Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer.

Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

[Opioid Induced Pituitary Dysfunction].

A 77-year-old woman with a history of anal squamous cell carcinoma was admitted because of malaise, diarrhea and nausea, in addition to back pain related to a verte- bral compression fracture. During the course of treatment, opioid therapy was initiated, following which the patient became progressively hypotensive and hyponatraemic and respiratory drive progressively decreased. Serum levels of cortisol, TSH and LH were decreased and prolactin slightly elevated, but a Synacthen test and brain MRI turned out normal, suggesting a diagnosis of opioid-induced pituitary dysfunction. The patient was given glucocorticoid replacement therapy with good results. Here we present a case of this serious but less well recognised side-effect of opioids.

Radiotherapy equipment and departments in the European countries: final results from the ESTRO-HERO survey.

BACKGROUND: Documenting the distribution of radiotherapy departments and the availability of radiotherapy equipment in the European countries is an important part of HERO - the ESTRO Health Economics in Radiation Oncology project. HERO has the overall aim to develop a knowledge base of the provision of radiotherapy in Europe and build a model for health economic evaluation of radiation treatments at the European level. The aim of the current report is to describe the distribution of radiotherapy equipment in European countries. METHODS: An 84-item questionnaire was sent out to European countries, principally through their national societies. The current report includes a detailed analysis of radiotherapy departments and equipment (questionnaire items 26-29), analyzed in relation to the annual number of treatment courses and the socio-economic status of the countries. The analysis is based on validated responses from 28 of the 40 European countries defined by the European Cancer Observatory (ECO). RESULTS: A large variation between countries was found for most parameters studied. There were 2192 linear accelerators, 96 dedicated stereotactic machines, and 77 cobalt machines reported in the 27 countries where this information was available. A total of 12 countries had at least one cobalt machine in use. There was a median of 0.5 simulator per MV unit (range 0.3-1.5) and 1.4 (range 0.4-4.4) simulators per department. Of the 874 simulators, a total of 654 (75%) were capable of 3D imaging (CT-scanner or CBCT-option). The number of MV machines (cobalt, linear accelerators, and dedicated stereotactic machines) per million inhabitants ranged from 1.4 to 9.5 (median 5.3) and the average number of MV machines per department from 0.9 to 8.2 (median 2.6). The average number of treatment courses per year per MV machine varied from 262 to 1061 (median 419). While 69% of MV units were capable of IMRT only 49% were equipped for image guidance (IGRT). There was a clear relation between socio-economic status, as measured by GNI per capita, and availability of radiotherapy equipment in the countries. In many low income countries in Southern and Central-Eastern Europe there was very limited access to radiotherapy and especially to equipment for IMRT or IGRT. CONCLUSIONS: The European average number of MV machines per million inhabitants and per department is now better in line with QUARTS recommendations from 2005, but the survey also showed a significant heterogeneity in the access to modern radiotherapy equipment in Europe. High income countries especially in Northern-Western Europe are well-served with radiotherapy resources, other countries are facing important shortages of both equipment in general and especially machines capable of delivering high precision conformal treatments (IMRT, IGRT).

Radiotherapy staffing in the European countries: final results from the ESTRO-HERO survey.

BACKGROUND: The ESTRO Health Economics in Radiation Oncology (HERO) project has the overall aim to develop a knowledge base of the provision of radiotherapy in Europe and build a model for health economic evaluation of radiation treatments at the European level. The first milestone was to assess the availability of radiotherapy resources within Europe. This paper presents the personnel data collected in the ESTRO HERO database. MATERIALS AND METHODS: An 84-item questionnaire was sent out to European countries, through their national scientific and professional radiotherapy societies. The current report includes a detailed analysis of radiotherapy staffing (questionnaire items 47-60), analysed in relation to the annual number of treatment courses and the socio-economic status of the countries. The analysis was conducted between February and July 2014, and is based on validated responses from 24 of the 40 European countries defined by the European Cancer Observatory (ECO). RESULTS: A large variation between countries was found for most parameters studied. Averages and ranges for personnel numbers per million inhabitants are 12.8 (2.5-30.9) for radiation oncologists, 7.6 (0-19.7) for medical physicists, 3.5 (0-12.6) for dosimetrists, 26.6 (1.9-78) for RTTs and 14.8 (0.4-61.0) for radiotherapy nurses. The combined average for physicists and dosimetrists is 9.8 per million inhabitants and 36.9 for RTT and nurses. Radiation oncologists on average treat 208.9 courses per year (range: 99.9-348.8), physicists and dosimetrists conjointly treat 303.3 courses (range: 85-757.7) and RTT and nurses 76.8 (range: 25.7-156.8). In countries with higher GNI per capita, all personnel categories treat fewer courses per annum than in less affluent countries. This relationship is most evident for RTTs and nurses. Different clusters of countries can be distinguished on the basis of available personnel resources and socio-economic status. CONCLUSIONS: The average personnel figures in Europe are now consistent with, or even more favourable than the QUARTS recommendations, probably reflecting a combination of better availability as such, in parallel with the current use of more complex treatments than a decade ago. A considerable variation in available personnel and delivered courses per year however persists among the highest and lowest staffing levels. This not only reflects the variation in cancer incidence and socio-economic determinants, but also the stage in technology adoption along with treatment complexity and the different professional roles and responsibilities within each country. Our data underpin the need for accurate prediction models and long-term education and training programmes.

Cost-effectiveness of human papilloma virus vaccination in Iceland.

OBJECTIVE: To evaluate the likely cost-effectiveness of introducing routine HPV vaccination in Iceland. DESIGN: Prospective cost-effectiveness analysis of human papilloma virus (HPV) vaccination. SETTING AND SAMPLE: Population of 12-year-old girls in the Icelandic population. METHODS: A model was developed, comparing a cohort of all 12-year-old girls alive in year 2006, with or without vaccination. The model was based on the epidemiology of cervical cancer in Iceland and its premalignant stages as well as the costs involved in the treatment of each stage, assuming that the vaccines only prevent infections caused by HPV 16/18 at an efficacy of 95% and participation rate of 90%, no catch-up vaccination, no vaccination of boys and no booster dose needed. All costs were calculated on the basis of the price level of mid-year 2006 with a 3% discount rate. Incremental cost-effectiveness ratio calculations were performed and sensitivity analysis was carried out on factors most relevant for cost-effectiveness. RESULTS: Vaccination costs in excess of savings would be about euro313.000/year. Vaccination would reduce the number of women diagnosed with cervical cancer by almost 9, prevent the death of 1.7 women and result in 16.9 quality-adjusted life years gained annually. The incremental cost-effectiveness ratio was calculated to be about euro18.500/quality-adjusted life year saved. CONCLUSION: HPV vaccination seems to be cost-effective in Iceland, but this was sensitive to various parameters in the model, mainly the discount rate, the price of the vaccines and the need for a booster dose.

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

[Anal cancer in Iceland 1987-2003. A population based study]. / Carcinoma ani á Islandi 1987-2003 -- lýethgrundueth rannsókn.

OBJECTIVE: Anal cancer is a rare disease. The aim of this study was to describe anal cancer in Iceland in 1987-2003 with respect to incidence, histologic type, treatment, recurrence rate and survival. MATERIAL AND METHODS: This is a retrospective study in which all malignant anal tumours diagnosed in Iceland in the period 1987-2003 were reviewed with respect to patient outcome. Information was obtained from hospitals registers. All histological material was reviewed by a consultant histopathologist (JGJ). This is a nationwide, population-based study of malignant tumours of the anal region. RESULTS: From 1987-2003 thirty-eight patients were diagnosed with anal cancer, 28 females and 10 males. The average age at diagnosis was 63.4 years. Age standardized incidence rates for anal cancer in Iceland were 0.3 (+/-0.2) of 100.000 males and 0.9 (+/-0.4) of 100.000 females. Most patients had squamous cell carcinoma (n=30). The remaining histologic types were malignant melanoma (n=3), adenosquamous carcinoma (n=1), adenocarcinoma (n=1), GIST (n=1) and undifferentiated carcinoma (n=2). The most common symptoms were rectal bleeding (n=27), mass lesion (n=28), pain (n=19) and pruritus (n=4). Most patients had more than one symptom. The duration of symptoms before diagnosis ranged from 2 weeks to 96 months (mean value 3.5 months). Treatment modalities used were chemotherapy (n=12), radiotherapy (n=25) and local excision (n=18) and/or APR (n=5). One patient received no treatment. Many patients were treated with more than one treatment modality (n=18). Twelve patients had recurrent cancer. The mean value of the time from diagnosis of the primary to the recurrent cancer was 15.6 months (range, 5.9-117). Sixteen patients remain with disease and ten have died of anal cancer. The five year survival rate for patients diagnosed in the years 1987 to 1998 is 75% but cancer-specific survival is 82%. CONCLUSION: Age-standardized incidence for anal cancer in Iceland is similar to other regions. Average age at diagnosis, male-female ratio and prognosis is similar to reports in other studies. The proportion of adenocarcinoma of the anus is lower in Iceland than elsewhere.

The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

PURPOSE: Indolent non-Hodgkin's lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in 2 fractions, which prompted this prospective Phase II trial of the palliative effect of this regimen in patients with disseminated INHL or CLL. METHODS AND MATERIALS: Twenty-two patients (11 men, 11 women, median age 62 years, range 30-89) with disseminated INHL (n = 15) or CLL (n = 7) were treated with local low-dose RT, 2 Gy x 2 within 3 days, with the aim of achieving palliation from localized lymphoma masses. The patients were treated to a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3-26). RESULTS: All patients and all irradiated sites were assessable for response. Of the 22 patients, 18 responded to the treatment, corresponding to an overall response rate (RR) of 82%; 12 patients (55%) achieved a complete response (CR), 5 patients (22%) a partial response (PR), and 1 patient had a CR at three sites and a PR at one site. Of the 31 irradiated sites, 27 responded to treatment, corresponding to an overall RR of 87%; in 20 sites (65%) a CR was achieved and in 7 sites (22%) a PR. Patients with disseminated INHL had an overall RR of 87% (74% CR, 13% PR); patients with CLL had an overall RR of 71% (29% CR, 42% PR). The median duration of response was estimated at 22 months. None of the patients had significant side effects from the treatment. CONCLUSION: Low-dose RT (4 Gy in 2 fractions) is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects.