An evaluation of chemical photoreactivity and the relationship to phototoxicity

The existing regulatory guidance for photosafety testing of new drug products states that studies are warranted for those chemicals that both absorb light in the range of 290–700 nm, and that are either applied locally/topically, or “reach” (EMEA)/“significantly partition” (FDA) to the skin or eyes. The initial in vitro study recommended for the assessment of phototoxic potential is the 3T3 Neutral Red Uptake (NRU) Assay. The current study was undertaken to establish superior triggers for the initiation of biological photosafety testing. In this study, photophysical and photochemical parameters for 40 drug or drug-like molecules were studied. Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and a fivefold cross-validation PLS algorithm were used to evaluate the relationship between subsets of photophysical and photochemical parameters with the 3T3 NRU PIF/MPE (Photo Irritation Factor/Mean Photo Effect) results. The parameters most indicative of a 3T3 NRU positive PIF or MPE score were the extent of degradation in solution, the quantum yield of formation of singlet oxygen and the relative formation of superoxide anion. The results demonstrate that while absorption of light is critical to the induction of a light-induced process, it is the resultant events that may be used to predict the 3T3 NRU assay result. It is therefore proposed that the trigger for photosafety testing be revised to include a molecular basis for photoreactivity. From this limited investigation, estimated thresholds leading to 3T3 NRU positive results due to photodegradation, formation of singlet oxygen quantum yield or a relative superoxide anion formation value are proposed.     

Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2

A 14-year-old male presented with a T4 sigmoid adenocarcinoma, <10 colonic adenomas and multiple café-au-lait macules. Family history was not suggestive of a dominant hereditary form of colorectal cancer. Evaluation of the tumor revealed abnormal immunohistochemical staining of the PMS2 protein and high frequency microsatellite instability. Germline analysis identified biallelic PMS2 missense mutations. A new cancer syndrome caused by biallelic mutations in the mismatch repair genes, including PMS2, is now emerging and is characterized by café-au-lait macules, colonic polyps and a distinctive tumor spectrum.     

The Five Factor Model of personality applied to adults who stutter

Previous research has not explored the Five Factor Model of personality among adults who stutter. Therefore, the present study investigated the five personality domains of Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness, as measured by the NEO Five Factor Inventory (NEO-FFI), in a sample of 93 adults seeking speech treatment for stuttering, and compared these scores with normative data from an Australian and a United States sample. Results revealed that NEO-FFI scores for the stuttering group were within the ‘average’ range for all five personality domains. However, adults who stutter were characterized by significantly higher Neuroticism, and significantly lower Agreeableness and Conscientiousness, than normative samples. No significant differences were found between groups on the dimensions of Extraversion and Openness. These results are discussed with reference to the relationship between personality factors among adults who stutter, their directionality, and implications for predicting treatment outcome.Learning outcomes: The reader will be able to: (1) describe the Five Factor Model of personality, including the NEO-FFI personality domains of Extraversion, Neuroticism, Openness, Agreeableness, and Conscientiousness, and (2) discuss differences in NEO-FFI domain scores between adults who stutter and normative samples, and (3) understand the clinical implications of personality profiles in terms of treatment process and outcome for adults who stutter.     

Insights into pediatric rhabdomyosarcoma research: Challenges and goals

Overall survival rates for pediatric patients with high‐risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.     

Limitations in health care access and utilization among long‐term survivors of adolescent and young adult cancer

BACKGROUND:

Health care outcomes for long‐term survivors of adolescent and young adult (AYA) cancer were compared with young adults without a cancer history, using the 2009 Behavioral Risk Factor Surveillance System data.

METHODS:

Eligible participants were 20 to 39 years of age. There were N = 979 who self‐reported a cancer diagnosis between the ages of 15 to 34 years and were at least 5 years from diagnosis (excluding nonmelanoma skin cancer). The remaining 67,216 participants with no cancer history were used as controls. Using multivariable regressions, relative risks and 95% confidence intervals were generated to examine the relationship of survivor status on indicators of poor health care (uninsured, no personal health care provider, no routine care, and avoiding seeing a doctor due to cost). Adjusted proportions were calculated by demographic groups. Results are weighted by Behavioral Risk Factor Surveillance System survey design.

RESULTS:

Although the proportion uninsured did not differ (21% of survivors vs 23% of controls), AYA survivors reported forgoing care due to cost at higher levels than controls (relative risk = 1.67, 95% CI = 1.44‐1.94). Cost barriers were particularly high for survivors aged 20 to 29 years (44% vs 16% of controls; P < .001) and female survivors (35% vs 18% of controls; P < .001). Survivors reporting poorer health had more cost barriers. Moreover, uninsured survivors tended to report lower use of health care than did controls.

CONCLUSIONS:

AYA cancer survivors may forgo health care due to cost barriers, potentially inhibiting the early detection of late effects. Expanding health insurance coverage for young cancer survivors may be insufficient without adequate strategies to reduce their medical cost burdens. Cancer 2012. © 2012 American Cancer Society.