What are SNPs and haplotypes and how will they help us manage the prevention of adult cancer?

Human genetic variation data are now publicly available on a large scale, from public and private discovery efforts. Datasets from the International Haplotype Map Consortium and Perlegen Sciences provide a level of knowledge about human genetic variation that is unprecedented. In combination with novel high-throughput genotyping technologies, these new resources will allow cancer prevention investigators to identify in a more precise way which genetic subsets of patients are likely to benefit most from chemoprevention and screening interventions.     

Nitric oxide delivery to cancer: Why and how?

Hypoxia and blood flow heterogeneities are characteristics of solid tumours and are major obstacles for therapy. Exploiting the biology of nitric oxide (NO), a small radical with multiple functions, is particularly attractive to circumvent these sources of resistance and to sensitise tumour to cytotoxic treatments such as radiotherapy and chemotherapy. Indeed, while NO mediates angiogenic effects, NO may also promote tumour perfusion, drug delivery and oxygenation. Different strategies to deliver NO to tumours and pertaining to the FECS-EJC award laureate’s work are reviewed, with a focus on their therapeutic potential. The development of techniques to monitor how and to which extent NO delivery influences the phenotype of a given tumour in a given patient is also discussed.     

Immune function and adjustment style: Do they predict survival in breast cancer?

The aim of this study was to investigate the role of immune status and psychosocial factors in survival from early breast cancer (N=61). Baseline assessments included lymphocyte number and function, natural killer cell activity (NKA), plasma cortisol and prolactin level. Psychosocial measures included anxiety, depression and mental adjustment to cancer and social support. Length of follow-up was 6.1-7.9 years with 14 (23%) breast cancer deaths. In Cox proportional hazards models adjusting for lymph node status two parameters predicted longer survival, low NKA (HR 29 per LLU, p=0.003) and minimizing the illness adjustment (HR 0.64 per scale point, p=0.012). These data provide little evidence for a psychoneuroimmunological mechanism in the survival from breast cancer. While this study is limited due to small sample size, and therefore the possibility of inflated estimates, longer survival in those minimizing the illness is a finding consistent with recent studies; however, the counter-intuitive finding that high NKA predicts shorter survival may be a marker for current disease or response to treatments.     

Competing risk analyses: how are they different and why should you care?

Competing risks are events in which at least one precludes the observation of the other, such as toxicity and death. This commentary discusses and distinguishes between the two common types of competing risk analyses, the Kaplan-Meier and cumulative incidence curves.     

Radiation-related toxicities and outcomes in endometrial cancer: are obese women at a disadvantage?

Objective

To assess the impact of body mass index (BMI) on radiotherapy toxicities in endometrial cancer patients.

Methods

This was a retrospective cohort study of women diagnosed with endometrial cancer between January 2006 and December 2014 at the Royal Cornwall Hospital Trust. Women who received radiotherapy as part of their treatment, including external beam radiotherapy (EBRT) and/or vaginal brachytherapy were included. Radiation-related toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) guidelines. Toxicity outcomes were compared across BMI groups—non-obese (BMI <30 kg/m²) and obese (BMI ≥30 kg/m²)—according to radiotherapy treatment received (EBRT, brachytherapy or a combination).

Results

Of a total of 159 women who received radiotherapy, 110 were eligible for inclusion in the study. Sixty-three women had a BMI <30 kg/m² and 47 women were obese. Obese women had poorer Eastern Cooperative Oncology Group performance status (P = 0.021) and more comorbidities (P < 0.001) compared to the non-obese group. Total (any) toxicity rates were 60.3, 72.7 and 52.0% for EBRT and brachytherapy (N = 63), single-mode EBRT (N = 22) and brachytherapy (N = 25), respectively. BMI was not associated with the incidence of acute and late radiation toxicities in the different radiotherapy groups, and there were no differences in individual complications between the BMI groups.

Conclusion

When comparing obese to non-obese women, obesity does not negatively impact the incidence of radiation toxicities in endometrial cancer. However, toxicities remain an important challenge as they are common and negatively influence the quality of life (QoL) of survivors. Future studies need to further explore the role of BMI and possible interventions to improve toxicities and QoL.

     

A population-based study: how to identify high-risk T1 gastric cancer patients?

In T1 gastric cancer (GC), lymph nodes metastasis (LNM) is considered as a significant prognostic predictor and closely associated with following therapeutic approaches as well as distant metastasis (DM). This study aimed to not only seek risk factors of LNM and DM but also unpack the prognosis in T1 GC patients. We performed a retrospective study enrolling 5547 patients in T1 GC from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic regression models were produced to recognize independent risk factors of LNM and DM. Cox regression analyses were performed to identify important prognostic factors of overall survival (OS). Cancer-specific cumulative incidence was plotted by cumulative incidence function. Three nomograms of LNM, DM and OS were established and validated by receiver operating characteristic (ROC) and calibration curves to evaluate discrimination and accuracy. Decision curve analysis (DCA), clinical impact curves (CIC) and subgroups based on risk scores were constructed to measure nomograms clinical utility. The area under the curve (AUC) of LNM nomogram and DM nomogram were 0.735 and 0.896, respectively. OS nomogram was constructed and the corresponding C-index was 0.797. In conclusion, our user-friendly nomograms, which aimed to predict LNM, DM and OS in T1 gastric cancer patients, have shown high efficiency of discrimination and accuracy. These useful and visual tools may have advantageous clinical utility to identify high-risk T1 gastric patients and help clinicians to draw up an individual therapeutic strategy.     

Patient decision aids for prevention and treatment of cancer diseases: are they really personalised tools?

This article provides an analysis of cancer decision aids (DAs), instruments developed to support oncologic patients facing tough screening or treatment decisions, with a particular attention to their level of personalisation. As discussed in our previous works, we argue that the personalisation of medicine should regard not only the genetic and clinical aspects of diseases but also the different cognitive, psychological and social factors involved in clinical choices. According to this vision, we analysed the existing randomised controlled studies on cancer DAs concluding that only few of them take into account individual variables such as cultural level, individual risk attitudes, personal beliefs, and emotional state that are crucial to determine people's reactions and health‐related choices. For these reasons, although quality standards have been published for these interventions, we suggest the need for further research in order to make these instruments more efficient in transforming and improving the actual clinical practice, improving patient empowerment and participation in health‐related decisions.     

Bronchial stenosis: An underreported complication of high-dose external beam radiotherapy for lung cancer?

PURPOSE: To assess the incidence of clinically significant bronchial stenosis in patients treated with high doses (i.e., >70 Gy) of twice-daily external beam radiation therapy (RT). METHODS AND MATERIALS: The outcomes of 103 patients with unresectable non-small-cell lung cancer, treated twice daily to doses ranging from 7080 to 8640 cGy between 1992 and 2001, were analyzed. Most were treated on prospective clinical trials. For the dose-effect comparison, the patients were divided on the basis of the total dose: 67 received 74 Gy (range, 70.8-74.5 Gy; median, 73.6 Gy), 20 received 80 Gy, and 16 received 86 Gy (range, 85.2-86.4 Gy; median, 86.4 Gy). Sixty-six patients received sequential chemotherapy before RT. RT-induced bronchial stenosis was defined as symptomatic airway narrowing diagnosed by bronchoscopy or computed tomography scan without evidence of recurrent tumor in that region. RESULTS: Eight patients developed RT-induced, clinically significant, bronchial stenosis 2-48 months (median, 6 months) after RT. The 1-year and 4-year actuarial rate of stenosis was 7% and 38%, respectively. The median overall survival was 2.5 years (5 of 8 were alive at the writing of this report). A suggestion was also found of a dose-response effect with external beam radiotherapy-induced stenosis, with a rate of 4% and 25% at a dose of approximately 74 Gy and 86 Gy, respectively. CONCLUSION: Radiation therapy-induced bronchial stenosis is a significant clinical complication of dose escalation for lung cancer. This complication has been previously mentioned in the literature, but ours is the largest report to date, and the findings suggest that the risk rises with increasing dose. It is likely that this process would manifest in more patients if their disease were controlled well enough for more prolonged survival.     

Prognostic factors in ovarian cancer: how close are we to a complete picture?

Ovarian cancer is the fourth most common cause of cancer-relateddeath in women, but is the most lethal of the gynaecologicalmalignancies with 30–40% overall survival at 5 years [1].This is in part because the majority of patients with ovariancancer present with advanced disease, and treatment optionsat presentation are confined to a combination of debulking surgeryand platinum based chemotherapy, which are only partially effective[2]. Consequently, almost all patients with advanced diseaseultimately relapse and die of their disease. Advances in themanagement of these patients are therefore urgently required.  Prognostic factors are defined as phenotypes which correlatewith overall survival. In general prognostic factors reflectthe intrinsic biology of a tumour (e.g. histological subtype,grade), disease extent (e.g. stage) and/or the capacity of apatient to cope with the morbidity associated with the tumourand treatment (e.g.     

Improving decision-making in early breast cancer: who to treat and how?

Response to treatment with the antiestrogen tamoxifen is variable and at least partially due to its highly complex metabolism. Tamoxifen is transformed by polymorphic and inducible cytochrome P450 enzymes to a large number of metabolites with varying biological activities. The estrogen receptor dependent growth inhibitory effect of antiestrogens is mediated by activation of antiproliferative Transforming Growth Factor beta (TGFβ) signal transduction pathways. The aim of the present study was to establish if TGFβ2 or TGFβ receptor II (TβRII), could be used as markers to assess the pharmacological potency of tamoxifen and its metabolites. Consequently, we analyzed the growth inhibitory effect of tamoxifen and its major metabolites and explored whether it correlated with their capacity to induce TGFβ2 and TβRII expression. Human breast cancer cells (MCF-7 and T47D) were treated with tamoxifen and tamoxifen metabolites and mRNA expression of TGFβ2 and TβRII was analyzed by quantitative RT-PCR. Only two metabolites 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen had significant antiproliferative activity and were able to induce TGFβ2 and TβRII. Plasma concentrations of these metabolites are usually very low in patients. However, even minor growth inhibitory effects at concentrations which are below the limit of quantification in plasma samples resulted in clearly discernible effects on expression of TGFβ2 and TβRII. Taken together, our data demonstrate that TGFβ2 and TβRII are very specific and sensitive biomarkers for the antiestrogenic activity of tamoxifen metabolites in breast cancer.     

Surgical therapy of vulvar cancer: how to choose the correct reconstruction?

ObjectiveTo create a comprehensive algorithmic approach to reconstruction after vulvar cancer ablative surgery, which includes both traditional and perforator flaps, evaluating anatomical subunits and shape of the defect.MethodsWe retrospectively reviewed 80 cases of reconstruction after vulvar cancer ablative surgery, performed between June 2006 and January 2016, transferring 101 flaps. We registered the possibility to achieve the complete wound closure, even in presence of very complex defects, and the postoperative complications. On the basis of these experience, analyzing the choices made and considering the complications, we developed an algorithm to help with the selection of the flap in vulvoperineal reconstruction after oncologic ablative surgery for vulvar cancer.ResultsWe employed eight types of different flaps, including 54 traditional fasciocutaneous V-Y flaps, 23 rectus abdominis myocutaneous flaps, 11 anterolateral thigh flaps, three V-Y gracilis myocutaneous flaps, three free style perforators V-Y flaps from the inner thigh, two Limberg flaps, two lotus flaps, two deep inferior epigastric artery perforator flap, and one superficial circumflex iliac artery perforator flap. The structures most frequently involved in resection were vulva, perineum, mons pubis, groins, vagina, urethra and, more rarely, rectum, bladder, and lower abdominal wall.ConclusionThe algorithm we implemented can be a useful tool to help flap selection. The key points in the decision-making process are: anatomical subunits to be covered, overall shape and symmetry of the defect and some patient features such as skin laxity or previous radiotherapy. Perforator flaps, when feasible, must be considered standard in vulvoperineal reconstruction, although in some cases traditional flaps remain the best choice.     

Socio-economic inequalities in cancer survival: how do they translate into Number of Life-Years Lost?

Background We aimed to investigate the impact of socio-economic inequalities in cancer survival in England on the Number of Life-Years Lost (NLYL) due to cancer.Methods We analysed 1.2 million patients diagnosed with one of the 23 most common cancers (92.3% of all incident cancers in England) between 2010 and 2014. Socio-economic deprivation of patients was based on the income domain of the English Index of Deprivation. We estimated the NLYL due to cancer within 3 years since diagnosis for each cancer and stratified by sex, age and deprivation, using a non-parametric approach. The relative survival framework enables us to disentangle death from cancer and death from other causes without the information on the cause of death.Results The largest socio-economic inequalities were seen mostly in adults <45 years with poor-prognosis cancers. In this age group, the most deprived patients with lung, pancreatic and oesophageal cancer lost up to 6 additional months within 3 years since diagnosis than the least deprived. For most moderate/good prognosis cancers, the socio-economic inequalities widened with age.Conclusions More deprived patients and particularly the young with more lethal cancers, lose systematically more life-years than the less deprived. To reduce these inequalities, cancer policies should systematically encompass the inequities component.Subject terms: Cancer epidemiology, Health policy, Prognosis, Epidemiology, Cancer     

Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case–control study in Italy

Background:

Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells.

Methods:

In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case–control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors.

Results:

Women in the highest quartile category of proanthocyanidins with ⩾3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48–0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m⁻², and, for flavanones, among parous or non-users of hormone-replacement therapy women.

Conclusion:

High consumption of selected proanthocyanidins may reduce endometrial cancer risk.