background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

/pdf/bevacizumab-plus-irinotecan-fluorouracil-and-leucovorin-for-4t02v4tvt6.pdf

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

/pdf/cancer-related-inflammation-ltml0xgfd3.pdf

Cancer-related inflammation.

The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P = 0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. Conclusions The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non–small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)

/pdf/paclitaxel-carboplatin-alone-or-with-bevacizumab-for-non-4d5hxp2t6m.pdf

Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer

Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. The widely held view is that these antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Here, I review emerging evidence supporting an alternative hypothesis-that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. Drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if both are carefully scheduled. A better understanding of the molecular and cellular underpinnings of vascular normalization may ultimately lead to more effective therapies not only for cancer but also for diseases with abnormal vasculature, as well as regenerative medicine, in which the goal is to create and maintain a functionally normal vasculature.

http://science.sciencemag.org/content/sci/307/5706/58.full.pdf

Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy

Pupillometry is used clinically to evaluate retinal and optic nerve health by measuring pupillary function in response to light stimuli. We have developed an algorithm using murine pupillometric measurements to automate the analysis of pupillometric data. The raw data is filtered and thresholding is used to remove data caused by eye blinking, loss of pupil tracking, and/or head movement. Twelve physiologically relevant parameters are extracted from the collected data. Algorithm derived values do not deviate significantly from the manually calculated parameters (p ≥ 0.05). This algorithm can be used to establish normative values of pupillary light responses for humans, as well as wild-type and transgenic mouse strains, which can subsequently be used as reference metrics for characterizing the retinal phenotype of retinal disease. Furthermore, it will be instrumental in the assessment of functional visual recovery in humans and pre-clinical models of retinal degeneration and optic nerve disease following pharmacological or gene-based therapies.

Algorithm for pupillometric data analysis

Rationale, aims and objectives

Variation in the workup of rectal bleeding may result in guideline-discordant care and delayed diagnosis of colorectal cancer. Accordingly, we undertook this study to characterize primary care clinicians' initial rectal bleeding evaluation.



Methods

We studied 438 patients at 10 adult primary care practices affiliated with three Boston, Massachusetts, academic medical centres and a multispecialty group practice, performing medical record reviews of subjects with visit codes for rectal bleeding, haemorrhoids or bloody stool. Nurse reviewers abstracted patients' sociodemographic characteristics, rectal bleeding-related symptoms and components of the rectal bleeding workup. Bivariate and multivariable logistic regression models examined factors associated with guideline-discordant workups.



Results

Clinicians documented a family history of colorectal cancer or polyps at the index visit in 27% of cases and failed to document an abdominal or rectal examination in 21% and 29%. Failure to order imaging or a diagnostic procedure occurred in 32% of cases and was the only component of the workup associated with guideline-discordant care, which occurred in 27% of cases. Compared with patients at hospital-based teaching sites, patients at urban clinics or community health centres had 2.9 (95% confidence interval 1.3–6.3) times the odds of having had an incomplete workup. Network affiliation was also associated with guideline concordance.



Conclusion

Workup of rectal bleeding was inconsistent, incomplete and discordant with guidelines in one-quarter of cases. Research and improvements strategies are needed to understand and manage practice and provider variation.

/pdf/working-up-rectal-bleeding-in-adult-primary-care-practices-39d12j9v7k.pdf

Daniel C. Chung

Papers

Algorithm for pupillometric data analysis

Working up rectal bleeding in adult primary care practices

Method and apparatus for receiving listings of similar vehicles from an image

Method and apparatus for identifying vehicle information from an image

Year 2 results for a phase 3 trial of voretigene neparvovec in biallelic RPE65-mediated inherited retinal disease