Dimorphic glioblastoma with glial and epithelioid phenotypes: Clonal evolution and immune selection.

Purpose: Epithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor. Methods: Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies. Results: An epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85-90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53. Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts from myeloid cells as well as M1 and M2 macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section. Conclusion: Epithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different.

Progressive Multifocal Leukoencephalopathy After Chimeric Antigen Receptor T-Cell Therapy for Recurrent Non-Hodgkin Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy targeting cluster of differentiation (CD)19 has had a transformative impact on patient outcomes in a subset of patients with relapsed/refractory non-Hodgkin lymphoma. We present a patient with refractory large B-cell lymphoma in complete remission for 2 years following treatment with CD19-targeted CAR T-cell therapy, who presented with 2 weeks of progressive aphasia. Imaging revealed a left occipital brain lesion and biopsy demonstrated features diagnostic of progressive multifocal leukoencephalopathy. Further evaluation revealed severe hypogammaglobulinemia and a low CD4 count. She was treated with pembrolizumab and intravenous immunoglobulin resulting in decreased cerebrospinal fluid viral load without clinical improvement and died 8 weeks after presentation. This case highlights that there is potential for severe opportunistic infections after CAR T-cell therapy, including fatal progressive multifocal leukoencephalopathy. Strategies to enhance post-treatment immune reconstitution are essential to further harness the unique potency of CAR T-cell therapy.

Parkinsonism reversed from treatment of pineal non-germinomatous germ cell tumor.

BACKGROUND: Parkinsonism is a rare complication of non-germinomatous germ cell tumors (NGGCTs) arising from the pineal region. CASE DESCRIPTION: We describe a 23-year-old man who presented with Parinaud syndrome, fatigue, and hypersomnia that were caused by a pineal region NGGCT with yolk sac component and an initial α-fetoprotein (AFP) of 1011.0 ng/ml. MRI revealed that the tumor was causing 10 mm of midline shift and compressing the cerebral aqueduct, the left thalamus, and the midbrain. Obstructive hydrocephalus was relieved by ventriculoperitoneal shunting. Six cycles of induction chemotherapy with ifosfamide, carboplatin, and etoposide reduced tumor size and decreased AFP levels in both serum and cerebrospinal fluid. Following the first cycle, the patient developed asymmetric, bilateral Parkinsonism consisting of bradykinesia, bradyphrenia, facial hypomimia, drooling, and dysphagia. Levodopa, amantadine, and methylphenidate were administered and resulted in symptom improvement. Second look neurosurgery revealed residual yolk sac tumor and a second induction regimen of gemcitabine, paclitaxel, and oxaliplatin was administered for rising AFP. The patient eventually received an autologous bone marrow transplant using a regimen of high-dose carboplatin, thiotepa, and etoposide with concomitant colony-stimulating factor and romiplostim support followed by consolidative proton craniospinal radiotherapy. Posttreatment head MRI showed that no evidence of tumor growth and serum AFP was within normal limits. His Parkinsonism eventually resolved and he was weaned off all dopaminergic drugs. CONCLUSION: Bilateral Parkinsonism from NGGCT in this patient is probably caused by pressure on nigrostriatal tracts, substantia nigra, or both. The Parkinsonian symptoms can be reversed by aggressive treatment of the tumor and administration of dopaminergic drugs.

The Evolving Role of Circulating Tumor Cells in the Personalized Management of Breast Cancer: from Enumeration to Molecular Characterization.

Circulating Tumor cells (CTCs) represent tumor cells in the blood stream dislodged from the primary tumor. The presence of CTCs in the bloodstream provides a unique opportunity to sample cancer tissue by means of a relatively less-invasive "liquid biopsy." Over the past decade, there has been a tremendous increase in the amount of research examining the potential clinical utility of CTCs in the management of cancer. A number of techniques to refine the sensitivity and range of CTC assays are also in development. In this article, we review the recent developments in the current and potential clinical applications of CTCs in breast cancer. CTC enumeration already has an established role as a prognostic biomarker in metastatic breast cancer, while molecular characterization of CTCs can serve as a potential predictive biomarker for therapy selection, pharmacodynamic evaluation, and identification of novel actionable targets for novel therapies. The role of CTCs in breast cancer screening and detection of recurrence is currently limited. Further development in techniques will be pivotal in enhancing the broad applicability of CTCs and advancing the field of personalized breast cancer therapy.

Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery.

Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

Precision medicine and personalized breast cancer: combination pertuzumab therapy.

Trastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer.

Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy.

Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer.

PEGylated liposomal Gemcitabine: insights into a potential breast cancer therapeutic.

PURPOSE: Nanoencapsulation of chemotherapeutics is an established method to target breast tumors and has been shown to enhance the efficacy of therapy in various animal models. During the past two decades, the nucleoside analog Gemcitabine has been under investigation to treat both recalcitrant and localized breast cancer, often in combination with other chemotherapeutics. In this study, we investigated the chemotherapeutic efficacy of a novel Gemcitabine-encapsulated liposome previously formulated by our group, GemPo, on both sensitive (4T1) and recalcitrant (MDA-MB-231) breast cancer cell lines. METHODS: Gemcitabine free drug and liposomal Gemcitabine were compared both in vitro and in vivo using breast cancer models. RESULTS: We demonstrated that GemPo differently hindered the growth, survival and migration of breast cancer cells, according to their drug sensitivities. Specifically, whereas GemPo was a more potent cytotoxic and apoptotic agent in sensitive breast cancer cells, it more potently inhibited cell migration in the resistant cell line. However, GemPo still acted as a more potent inhibitor of migration, in comparison with free Gemcitabine, irrespective of cell sensitivity. Administration of GemPo in a 4T1-bearing mouse model inhibited tumor growth while increasing mice survival, as compared with free Gemcitabine and a vehicle control. Interestingly, the inclusion of a mitotic inhibitor, Paclitaxel, synergized only with free Gemcitabine in this model, yet was as effective as GemPo alone. However, inclusion of Paclitaxel with GemPo significantly improved mouse survival. CONCLUSIONS: Our study is the first to demonstrate the pleiotropic effects of Gemcitabine and Gemcitabine-loaded nanoparticles in breast cancer, and opens the door for a novel treatment for breast cancer patients.

P2Y12 receptor inhibition augments cytotoxic effects of cisplatin in breast cancer.

Expression of P2Y12 receptors has been documented in some cancer cell lines like C6 glioma, renal carcinoma and colon carcinoma. However, its direct role in altering response to chemotherapeutics has not been studied. In this study, we characterize the expression of P2Y12 receptor in breast cancer cell lines and evaluate its role in enhancing the cytotoxic effects of cisplatin. We observed a significant upregulation in P2Y12 expression in 4T1 breast cancer cell line with cisplatin treatment. Co-administration of P2Y12 inhibitor with cisplatin resulted in significantly higher cytotoxic response in 4T1 cancer cell line. This was mediated by HIF1α-dependent upregulation of cellular apoptotic pathways. These findings identify P2Y12 receptor as a potential target to enhance antitumor efficacy of chemotherapeutic agents like cisplatin.

Smartphone apps as a source of cancer information: changing trends in health information-seeking behavior.

There is an increased interest in smartphone applications as a tool for delivery of health-care information. There have been no studies which evaluated the availability and content of cancer-related smartphone applications. This study aims to identify and analyze cancer-related applications available on the Apple iTunes platform. The Apple iTunes store was searched for cancer-related smartphone applications on July 29, 2011. The content of the applications was analyzed for cost, type of information, validity, and involvement of health-care agencies. A total of 77 relevant applications were identified. There were 24.6 % apps uploaded by health-care agencies, and 36 % of the apps were aimed at health-care workers. Among the apps, 55.8 % provided scientifically validated data. The difference in scientific validity between the apps aimed at general population versus health-care professionals was statistically significant (P < 0.01). Seventy-nine percent of the apps uploaded by health-care agencies were found to be backed by scientific data. There is lack of cancer-related applications with scientifically backed data. There is a need to improve the accountability and reliability of cancer-related smartphone applications and encourage participation by health-care agencies to ensure patient safety.

Effect of rotating acoustic stimulus on heart rate variability in healthy adults.

Acoustic stimulus can modulate the Autonomic Nervous System. However, previous reports on this topic are conflicting and inconclusive. In this study we have shown, how rotating acoustic stimulus, a novel auditory binaural stimulus, can change the autonomic balance of the cardiac system. We have used Heart rate Variability (HRV), an indicator of autonomic modulation of heart, both in time and frequency domain to analyze the effect of stimulus on 31 healthy adults.A decrease in the heart rate accompanied with an increase in SD and RMSSD indices on linear analysis was observed post-stimulation. In the Poincaré Plot, Minor Axis (SD1), Major Axis (SD2) and the ratio SD12 (SD1/SD2) increased after the stimulation. Post stimulus greater increment of SD12 with higher lag numbers of (M) beat to beat intervals, when compared to pre stimulus values, resulted in increased curvilinearity in the SD12 vs. Lag number plot. After stimulation,value of exponent alpha of Dretended Flactuation Analysis of HRV was found to be decreased. From these characteristic responses of the heart after the stimulus, it appears that rotating acoustic stimulus may be beneficial for the sympathovagal balance of the heart.

Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity.

Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC(50) values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.

YouTube as a source of information on kidney stone disease.

OBJECTIVE: To look into effective use of popular Internet site YouTube as an information source on kidney stone disease. Urolithiasis is among the most common urological conditions, accounting for significant morbidity, however adequate education regarding simple lifestyle modifications and early recognition of symptoms can reduce recurrence and visits to emergency department. MATERIALS AND METHODS: YouTube was searched using Keywords "nephrolithiasis"; "renal calculi"; "renal stones"; and "kidney stones" for videos uploaded containing relevant information about the disease. Only videos in English were included. Two physician viewers watched each video and classified them as useful; misleading; or personal experiences. The kappa-statistic was used to measure inter-observer variability. Total-viewership; duration; rating; days since upload; source; and information content were noted RESULTS: One-hundred ninety-nine videos had relevant information about nephrolithiasis; 58.3% of the videos had useful information and 18.1% were misleading. Useful videos had 47.2% of total viewership (i.e. total no. of views) share, whereas misleading videos had 2.8%, with statistically significant difference in viewership/day and rating among useful videos vs misleading videos. Universities'channel videos provided the best overall information coverage among the useful videos (prevention = 100%, symptoms = 80%, treatments = 60%, other information = 80%). No significant difference was seen in viewership/day or rating of useful videos based on the kind of information they contained. CONCLUSIONS: YouTube has a substantial amount of information on urolithiasis. Therefore, consumer-generated outlets such as YouTube have significant potential to sway individuals' attitudes both for and against the right choice. In view of this, authoritative videos by trusted sources should be posted for dissemination of reliable information.

Principles of physics in surgery: the laws of mechanics and vectors physics for surgeons-part 2.

In this sequel, to an earlier article, we discuss the laws of Mechanics, Thermodynamics and Vectors as they apply to soft and bony tissues. These include the Laplace's Law as applied to colonic perforation, compression therapy, parturition, variceal rupture, disc herniations etc. The Pascal's Law finds use in hernia repair and the Heimlich maneuver. Trigonometrically derived components of forces, acting after suturing, show ways to reduce cut-through; the thickness and the bite of suture determines the extent of tissue reaction. The heating effect of current explains the optimum gap between the prongs of a bipolar cautery and the use of law of transfer of heat in determining relation between healthy wound healing and ambient temperature.

Association of exclusive smokeless tobacco consumption with hypertension in an adult male rural population of India.

INTRODUCTION: Tobacco consumption is a major source of mortality and morbidity in India . Prevalence of smokeless tobacco (ST) consumption in India is around 20%. Studies have shown increased prevalence of cardiovascular disease risk factors and an increased incidence of adverse cardiovascular events among the ST consumers. This is a cross-sectional study done to look into the association of exclusive smokeless tobacco consumption with hypertension, in an adult male rural population of north India. METHODS: All male residents of a village in north India above 15 years of age, who did not have any acute or chronic morbidity were included after taking an informed consent. Subjects were interviewed regarding their demographic profile, socioeconomic status and tobacco consuming habits. Current smokeless tobacco user was defined as one who has ever consumed tobacco orally in past 1 month. Blood pressure of the subjects was also recorded. Cut offs used for systolic and diastolic hypertension were 140 mm hg and 90 mm Hg respectively. RESULTS: 443 subjects were included in the study. Prevalence of exclusive ST users was 21% while 19.4% consumed both forms and 26.6% did not take any form of tobacco. Mean systolic and diastolic BP were significantly higher in exclusive ST users(systolic BP=139.2+17.4,diastolic BP = 86.8+11.5)as compared to the non users(systolic BP= 135.7+18.8 , diastolic BP= 82.6 +11.5; p value < 0.05). The prevalence of diastolic hypertension was significantly higher in exclusive ST users as compared to non users ( 40.9%, 22.9% ;p value = 0.01) . The OR for diastolic hypertension in male ST users was 2.3( 95% C.I. = 1.3-4.3). Prevalence of systolic hypertension was higher in exclusive ST users too though this was not statistically significant (43%,36.4%;p value = 0.39.). CONCLUSION: ST consumption is associated with increased prevalence of high BP in the adult male rural population.This is an indicator of increased predisposition to major adverse cardiac events later in their life time. Prevention of ST consumption could be an important intervention in preventing the ongoing upswing in prevalence of chronic heart disease.