Reimagining Cancer: Moving from the Cellular to the Tissue Level.

The current universally accepted explanation of cancer origin and behavior, the somatic mutation theory, is cell-centered and rooted in perturbation of gene function independent of the external environmental context. However, tumors consist of various epithelial and stromal cell populations temporally and spatially organized into an integrated neoplastic community, and they can have properties similar to normal tissues. Accordingly, we review specific normal cellular and tissue traits and behaviors with adaptive temporal and spatial self-organization that result in ordered patterns and structures.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration.

Reduction of breast cancer relapses with perioperative non-steroidal anti-inflammatory drugs: new findings and a review.

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category.

Guideline-Based Peer-to-Peer Consultation Optimizes Pegfilgrastim Use With No Adverse Clinical Consequences.

Purpose: Practice guidelines do not recommend the routine use of colony-stimulating factors when there is a low risk (< 10%) of febrile neutropenia (FN). We prospectively determined whether expert peer-to-peer consultation with prescribing oncologists would improve adherence to guidelines and whether there would be any adverse events associated with that adherence.

Methods: Commencing in March 2010, we reviewed requests for pegfilgrastim from 22 community oncology practices comprising 78 physicians providing service to approximately 97,000 Medicare members.

Guideline-based peer-to-peer consultation optimizes pegfilgrastim use with no adverse clinical consequences.

Objectives: Practice guidelines do not recommend the routine use of colony-stimulating factors when there is a low risk (<10%) of febrile neutropenia (FN). We prospectively determined whether expert peer-to-peer consultation with prescribing oncologists would improve adherence to guidelines and whether there would be any adverse events associated with that adherence.

Methods: Commencing in March 2010, we reviewed requests for pegfilgrastim from 22 community oncology practices comprising 78 physicians providing service to approximately 97,000 Medicare members.

The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer.

Background: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer.

Methods: We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI.

Sunspot dynamics are reflected in human physiology and pathophysiology.

Periodic episodes of increased sunspot activity (solar electromagnetic storms) occur with 10-11 and 5-6 year periodicities and may be associated with measurable biological events. We investigated whether this sunspot periodicity characterized the incidence of Pap smear-determined cervical epithelial histopathologies and human physiologic functions. From January 1983 through December 2003, monthly averages were obtained for solar flux and sunspot numbers; six infectious, premalignant and malignant changes in the cervical epithelium from 1,182,421 consecutive, serially independent, screening Pap smears (59°9″N, 4°29″E); and six human physiologic functions of a healthy man (oral temperature, pulse, systolic and diastolic blood pressure, respiration, and peak expiratory flow), which were measured ∼5 times daily during ∼34,500 self-measurement sessions (44°56″N, 93°8″W).

Circadian transcription profile of mouse breast cancer under light-dark and dark-dark conditions.

The circadian clock exists in virtually every cell and regulates key biological processes in cells and tissues. Even in cancer cells, DNA synthesis, cell division and tumor growth are gated by the circadian clock. This study examined the gene expression profiles of transplanted mouse breast tumor cells under normal light-dark (LD) as well as constant dark (DD) conditions.

Recurrence and mortality according to estrogen receptor status for breast cancer patients undergoing conservative surgery. Ipsilateral breast tumour recurrence dynamics provides clues for tumour biology within the residual breast.

Background: The study was designed to determine how tumour hormone receptor status affects the subsequent pattern over time (dynamics) of breast cancer recurrence and death following conservative primary breast cancer resection.

Methods: Time span from primary resection until both first recurrence and death were considered among 2825 patients undergoing conservative surgery with or without breast radiotherapy. The hazard rates for ipsilateral breast tumour recurrence (IBTR), distant metastasis (DM) and mortality throughout 10 years of follow-up were assessed.

Prohibitin as an oxidative stress biomarker in the eye.

Identification of biomarker proteins in the retina and retinal pigment epithelium (RPE) under oxidative stress may imply new insights into signaling mechanisms of retinal degeneration at the molecular level. Proteomic data from an in vivo mice model in constant light and an in vitro oxidative stress model are compared to controls under normal conditions. Our proteomic study shows that prohibitin is involved in oxidative stress signaling in the retina and RPE.

Cleavage of the retinal pigment epithelium-specific protein RPE65 under oxidative stress.

The regeneration of the 11-cis-retinyl imine chromophore of rhodopsin during the visual cycle and mechanisms that control this process are central questions in the field of vision research. The retinal pigment epithelium (RPE)-specific protein RPE65 is centrally involved in the isomerization and hydrolysis of all-trans-retinyl esters. In this study, we investigated RPE65 cleavage and potential regulatory mechanisms under oxidative stress conditions.

Melatonin reprogrammes proteomic profile in light-exposed retina in vivo.

Melatonin, a small organic molecule synthesized by the pineal gland and the retina, has a variety of physiologic functions such as circadian clock pacemaker and antioxidant. Retinal melatonin is down-regulated by light and is barely detectable during the day. The absence of melatonin in the retina during prolonged light exposure may contribute to light-induced retinal degeneration.

Global breast cancer seasonality.

Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fall, both in the Northern and Southern Hemispheres, regardless of presumable menopausal status (50).

Clock genes and cancer.

Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response.

Mammalian TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control.

Timeless (Tim), a core circadian clock gene in Drosophila, is retained in mammals but has no apparent mammalian circadian clock function. Mammalian TIM is essential for ATR-dependent Chk1 activation and S-phase arrest. We report that TIM is likewise essential for ATM-dependent Chk2-mediated signaling of doxorubicin-induced DNA double strand breaks.

Circadian time-dependent tumor suppressor function of period genes.

The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture.

Circadian clock manipulation for cancer prevention and control and the relief of cancer symptoms.

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations.

Circadian disruption, Per3, and human cytokine secretion.

Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70).

The circadian clock gene Per1 suppresses cancer cell proliferation and tumor growth at specific times of day.

Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock.

Imaging multidimensional therapeutically relevant circadian relationships.

Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers.

Neuroprotective role of erythropoietin by antiapoptosis in the retina.

Erythropoietin (EPO) stimulates red blood cell production, in part by inhibiting apoptosis of the red blood cell precursors. The erythropoietic effects of EPO are circadian stage dependent. Retinal injury due to light occurs through oxidative mechanisms and is manifest by retinal and retinal pigment epithelium (RPE) cells apoptosis.

Actigraphic assessment of daily sleep-activity pattern abnormalities reflects self-assessed depression and anxiety in outpatients with advanced non-small cell lung cancer.

Objectives: We measured subjectively evaluated depression and anxiety, and objectively measured daily sleep-activity patterns in inpatients and outpatients with advanced non-small cell lung cancer (NSCLC) and determined whether cancer-associated depression and anxiety are accompanied by characteristic circadian rhythm abnormalities.

Methods: Equal numbers of inpatients (n=42) and outpatients (n=42) with advanced NSCLC were studied. Baseline depression and anxiety, assessed by the Hospital Anxiety and Depression Scale (HADS), and actigraphy were recorded before chemotherapy initiation.

Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer.

Background: Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery.