

In this commentary, we submit that the current emphasis of precision cancer screening and treatment (PCST) has been to provide and interpret the implications of "positive" screening results for those deemed to be at greatest risk for cancer or most likely to benefit from targeted treatments. This is an important, but proportionately small target group, regardless of the cancer context. Overlooked by this focus is the larger majority of those screened who receive "negative" results. We contend that for optimal dissemination of PCST, the complement of positive and negative results be viewed as an inseparable yin-yang duality with the needs of those who receive negative screening results viewed as important as those deemed to be at highest risk or derive targeted treatment benefit. We describe three areas where communication of negative PCST results warrant particular attention and research consideration: population-based family history screening, germline testing for hereditary cancer syndromes, and tumor testing for targeted cancer treatment decision-making. Without thoughtful consideration of the potential for negative results to have psychological and behavioral influences, there is a potential to create a "neglected majority". This majority may be inclined to misinterpret results, disseminate inaccurate information to family, dismiss the credibility of results, or become disillusioned with existing medical treatments.

Cardiotoxicity of Novel Targeted Chemotherapeutic Agents.

PURPOSE OF REVIEW: With the continuing development of newer targeted therapies in oncology, it is necessary to understand their potential cardiovascular side effects. In this review, we discuss the association of novel targeted agents and left ventricular systolic dysfunction. RECENT FINDINGS: Within the last 5 years, multiple new agents have been developed to target specific cancer pathways and found to have off-targeted cardiotoxicity. The most recent example is the recognition of myocarditis caused by immune checkpoint inhibitors. The development of targeted cancer therapies has revolutionized oncology, but many of these agents are inherently toxic to the cardiovascular system. Nearly all vascular endothelial growth factor (VEGF) inhibitors cause cardiotoxicity to varying degrees. Epidermal growth factor receptor (EGFR) inhibitors developed since the discovery of trastuzumab are significantly less cardiotoxic than their predecessor, but still convene risk. BCR-ABL tyrosine kinase inhibitors (TKI), once thought to pose significant risk as a class effect, appear to only be cardiotoxic if they have anti-VEGF activity. The newer generation of proteasome inhibitors such as carfilzomib appears to have significant cardiotoxicity, with almost 5% of patients developing symptomatic heart failure (HF). Immune checkpoint inhibitors can very rarely cause rapidly fatal myocarditis. As of now, there are no sufficient guidelines to direct clinical care for patients on these new classes of agents, but this is likely to change as more data and clinical experience accumulate.

Targeted agents in the management of small cell lung cancer - present and future.

Lung cancer is the leading cause of cancer-related mortality worldwide and is the second most common cancer in both sexes. The small cell lung cancer (SCLC) subtype constitutes about 13% to 15% of all diagnosed lung cancers with an expected 5-year mortality of about 90%. In the past decades, various strategies used to treat newly diagnosed, relapsed or refractory SCLC have shown no significant improvement in clinical outcomes. In the genomic era of oncology, with a better understanding of tumor biology and pathway specific investigations, multiple investigational agents have been studied with the aim to improve clinical outcomes. Some of them include epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), BCR-ABL TKIs, mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, etc. All of them have been unsuccessful in adding any survival advantage. DNA repair inhibitors, immunotherapies and anti-delta-like protein 3 (DLL3) antibody-drug conjugates have also been tested so far. This article aims to review the current literature and investigational approaches to improving clinical outcomes of SCLC.

Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA's adverse event reporting system.

OBJECTIVE: To identify and summarize FDA's Adverse Event Reporting System (FAERS) cases of progressive multifocal leukoencephalopathy (PML) associated with biological and targeted cancer therapies (BTCT) that were approved between 2009 and 2015. METHODS: FAERS was searched using each BTCT name as primary or secondary suspect drug and the adverse reaction of PML. Among BTCTs with >2 case reports of PML, proportional reporting ratios (PRR) and 95% confidence intervals (CI) were calculated. RESULTS: Among 49 new BTCTs, 82 cases of PML were found for 16 drugs. Significant PRR signals were found among 7 (14.6%) BTCTs including: brentuximab (24.5, CI:14.8-40.6), ofatumumab (16.3, CI:9.6-27.4), alemtuzumab (9.9, CI:6.0-16.4), obinutuzumab (7.4, CI:2.4-22.8), ibrutinib (5.6 CI:3.0-10.5), belimumab (4.5 CI:2.3-9.0), and idelalisib (4.1, CI:1.3-12.6). Among the 82 cases with significant signals, confirmation of the diagnosis of PML using objective criteria was found in 56% of the cases. A limitation of FAERS data is that missing data are common. CONCLUSIONS: When using BTCTs, clinicians and patients consider the risk of PML versus the therapeutic benefit, particularly when used in combination with other drugs which may cause PML, such as rituximab. It is important to recognize that PML may occur in some conditions, such as chronic lymphocytic leukemia, regardless of drug therapy.

Translational modeling and simulation approaches for molecularly targeted small molecule anticancer agents from bench to bedside.

INTRODUCTION: Recent advances in molecular biology have enabled personalized cancer therapies with molecularly targeted agents (MTAs), which offer a promising future for cancer therapy. Dynamic modeling and simulation (M&S) is a powerful mathematical approach linking drug exposures to pharmacological responses, providing a quantitative assessment of in vivo drug potency. Accordingly, a growing emphasis is being placed upon M&S to quantitatively understand therapeutic exposure-response relationships of MTAs in nonclinical models. AREAS COVERED: An overview of M&S approaches for MTAs in nonclinical models is presented with discussion about mechanistic extrapolation of antitumor efficacy from bench to bedside. Emphasis is placed upon recent advances in M&S approaches linking drug exposures, biomarker responses (e.g. target modulation) and pharmacological outcomes (e.g. antitumor efficacy). EXPERT OPINION: For successful personalized cancer therapies with MTAs, it is critical to mechanistically and quantitatively understand their exposure-response relationships in nonclinical models, and to logically and properly apply such knowledge to the clinic. Particularly, M&S approaches to predict pharmacologically active concentrations of MTAs in patients based upon nonclinical data would be highly valuable in guiding the design and execution of clinical trials. Proactive approaches to understand their exposure-response relationships could substantially increase probability of achieving a positive proof-of-concept in the clinic.

Structural and functional insights on folate receptor α (FRα) by homology modeling, ligand docking and molecular dynamics.

Folate receptor α (FRα) is a cell surface, glycophosphatidylinositol (GPI)-anchored protein with a high affinity for its ligand partner, which is highly expressed in malignant cells and has been selected as a therapeutic target and marker for the diagnosis of cancer. No direct structural information is available from either X-ray diffraction or NMR on the post-translational structure of this disulfide-rich protein. Three-dimensional models of the FRα structure have been derived with the recent homology modeling packages, using the crystal structure of the riboflavin-binding protein (RfBP) as a template. Molecular dynamics trajectories have been exploited allowing successfully the formation of a full disulfide bridge network, which was expected based on the similarities between FRα and RfBP. After the selection of the best model, a folic acid molecule was docked "in silico" onto the putative binding site and its binding mode was compared with that of vintafolide, a much larger molecule designed as a chemotherapy agent targeting specifically FRα. In both cases, a 40ns molecular dynamics trajectory was calculated, providing suggestions regarding the key structural determinants driving the affinity and specificity of FRα for folic acid with respect to other folate homologues. Moreover, some other crucial experimental results related to the structure of the receptor are discussed, such as the expected location/accessibility of known immune epitopes, the set of N-linked glycosylation sites and the effect of point mutations on the impairment of folate binding. Our results may provide useful insights for studies related to folate-targeted drug delivery or cancer therapies involving folate uptake.