Time to Surgery Following Short-Course Radiotherapy in Rectal Cancer and its Impact on Postoperative Outcomes. A Population-Based Study Across the English National Health Service, 2009-2014.

AIMS: Preoperative short-course radiotherapy (SCRT) is an important treatment option for rectal cancer. The length of time between completing SCRT and surgery may influence postoperative outcomes, but the evidence available to determine the optimal interval is limited and often conflicting. MATERIALS AND METHODS: Information was extracted from a colorectal cancer data repository (CORECT-R) on all surgically treated rectal cancer patients who received SCRT in the English National Health Service between April 2009 and December 2014. The time from radiotherapy to surgery was described across the population. Thirty-day postoperative mortality, returns to theatre, length of stay and 1-year survival were investigated in relation to the interval between radiotherapy and surgery. RESULTS: Within the cohort of 3469 patients, the time to surgery was 0-7 days for 76% of patients, 8-14 days for 19% of patients and 15-27 days for 5% of patients. There was a clear variation in relation to different patient characteristics. There was, however, no evidence of differences in postoperative outcomes in relation to interval length. CONCLUSIONS: This study suggests that the time interval between SCRT and surgery does not influence postoperative outcomes up to a year after surgery. The study provides population-level, real-world evidence to complement that from clinical trials.

Radiologist and multidisciplinary team clinician opinions on the quality of MRI rectal cancer staging reports: how are we doing?

AIM: To evaluate the current opinion of magnetic resonance imaging (MRI) reports amongst specialist clinicians involved in colorectal cancer multidisciplinary teams (CRC MDTs). MATERIALS AND METHODS: Active participants at 16 UK CRC MDTs across a population of 5.7 million were invited to complete a questionnaire, this included 22 closed and three open questions. Closed questions used ordinal (Likert) scales to judge the subjective inclusion of tumour descriptors and impressions on the clarity and consistency of the MRI report. Open (free-text) questions allowed overall feedback and suggestions. RESULTS: A total of 69 participants completed the survey (21 radiologists and 48 other CRC MDT clinicians). Both groups highlighted that reports commonly omit the status of the circumferential resection margin (CRM; 83% versus 81% inclusion, other clinicians and radiologists, respectively, p>0.05), presence or absence of extra-mural venous invasion (EMVI; 67% versus 57% inclusion, p>0.05), and lymph node status (90% inclusion in both groups). Intra-radiologist agreement across MRI examinations is reported as 75% by other clinicians. Free-text comments included suggestions for template-style reports. CONCLUSION: Both groups recognise a proportion of MRI reports are suboptimal with key tumour descriptors omitted. There are also concerns around the presentation style of MRI reports and inter- and intra-radiologist report variability. The widespread implementation of standardised report templates may improve completeness and clarity of MRI reports for rectal cancer and thus clinical management and outcomes in rectal cancer.

Wide Variation in the Use of Radiotherapy in the Management of Surgically Treated Rectal Cancer Across the English National Health Service.

AIMS: Radiotherapy is an important treatment modality in the multidisciplinary management of rectal cancer. It is delivered both in the neoadjuvant setting and postoperatively, but, although it reduces local recurrence, it does not influence overall survival and increases the risk of long-term complications. This has led to a variety of international practice patterns. These variations can have a significant effect on commissioning, but also future clinical research. This study explores its use within the large English National Health Service (NHS). MATERIALS AND METHODS: Information on all individuals diagnosed with a surgically treated rectal cancer between April 2009 and December 2010 were extracted from the Radiotherapy Dataset linked to the National Cancer Data Repository. Individuals were grouped into those receiving no radiotherapy, short-course radiotherapy with immediate surgery (SCRT-I), short-course radiotherapy with delayed surgery (SCRT-D), long-course chemoradiotherapy (LCCRT), other radiotherapy (ORT) and postoperative radiotherapy (PORT). Patterns of use were then investigated. RESULTS: The study consisted of 9201 individuals; 4585 (49.3%) received some form of radiotherapy. SCRT-I was used in 12.1%, SCRT-D in 1.2%, LCCRT in 29.5%, ORT in 4.7% and PORT in 2.3%. Radiotherapy was used more commonly in men and in those receiving an abdominoperineal excision and less commonly in the elderly and those with comorbidity. Significant and substantial variations were also seen in its use across all the multidisciplinary teams managing this disease. CONCLUSION: Despite the same evidence base, wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer across the English NHS. Prospective population-based collection of local recurrence and patient-reported early and late toxicity information is required to further improve patient selection for preoperative radiotherapy.

Implications of polygenic risk for personalised colorectal cancer screening.

BACKGROUND: We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN: We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS: Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION: Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.

The Effect of the UK Coordinating Centre for Cancer Research Anal Cancer Trial (ACT1) on Population-based Treatment and Survival for Squamous Cell Cancer of the Anus.

Between 1987 and 1994, three randomised phase III trials showed that chemoradiotherapy with mitomycin C and 5-fluorouracil was superior to radiotherapy alone (ACT1, European Organization for Research and Treatment of Cancer) or radiotherapy with 5-fluorouracil (Radiation Therapy Oncology Group 87-04, Eastern Cooperative Oncology Group 1289) for squamous cell carcinoma of the anus. We explored the population-based changes in England before, during and after the UK-based ACT1 trial. Information was extracted from the National Cancer Data Repository on patients diagnosed with squamous cell anal cancer in England between 1981 and 2010 (n = 11 743). Robust treatment information was available for the Yorkshire region (n = 1065). Changes in treatment patterns and 3 year survival were investigated in 7 year cohorts before, during and after the ACT1 trial. In Yorkshire, the proportion of patients receiving surgery alone fell from 61.6% before, 29.8% during and 12.5% after ACT1; the proportion of patients receiving primary chemoradiotherapy rose from 6.5% before, 17.7% during and 58.8% after ACT1 and continued to rise to 70.3% in the subsequent period. Three year survival improved during the study period from 59.5% (95% confidence interval 56.6-62.2) before ACT1 to 73.6% (95% confidence interval 71.9-75.2) after the trial. Survival in Yorkshire was comparable with that in England. The treatment for squamous cell carcinoma of the anus changed dramatically during the study period. The predominant use of surgery before ACT1, a transition phase during the trial and a dramatic increase in the use of chemoradiotherapy after ACT1 provide strong evidence of the effect of the trial on population-based practice. Survival continued to increase during this period.

The rising incidence of anal cancer in England 1990-2010: a population-based study.

AIM: Although anal cancer is rare, its incidence has been reported to be rising in several countries. This study aimed to determine whether there have been any changes in incidence over time in England. METHOD: In the cancer registry component of the English National Cancer Data Repository, 13 940 patients were identified with a primary diagnosis of anal cancer made between 1990 and 2010. Tumours were grouped according to the ICD-O morphology codes into squamous cell carcinoma, basaloid and cloacogenic carcinoma, adenocarcinoma and other cancer types. The incidence over this period was investigated in relation to type of tumour, age and sex. RESULTS: In men there was a 69% increase in squamous cell anal carcinoma from 0.43 per 100 000 population in 1990-94 to 0.73 in 2006-10. For women these rates were 0.50 in 1990-94 and 1.13 in 2006-10, a rise of 126%. CONCLUSION: The study showed that between 1990 and 2010 there was a substantial rise in the incidence of anal cancer in England. This effect was more marked in women than men.

Emergency presentation of cancer and short-term mortality.

BACKGROUND: The short-term survival following a cancer diagnosis in England is lower than that in comparable countries, with the difference in excess mortality primarily occurring in the months immediately after diagnosis. We assess the impact of emergency presentation (EP) on the excess mortality in England over the course of the year following diagnosis. METHODS: All colorectal and cervical cancers presenting in England and all breast, lung, and prostate cancers in the East of England in 2006-2008 are included. The variation in the likelihood of EP with age, stage, sex, co-morbidity, and income deprivation is modelled. The excess mortality over 0-1, 1-3, 3-6, and 6-12 months after diagnosis and its dependence on these case-mix factors and presentation route is then examined. RESULTS: More advanced stage and older age are predictive of EP, as to a lesser extent are co-morbidity, higher income deprivation, and female sex. In the first month after diagnosis, we observe case-mix-adjusted excess mortality rate ratios of 7.5 (cervical), 5.9 (colorectal), 11.7 (breast ), 4.0 (lung), and 20.8 (prostate) for EP compared with non-EP. CONCLUSION: Individuals who present as an emergency experience high short-term mortality in all cancer types examined compared with non-EPs. This is partly a case-mix effect but EP remains predictive of short-term mortality even when age, stage, and co-morbidity are accounted for.

A retrospective observational study of the relationship between family history and survival from colorectal cancer.

BACKGROUND: Although family history is well established to be a risk factor for developing colorectal cancer (CRC), much less is known about its impact on patient survival. This study aimed to link CRC patient data from the National Study of Colorectal Cancer Genetics (NSCCG) to the National Cancer Data Repository (NCDR) to examine the relationship between family history and the characteristics and outcomes of CRC. METHODS: All eligible NSCCG patients underwent a matching process to the NCDR using combinations of their personal identifiers. The characteristics and survival of CRC patients with and without a family history of CRC were compared. RESULTS: Of the 10 937 NSCCG patients eligible to be matched into the NCDR, 10 782 (98.6%) could be fully linked. There were no significant differences between those with and without a family history of CRC (defined as having at least one affected first-degree relative) in terms of age, sex, tumour stage at diagnosis, presence of multiple cancers, mode of presentation to hospital and surgical management, although patients with familial CRC were more likely to have right-sided tumours (P<0.01). The survival of patients with familial CRC was significantly better than those with sporadic CRC (HR 0.89, 95%CI: 0.81-0.98, P=0.02). CONCLUSION: We have demonstrated that it is possible to robustly match patients recruited into the NSCCG into the NCDR and, by using this record linkage, enable genetic data to be related to CRC phenotype, clinical management and outcome. This study provides evidence that a family history of CRC is associated with better survival after a diagnosis of CRC.

Early mortality from colorectal cancer in England: a retrospective observational study of the factors associated with death in the first year after diagnosis.

BACKGROUND: The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease. METHODS: Patients diagnosed with colon (n=65,733) or rectal (n=26,123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1-3 months and 3-12 months after diagnosis. RESULTS: In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment. CONCLUSION: Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research.

Population-based study of laparoscopic colorectal cancer surgery 2006-2008.

BACKGROUND: Clinical guidelines recommend that, where clinically appropriate, laparoscopic tumour resections should be available for patients with colorectal cancer. This study aimed to examine the introduction of laparoscopic surgery in the English National Health Service. METHODS: Data were extracted from the National Cancer Data Repository on all patients who underwent major resection for a primary colorectal cancer diagnosed between 2006 and 2008. Laparoscopic procedures were identified from codes in the Hospital Episode Statistics and National Bowel Cancer Audit Project data in the resource. Trends in the use of laparoscopic surgery and its influence on outcomes were examined. RESULTS: Of 58 135 resections undertaken over the study period, 10 955 (18·8 per cent) were attempted laparoscopically. This increased from 10·0 (95 per cent confidence interval (c.i.) 8·1 to 12·0) per cent in 2006 to 28·4 (25·4 to 31·4) per cent in 2008. Laparoscopic surgery was used less in patients with advanced disease (modified Dukes' stage 'D' versus A: odds ratio (OR) 0·45, 95 per cent c.i. 0·40 to 0·50), rectal tumours (OR 0·71, 0·67 to 0·75), those with more co-morbidity (Charlson score 3 or more versus 0: OR 0·69, 0·58 to 0·82) or presenting as an emergency (OR 0·15, 0·13 to 0·17). A total of 1652 laparoscopic procedures (15·1 per cent) were converted to open surgery. Conversion was more likely in advanced disease (modified Dukes' stage 'D' versus A: OR 1·56, 1·20 to 2·03), rectal tumours (OR 1·29, 1·14 to 1·46) and emergencies (OR 2·06, 1·54 to 2·76). Length of hospital stay (OR 0·65, 0·64 to 0·66), 30-day postoperative mortality (OR 0·55, 0·48 to 0·64) and risk of death within 1 year (hazard ratio 0·60, 0·55 to 0·65) were reduced in the laparoscopic group. CONCLUSION: Laparoscopic surgery was used more frequently in low-risk patients.

A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme.

BACKGROUND: Colorectal cancer is common in England and, with long-term survival relatively poor, improving outcomes is a priority. A major initiative to reduce mortality from the disease has been the introduction of the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP). Combining data from the BCSP with that in the National Cancer Data Repository (NCDR) allows all tumours diagnosed in England to be categorised according to their involvement with the BCSP. This study sought to quantify the characteristics of the tumours diagnosed within and outside the BCSP and investigate its impact on outcomes. METHODS: Linkage of the NCDR and BCSP data allowed all tumours diagnosed between July 2006 and December 2008 to be categorised into four groups; screen-detected tumours, screening-interval tumours, tumours diagnosed in non-participating invitees and tumours diagnosed in those never invited to participate. The characteristics, management and outcome of tumours in each category were compared. RESULTS: In all, 76 943 individuals were diagnosed with their first primary colorectal cancer during the study period. Of these 2213 (2.9%) were screen-detected, 623 (0.8%) were screening-interval cancers, 1760 (2.3%) were diagnosed in individuals in non-participating invitees and 72 437 (94.1%) were diagnosed in individuals not invited to participate in the programme due to its ongoing roll-out over the time period studied. Screen-detected tumours were identified at earlier Dukes' stages, were more likely to be managed with curative intent and had significantly better outcomes than tumours in other categories. CONCLUSION: Screen-detected cancers had a significantly better prognosis than other tumours and this would suggest that the BCSP should reduce mortality from colorectal cancer in England.

Comparison of treatment and outcome information between a clinical trial and the National Cancer Data Repository.

BACKGROUND: Clinical trials are important but many factors limit their success, including the costs of long-term follow-up and participants often not being representative of the general population. The National Cancer Data Repository (NCDR) contains data about patients with cancer in England that may help overcome some of these problems. This study compared treatment and outcome information between the Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC) trial and the NCDR. METHODS: Participants in the CLASICC trial were identified in the NCDR, and management and outcome data were compared. Data on all surgically treated English patients with colorectal cancer were extracted from the NCDR and compared with those of CLASICC participants. RESULTS: Survival and treatment data for those in the CLASICC trial were available in the NCDR for 98·9 and 95·8 per cent of patients respectively. There was agreement in operation type for 86·1 per cent of patients but surgical approach coding was poor, with only 58·4 per cent of laparoscopic procedures coded in the NCDR. There was no significant difference in survival calculated from either data set. Surgical information was available in the NCDR for 19 of 20 trial participants with missing data. The trial population was younger (P < 0·001), of better socioeconomic status (P = 0·001) and with earlier disease (P < 0·001) than the general surgically treated colorectal cancer population. Rectal cancer survival was similar, but 5-year survival after treatment of colonic cancer was significantly better in the trial than in the national data: 57·1 (95 per cent confidence interval 51·5 to 62·3) versus 49·8 (49·3 to 50·2) per cent respectively. CONCLUSION: The National Cancer Data Repository demonstrates potential for informing clinical trials, but limitations prevent full intention-to-treat analyses.

Low abdominoperineal excision rates are associated with high-workload surgeons and lower tumour height. Is further specialization needed?

AIM: Wide variation, independent of disease extent and case mix, has been observed in the rate of use of abdominoperineal excision (APE) for rectal cancer. Previous analyses have, however, been confounded by failure to adjust for the location of the tumour within the rectum. This population-based study sought to examine whether variations in tumour height explained differences in APE use. METHOD: Information was obtained on all individuals who underwent a major resection for a rectal tumour diagnosed between 1998 and 2005 across the Northern and Yorkshire regions of the UK. Median distances from the dentate line were calculated for all tumours excised by APE and compared with rates of use of APE between specialists and nonspecialist surgeons and across hospital trusts. RESULTS: The completeness of pathological reporting of height of tumour within the rectum was variable. A low rate of APE use was associated with a lower median distance of tumours from the dentate line. Specialist colorectal cancer surgeons performed fewer APEs on patients with a tumour located lower in the rectum than nonspecialist surgeons. CONCLUSION: Variations in the height of tumour did not explain the variation in APE use. Specialist high-volume surgeons undertook fewer APEs and those they performed were closer to the dentate line than low-volume nonspecialist surgeons.

Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data.

BACKGROUND: Cancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival. METHODS: Data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995-2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985-2005. FINDINGS: Relative survival improved during 1995-2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2-6% at 1 year and by 2-3% at 5 years. INTERPRETATION: Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older. FUNDING: Department of Health, England; and Cancer Research UK.

Surgical management and outcomes of colorectal cancer liver metastases.

BACKGROUND: This population-based study investigated the frequency of hepatic resections for colorectal cancer metastases across England and their outcome. METHODS: Individuals who underwent surgery for colorectal cancer between January 1998 and June 2004 within the English National Health Service were identified via the National Cancer Data Repository. All episodes of care in the 3 years after the initial operation were examined to determine the frequency of liver resection. Variations in the use of liver resection and survival were assessed. RESULTS: Some 114 155 individuals underwent surgery for colorectal cancer over the study period, of whom 3116 (2.7 per cent) subsequently had one or more hepatic resections. The hepatectomy rate increased from 1.7 per cent in 1998 to 3.8 per cent in 2004. There was significant variation in the rate of liver resection across cancer networks (range 1.1-4.3 per cent) and hospitals (range 0.7-6.8 per cent). The crude 5-year survival rate after liver resection was 44.2 (95 per cent confidence interval (c.i.) 42.4 to 46.1) per cent from the time of hepatectomy and 45.9 (95 per cent c.i. 44.1 to 47.7) per cent from the time of colectomy. This was comparable to the 5-year survival rate of patients with stage III disease (42.2 (95 per cent c.i. 41.7 to 42.7) per cent). CONCLUSION: The rate of resection of liver metastases increased over the study period but varied significantly across the country. Patients who underwent liver resection had 5-year survival comparable to that of patients with stage III colorectal cancer.

Audit of cervical cytology in HIV-positive women.

The National Health Service (NHS) cervical-screening programme has recently produced guidelines specifically for HIV-positive women. This includes annual cervical cytology screening and colposcopy to follow national guidelines. The case notes of all women attending Sheffield genitourinary clinic were audited. Of the 46 notes available, there was no documentation that annual screening has been offered in 26, and 10% of women did not have appropriate management of an abnormal smear. Information on the cytology form could result in a breach in confidentiality in cases where general practitioners are not aware of a patient's HIV status.

The role of infertility nurses in ovulation induction programmes.

The role of the infertility nurse is continually expanding and changing to meet the demands of couples undergoing assisted reproduction. This article examines the responsibilities infertility nurses have in ovulation induction programmes in fertility clinics today. A simple questionnaire was sent to all fertility units listed in The Patients' Guide to DI and IVF Clinics. There was a response rate of 71%. Specialist infertility units had a higher number of nurses available to carry out various tasks within the fertility programme compared with other types of staff. Members of the nursing staff were involved in initial consultation, transvaginal ultrasound scanning, intrauterine inseminations, administration of medication, sperm preparation and pregnancy tests. Infertility nurses played a major role in ovulation induction programmes. In 39% of units, nurses performed intrauterine inseminations alone, in 23% of units they made decisions as to the requirement for human chorionic gonadotrophin administration, and in over 77% of units transvaginal scans were done by nurses. This role could be even broader, assuming adequate training is provided and undertaken. The extended role of infertility nurse practitioners allows more continuity of care and better understanding of patients' needs and results in the involvement of fewer people in the overall care.

Oxidative stress mediates neuronal DNA damage and apoptosis in response to cytosine arabinoside.

Cytosine arabinoside (AraC) is a nucleoside analog that produces significant neurotoxicity in cancer patients. The mechanism by which AraC causes neuronal death is a matter of some debate because the conventional understanding of AraC toxicity requires incorporation into newly synthesized DNA. Here we demonstrate that AraC-induced apoptosis of cultured cerebral cortical neurons is mediated by oxidative stress. AraC-induced cell death was reduced by treatment with several different free-radical scavengers (N-acetyl-L-cysteine, dipyridamole, uric acid, and vitamin E) and was increased following depletion of cellular glutathione stores. AraC induced the formation of reactive oxygen species in neurons as measured by an increase in the fluorescence of the dye 5-(6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate. AraC produced DNA single-strand breaks as measured by single-cell gel electrophoresis and the level of DNA strand breakage was reduced by treatment with the free radical scavengers. These data support a model in which AraC induces neuronal apoptosis by provoking the generation of reactive oxygen species, causing oxidative DNA damage and initiating the p53-dependent apoptotic program. These observations suggest the use of antioxidant therapies to reduce neurotoxicity in AraC chemotherapeutic regimens.

Cyclin-dependent kinases and P53 pathways are activated independently and mediate Bax activation in neurons after DNA damage.

DNA damage has been implicated as one important initiator of cell death in neuropathological conditions such as stroke. Accordingly, it is important to understand the signaling processes that control neuronal death induced by this stimulus. Previous evidence has shown that the death of embryonic cortical neurons treated with the DNA-damaging agent camptothecin is dependent on the tumor suppressor p53 and cyclin-dependent kinase (CDK) activity and that the inhibition of either pathway alone leads to enhanced and prolonged survival. We presently show that p53 and CDKs are activated independently on parallel pathways. An increase in p53 protein levels, nuclear localization, and DNA binding that result from DNA damage are not affected by the inhibition of CDK activity. Conversely, no decrease in retinoblastoma protein (pRb) phosphorylation was observed in p53-deficient neurons that were treated with camptothecin. However, either p53 deficiency or the inhibition of CDK activity alone inhibited Bax translocation, cytochrome c release, and caspase-3-like activation. Taken together, our results indicate that p53 and CDK are activated independently and then act in concert to control Bax-mediated apoptosis.