Equitable inclusion of diverse populations in oncology clinical trials: deterrents and drivers.

The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.

Pan-tissue scaling of stiffness versus fibrillar collagen reflects contractility-driven strain that inhibits fibril degradation.

Polymer network properties such as stiffness often exhibit characteristic power laws in polymer density and other parameters. However, it remains unclear whether diverse animal tissues, composed of many distinct polymers, exhibit such scaling. Here, we examined many diverse tissues from adult mouse and embryonic chick to determine if stiffness ( E tissue ) follows a power law in relation to the most abundant animal protein, Collagen-I, even with molecular perturbations. We quantified fibrillar collagen in intact tissue by second harmonic generation (SHG) imaging and from tissue extracts by mass spectrometry (MS), and collagenase-mediated decreases were also tracked. Pan-tissue power laws for tissue stiffness versus Collagen-I levels measured by SHG or MS exhibit sub-linear scaling that aligns with results from cellularized gels of Collagen-I but not acellular gels. Inhibition of cellular myosin-II based contraction fits the scaling, and combination with inhibitors of matrix metalloproteinases (MMPs) show collagenase activity is strain - not stress- suppressed in tissues, consistent with past studies of gels and fibrils. Beating embryonic hearts and tendons, which differ in both collagen levels and stiffness by >1000-fold, similarly suppressed collagenases at physiological strains of ∼5%, with fiber-orientation regulating degradation. Scaling of E tissue based on 'use-it-or-lose-it' kinetics provides insight into scaling of organ size, microgravity effects, and regeneration processes while suggesting contractility-driven therapeutics.

Monocyte chemoattractant protein-1 gene polymorphism and its serum level have an impact on anthropometric and biochemical risk factors of metabolic syndrome in Indian population.

Monocyte chemoattractant protein-1 (MCP-1), encoded by gene CCL-2 (Chemokine C-C motif 2), is the ligand of chemokine receptor CCR-2. Concurrent clinical alteration in several metabolic aspects, including central obesity, dysglycemia, dyslipidemia and hypertension, is clinically characterized as metabolic syndrome (MetS). Role of MCP-1 in each of these aspects has been established in vitro and in animal studies as well. We here report genetic association of -2518 A>G MCP-1 (rs 1024611) gene polymorphism and level of MCP-1 with MetS in North Indian subjects. We analysed (n=386, controls and n=384, MetS subjects) for MCP-1 gene polymorphism using PCR-RFLP, its serum level using ELISA, anthropometric (body mass index, waist and hip circumferences, waist-hip ratio and blood pressure) and biochemical (serum lipids, plasma glucose and insulin levels) variables in a genetic association study. The body mass index, waist circumference, hip circumference, waist-hip ratio, blood pressure, serum lipids, insulin and fasting plasma glucose level were significantly high in MetS subjects. Regression analysis showed significant correlation of body mass index, waist and hip circumference, systolic/diastolic blood pressure, fasting glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein fasting insulin and HOMA-IR with MetS. MCP-1 allele and genotype were significantly associated with MetS. Serum MCP-1 level was high in overall cases. In conclusions, the MCP-1 2518A>G (rs 1024611) polymorphism has significant impact on risk of MetS, and MCP-1 level correlates with anthropometric and biochemical risk factors of MetS.

The AURORA initiative for metastatic breast cancer.

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients.

Genomic grade adds prognostic value in invasive lobular carcinoma.

BACKGROUND: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. METHODS: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS). RESULTS: A total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HR(GG3 vs GG1) 5.6 (2.1-15.3); P < 0.001] and OS [HR(GG3 vs GG1) 7.2, 95% CI (1.6-32.2); P = 0.01]. CONCLUSIONS: GG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status.

Pertuzumab: new hope for patients with HER2-positive breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression is detected in approximately 15% to 20% of all breast cancers (BCs). A revolutionary change in the prognosis of this subgroup of patients has occurred since trastuzumab therapy was introduced into daily clinical practice. However, because trastuzumab resistance is common, new molecules with complementary and/or synergistic mechanisms of action have been developed. Pertuzumab is a new anti-HER2 humanized monoclonal antibody that prevents the formation of HER2 dimers. MATERIAL AND METHODS: A computer-based literature search was carried out using PubMed (keywords: breast neoplasm, dimerization, HER-2, pertuzumab); data reported at international meetings are included. RESULTS: This paper describes pertuzumab's mechanism of action, safety, and role in HER2-positive BCs. It also explores the role of pertuzumab as a single agent or combined with trastuzumab by reviewing data from preclinical research to ongoing clinical trials. Recently published trials, particularly the CLEOPATRA study, highlight the efficacy, tolerability, and increase in disease-free survival associated with this novel agent when combined with trastuzumab. CONCLUSION: The pertuzumab and trastuzumab anti-HER2 dual blockade is likely to represent a substantial advance for patients with HER2-positive BCs and a new milestone on the way to personalized medicine.

Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries.

BACKGROUND: The optimal management of patients with breast cancer (BC) requires the expertise of specialists from different disciplines. This has led to the evolution of multidisciplinary teams (MDTs), allowing all key professionals to jointly discuss individual patients and to contribute independently to clinical decisions. Data regarding BC MDTs in different regions and countries are scarce. METHODS: The investigators of a large global phase III adjuvant BC trial being conducted by the Breast International Group were invited to respond to a questionnaire about the extent, structure, and function of BC MDTs. RESULTS: One hundred and fifty-two responses from 39 countries were received, and remarkable differences were noted in different geographic regions. Sixty-five percent of the respondents from eastern Europe, 63% from western Europe, 35% from Asia, and 25% from South America declared that MDT was a mandatory part of BC care in their country. Ninety percent of the respondents from Europe stated their MDTs met weekly, compared with only half of the respondents from Asia. CONCLUSION: This survey is perhaps the first large-scale effort to collect information regarding BC MDTs from different parts of the world and provides objective information of frequency, composition, function, and working mechanism of BC MDTs.

Targeting miRNAs for drug discovery: a new paradigm.

The discovery of miRNAs and the establishment of it's clinical links with multiple diseases has led to a paradigm shift in the drug development pipeline of major pharmaceutical companies and has given birth to several biotechnology enterprises revolving around these magic molecules. The miRNA profiling studies over the last few years have indicated implicit involvement of miRNAs in the pathobiology of cancer, diabetes, infectious diseases as well as cardiovascular, neurological and immune system disorders. This information is currently being translated into tools for diagnosis, prognosis and predicting response to treatment. In addition, active and vigorous investigations are ongoing in several laboratories across academia and industry to decipher the precise molecular functions and mechanism of action for key miRNAs with therapeutic potential. Knowledge gained from these efforts will surely pave the way for designing effective R&D strategies and will revolutionize the way we diagnose and treat various diseases. The present review attempts to track the evolutionary progression of microRNA research from it's early infancy years to its maturity into a dynamic field of drug discovery.

Acute myeloid leukemia following radioactive iodine therapy for papillary carcinoma of the thyroid.

Radioactive iodine (RAI) therapy plays an important role in the management of thyroid malignancies. Leukemia is a very rare complication of radioactive therapy. There are very few case reports with doses below 100 mCi causing leukemia. We report a case of papillary carcinoma of the thyroid treated with 80 mCi RAI who later developed acute myeloid leukemia. Thus, all patients with thyroid carcinoma treated with RAI should undergo periodic hematological examinations irrespective of RAI dose.

Gene expression profile of ovalbumin-induced lung inflammation in a murine model of asthma.

BACKGROUND: Asthma is a chronic inflammatory disease that is associated with airway hyperresponsiveness, tissue remodeling, and airway obstruction, and that involves coordinate expression of multiple inflammatory genes in the lungs. OBJECTIVE: To evaluate the gene expression pattern in a mouse model of asthma and assess the effect of a new drug, R142571, on the gene expression profile. METHODS: Lung tissue from ovalbumin-sensitized mice was used to examine gene expression on the CodeLink oligonucleotide mouse 20 K bioarray platform. Data were validated for some genes by semiquantitative reverse-transcriptase polymerase chain reaction. RESULTS: Of the 19,736 genes represented on the microarray, expression of 378 genes was differentially regulated (215 upregulated and 163 downregulated), with at least a 2-fold change in expression (P <.05). The differentially regulated transcripts included genes known to be involved in several different biological processes, including signaling, DNA-dependent transcriptional regulation, immune response, proteolysis, and peptidolysis. Cluster analysis of the differentially regulated genes showed that at least 16 were downregulated by R142571 treatment at both of the doses used (1 and 10 mg/kg). In addition, 46 and 29 genes were downregulated at doses of 10 mg/kg and 1 mg/kg, respectively, as compared to the animals treated with vehicle. CONCLUSION: The cytokine expression pattern in our data, suggests that the murine model exhibits a predominantlyT helper 2-type response, as observed in asthmatic human subjects. Based on this study, we suggest that this mouse model would be an appropriate system for screening new drug molecules for treatment of atopic asthma.

Magnetic resonance spectroscopy in pituitary tuberculoma.

Magnetic resonance spectroscopy (MRS) is a new, noninvasive method of diagnosing a lesion in cases where magnetic resonance (MR) imaging cannot reliably differentiate between two or more possible aetiologies. This case report describes a 20-year-old pregnant woman who developed sudden onset of left-sided hemiparesis. MR imaging of the brain revealed an infarct of the right middle cerebral artery and a suprasellar mass. The endocrine workup was normal. As she was 20 weeks pregnant, the option of a transsphenoidal biopsy of the pituitary lesion was rejected in favour of MRS . It demonstrated features characteristic of a tuberculoma. She showed marked clinical improvement after she was started on anti-tuberculous drugs. MRS is a rapidly-developing diagnostic modality, and may be a useful and safe option for investigating intracranial lesions in patients who cannot undergo invasive procedures.

Increase in weight induced by muraglitazar, a dual PPARalpha/gamma agonist, in db/db mice: adipogenesis/or oedema?

BACKGROUND AND PURPOSE: Muraglitazar, a dual PPARalpha/gamma agonist, caused a robust increase in body weight in db/db mice. The purpose of the study was to see if this increase in weight was due to oedema and/or adipogenesis. EXPERIMENTAL APPROACH: The affinity of muraglitazar at PPARalpha/gamma receptors was characterized using transactivation assays. Pre-adipocyte differentiation, expression of genes for adipogenesis (aP2), fatty acid oxidation (ACO) and sodium reabsorption (ENaCgamma and Na+, K+-ATPase); haemodilution parameters and serum electrolytes were measured to delineate the role of muraglitazar in causing weight gain vis a vis rosiglitazone. KEY RESULTS: Treatment with muraglitazar (10 mg kg(-1)) for 14 days significantly reduced plasma glucose and triglycerides. Reduction in plasma glucose was significantly greater than after similar treatment with rosiglitazone (10 mg kg(-1)). A marked increase in weight was also observed with muraglitazar that was significantly greater than with rosiglitazone. Muraglitazar increased aP2 mRNA and caused adipocyte differentiation in 3T3-L1 cells similar to rosiglitazone. It also caused a marked increase in ACO mRNA in the liver of the treated mice. Expression of mRNA for ENaCgamma and Na+, K+-ATPase in kidneys was up-regulated after either treatment. Increased serum electrolytes and decreased RBC count, haemoglobin and haematocrit were observed with both muraglitazar and rosiglitazone. CONCLUSIONS AND IMPLICATIONS: Although muraglitazar has a better glucose lowering profile, it also has a greater potential for weight gain than rosiglitazone. In conclusion, muraglitazar causes both robust adipogenesis and oedema in a 14-day treatment of db/db mice as observed in humans.

Klippel Trénaunay syndrome.

Klippel-Trénaunay syndrome (KTS) is an uncommon entity. This congenital malformation is characterized by the triad of soft tissue or bony hypertrophy, cutaneous vascular malformations, and atypical venous abnormalities. We report here a case of KTS and discuss the clinical features, investigations, and management of this enigmatic condition.

The impact of genetic background on neurodegeneration and behavior in seizured mice.

We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies.

Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology.

The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimer's disease (AD). We have generated transgenic mice expressing BACE and double transgenic mice expressing BACE and the Swedish mutations of APP (SwAPP) in neurons. BACE transgenic mice did not develop beta-amyloid plaques by age of 14 months, but showed intracellular beta-amyloid immunoreactivity that was co-localized with transgenic BACE in neurons. Abeta levels were increased and AD-like pathology was accelerated in double transgenic mice expressing both BACE and SwAPP. At two months of age, early signs of extracellular Abeta deposition and reactive astrocytes were found in double transgenic, but not in single transgenic mice. Furthermore, at four months, well defined beta-amyloid deposits surrounded by activated astrocytes could be detected in the double transgenic mice. We suggest that BACE overexpression is not sufficient to produce beta-amyloid plaques, but simultaneous expression of BACE and its substrate (SwAPP) leads to an accelerated amyloid plaque formation.

Mild amyloid pathology in the primary visual system of nonagenarians and centenarians.

In order to study the patterns of Alzheimer disease (AD)-related pathology in the primary visual system of the oldest old, we performed a quantitative analysis of senile plaques (SP), diffuse beta amyloid (A beta) deposit and neurofibrillary tangle (NFT) distribution in primary area 17, and a semi-quantitative analysis in the dorsal lateral geniculate nucleus (LGN), lateral inferior pulvinar (LIP) and superior colliculus (SC) of 21 individuals aged between 93 and 102 years. Among them, 10 cases were considered as non-demented (ND), while 9 presented very mild cognitive impairment (VMCI), and 2 cases had a clinical diagnosis of AD. Silver methenamine and Gallyas staining, A beta and tau immunostaining revealed the distribution of AD lesions. In primary area 17, most cases, either ND or with VMCI displayed a low to medium number of SP. There was no significant difference in SP and A beta deposit densities between ND and VMCI groups. On the whole, 0.4--2.4% of the cross-sectional cortical area was covered with A beta deposits. Only 6 cases, either ND or with VMCI, were totally devoid of SP and diffuse A beta deposits. Among the subcortical structures, the LIP and SC exhibited low densities of SP and A beta deposits in about half of the ND and VMCI cases, while the LGN was totally spared. NFT were almost absent in area 17 and subcortical nuclei of ND and VMCI cases. These data imply that the ageing of the primary visual system in ND and VMCI nonagenarians and centenarians is characterised by the frequent development of mild amyloid pathology in area 17 in the absence of NFT. In agreement with previous studies in very old cohorts, they also suggest that amyloid deposition is not related to the early stages of the dementia process in the oldest old.

Molecular analysis of PTEN and MXI1 in primary bladder carcinoma.

Loss of heterozygosity (LOH) on 10q is associated with late-stage events in urothelial neoplastic progression. The tumor suppressor gene PTEN, which is mutated or homozygously deleted in numerous cancers, maps to a region of 10q within the reported region of minimal loss in bladder tumors. In two recent studies alterations in the PTEN gene occur at a low frequency in bladder tumors displaying 10q LOH. We have screened 35 late-stage bladder tumors for mutations in PTEN and MXI1, both genes mapping to chromosome 10q. Using single-strand conformation polymorphism analysis, we identified 6 tumors harboring mutations in PTEN and 2 additional tumors displaying homozygous deletion at this locus. No MXI1 mutations were identified within the same tumor panel. Of 16 bladder tumor cell lines analyzed, 2 showed homozygous deletion of PTEN and 3 harbored point mutations resulting in an amino acid change. Two cell lines harbored missense mutations in MXI1. We report a significantly higher frequency of PTEN alterations in bladder carcinoma (23%) than was previously recorded, with no accompanying mutations in the MXI1 gene.