Improving Health and Cancer Services in Low-Resource Countries to Attain the Sustainable Development Goals Target 3.4 for Noncommunicable Diseases.

The United Nations Sustainable Development Goals 2015 to 2030 includes a specific goal for health (Sustainable Development Goal [SDG] 3) with 13 targets, including SDG3.4 for the control and treatment of noncommunicable diseases (NCDs), namely, cardiovascular diseases, cancer, diabetes, and chronic lung disease. There is considerable concern that SDG3.4 may not be achieved. The WHO Best Buys for NCDs has emphasized prevention, and although crucial, it alone will not achieve the 30% reduction in NCDs by 2030. Likewise, a strengthened health system is required as all NCDs are likely to require hospital facilities and community services for optimal management. This is a major problem for low-resource countries (LRCs) -that is, low-income countries and lower-middle-income countries-as most currently have a poorly developed health system, including cancer services, in need of upgrading. This is a result of the extreme poverty of LRCs, where 40% to 80% of the population live on less than USD $1.25 per day, with the average health spending by governments in low-income countries at $110 per person per year. In this article, we outline a comprehensive national cancer services plan for LRCs. Surgery, radiotherapy, and chemotherapy for cancer treatment also require input from other specialties, such as anesthesia, pathology, laboratory medicine, a blood bank, and diagnostic radiology. This will provide a focus for adding additional specialties, including cardiology, respiratory medicine, and psychiatry, to support the management of all NCDs and to contribute to the overall strengthening of the health system. The national cancer services plan for LRCs will require significant funding and input from both in-country and overseas experts in health, cancer, and finance working collaboratively. Success will depend on thoughtful strategic planning and providing the right balance of overseas support and guidance, but ensuring that there is in-country ownership and control of the program is essential.

Use of Bayes' formula to make a genetic risk estimate.

Izabella and her partner sought pre-implantation genetic diagnosis (PGD) because Izabella had retinoblastoma due to a deletion in chromosome 13 and they want to have children not at genetic risk of retinoblastoma. Fortunately, Izabella's tumor was unilateral and was treated successfully and she is well. Izabella's chromosome abnormality is mosaic with 70% of lymphocytes having the deletion. This mosaicism may not be present in Izabella's ovaries. The couple went through PGD on two occasions and 13 embryos were tested. None had the deleted chromosome 13. IVF and PGD failed to produce a pregnancy. The couple wished to know what the experience provides as to the risk to their offspring: in particular, does it indicate a risk low enough to be acceptable if they go ahead with a natural pregnancy instead of another resort to PGD? Also, the couple did not want prenatal diagnosis. The situation therefore requires an estimate of the probability that an embryo will have the deletion. Counseling is problematic because there is no obvious way of selecting a prior probability from which to compute a Bayesian estimate of risk. Two solutions are offered, depending on the amount of information available about genes transmitted from the maternal grandparents.

A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

CONTEXT: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). OBJECTIVE: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. DESIGN AND PATIENTS: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. RESULTS: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. CONCLUSION: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.

A 'Catch Up' Plan for radiotherapy in New South Wales to 2012.

In New South Wales (NSW) from 1996 to 2006, only 34-37% of newly diagnosed cancer patients were treated with radiotherapy instead of the 50% proposed by NSW Health in Radiotherapy Plans released in 1991, 1995 and 2003. As a consequence, over 50 000 cancer patients were not treated and has resulted in the estimated premature death of over 8000 patients and over 40 000 years of life lost. In 2008, there were 42 linear accelerators in NSW rather than the 62 recommended. Based on cancer incidence projections, NSW will require 69 linear accelerators in 2012--a shortfall of 27 linear accelerators. Already 15 linear accelerators have been approved. NSW Health has funding for seven extra linear accelerators, and eight extra linear accelerators are to be funded by the private sector. To make up the shortfall, a 'Catch Up' Plan is proposed for an additional 12 linear accelerators by the end of fiscal year 2012. This is estimated to cost $200 million over 4 years for one-off establishment costs for buildings and equipment plus $50 million per year for recurrent operating costs such as staff salaries. The 'Catch Up' Plan will create five new departments of radiation oncology in country hospitals and three new departments in metropolitan hospitals. These will be in addition to those already approved by NSW Health and will markedly improve access for treatment and result in an improvement in cancer survival. This significant increase in departments and equipment can only be achieved by the creation of an NSW Radiotherapy Taskforce similar to that proposed in the Baume report of 2002, 'A vision for radiotherapy'. Even if the 'Catch Up' Plan bridges the gap in service provision, forward planning beyond 2012 should commence immediately as 76 linear accelerators will be required for NSW in 2015 and 81 linear accelerators in 2017.

Dosimetric comparison of intensity modulated radiotherapy techniques and standard wedged tangents for whole breast radiotherapy.

Prior to introducing intensity modulated radiotherapy (IMRT) for whole breast radiotherapy (WBRT) into our department we undertook a comparison of the dose parameters of several IMRT techniques and standard wedged tangents (SWT). Our aim was to improve the dose distribution to the breast and to decrease the dose to organs at risk (OAR): heart, lung and contralateral breast (Contra Br). Treatment plans for 20 women (10 right-sided and 10 left-sided) previously treated with SWT for WBRT were used to compare (a) SWT; (b) electronic compensators IMRT (E-IMRT); (c) tangential beam IMRT (T-IMRT); (d) coplanar multi-field IMRT (CP-IMRT); and (e) non-coplanar multi-field IMRT (NCP-IMRT). Plans for the breast were compared for (i) dose homogeneity (DH); (ii) conformity index (CI); (iii) mean dose; (iv) maximum dose; (v) minimum dose; and dose to OAR were calculated (vi) heart; (vii) lung and (viii) Contra Br. Compared with SWT, all plans except CP-IMRT gave improvement in at least two of the seven parameters evaluated. T-IMRT and NCP-IMRT resulted in significant improvement in all parameters except DH and both gave significant reduction in doses to OAR. As on initial evaluation NCP-IMRT is likely to be too time consuming to introduce on a large scale, T-IMRT is the preferred technique for WBRT for use in our department.

Poor-prognosis estrogen receptor-positive breast cancer identified by histopathologic subclassification.

PURPOSE: Identification of biologically and clinically distinct breast cancer subtypes could improve prognostic assessment of primary tumors. The characteristics of "molecular" breast cancer subtypes suggest that routinely assessed histopathologic features in combination with limited biomarkers may provide an informative classification for routine use. EXPERIMENTAL DESIGN: Hierarchical cluster analysis based on components of histopathologic grade (tubule formation, nuclear pleomorphism, and mitotic score), expression of ER, cytokeratin 5/6, and HER2 amplification identified four breast cancer subgroups in a cohort of 270 cases. Cluster subgroup membership was compared with observed and Adjuvant! Online predicted 10-year survival. Survival characteristics were confirmed in an independent cohort of 300 cases assigned to cluster subgroups using a decision tree model. RESULTS: Four distinct breast cancer cluster subgroups (A-D) were identified that were analogous to molecular tumor types and showed a significant association with survival in both the original and validation cohorts (P < 0.001). There was a striking difference between survival for patients in cluster subgroups A and B with ER(+) breast cancer (P < 0.001). Outcome for all tumor types was well estimated by Adjuvant! Online, with the exception of cluster B ER(+) cancers where Adjuvant! Online was too optimistic. CONCLUSIONS: Breast cancer subclassification based on readily accessible pathologic features could improve prognostic assessment of ER(+) breast cancer.

Dounreay hot particles: the story so far.

The first Dounreay hot particle (hereafter 'Particle') to be formally identified was recovered from the Dounreay foreshore in 1983. A further single Particle was recovered from Sandside beach the following year. Particles have been detected and removed from the Dounreay foreshore regularly since 1984 and from the offshore sediments since 1997. Since 1997, an extensive research and development programme has been undertaken to identify the source of Particles, their movement and lifetimes in the marine environment, and their potential effects on human and environmental health. It is now known that Particles were released to the North Atlantic Ocean in the mid to late 1960s and early 1970s. There is no evidence of an on-going source of Particles from the Dounreay site today. The source of Particles recovered from the Dounreay foreshore and from local beaches is the cache currently residing in marine sediments adjacent to Dounreay. Monitoring and sediment modelling studies indicate that the Dounreay Particles are transported approximately parallel to the coast in a north-easterly direction. Studies to define contact frequencies and risks to human health suggest that the health risks associated with Particles are very low There is, however, a significant perception of risk. UKAEA will define a long-term Particle management programme via the development of a best practical environmental option (BPEO) facilitated through consultation with all stakeholders.

Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.

Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australasian Radiation Oncology Lymphoma Group.

BACKGROUND: The curative potential of radiotherapy (RT) alone as initial treatment for patients with Stage I-II lymphocyte-predominant Hodgkin lymphoma (LPHL) has not been defined well. METHODS: Two hundred two patients who were treated between 1969 and 1995 were evaluated in a retrospective, multicenter study. RESULTS: Patient characteristics were as follows: The median age was 31 years, 75% of patients were male, 80% of patients had Ann Arbor Stage I disease, 1% of patients had bulky disease, 3% of patients had B symptoms, 1% of patients had extranodal involvement, and 80% of patients had supradiaphragmatic disease. The RT fields were a full mantle field in 52% of patients, less than a full mantle field in 24% of patients, an inverted-Y field in 17% of patients, less than an inverted-Y field in 3% of patients, and total lymph node irradiation in 3% of patients. The median dose was 36 Gray. The median follow-up was 15 years. The overall survival (OS) rate at 15 years was 83%, and freedom from progression (FFP) was observed in 82% of patients, including 84% of patients with Stage I disease and 73% of patients with Stage II disease. No recurrent LPHL and only 1 patient with non-Hodgkin lymphoma (NHL) were reported after 15 years. Adverse prognostic factors that were identified on multifactor analysis were as follows: for OS, age 45 years or older (P < 0.0005), the presence of B symptoms (P = 0.002), increasing number of sites (P = 0.015); for FFP, increasing number of sites (P = 0.002). No significant difference was found in FFP in a comparison of patients who received elective mediastinal RT with patients who did not receive mediastinal RT (P = 0.11). Causes of death at 15 years were LPHL in 3% of patients, NHL in 2% of patients, in-field malignancy in 2% of patients, in-field cardiac/respiratory in 4% of patients, and other in 6% of patients. CONCLUSIONS: The current data suggested that RT potentially may be curative for patients with Stage I-II LPHL and raise the possibility that limited-field RT may be used without loss of treatment efficacy. Involved-field RT warrants further investigation for patients with early-stage LPHL.

Pulmonary complications of radiation therapy.

There have been important developments in understanding the difference in pathogenesis and clinical significance between acute or sporadic pneumonitis and late radiation fibrosis. Corticosteroid therapy and other forms of therapy are useful in the treatment of acute pneumonitis. Late radiation fibrosis is refractory to treatment; therefore, minimizing the likelihood of developing it is particularly important. Baseline lung assessments are appropriate in patients who are clinically at risk. A new development is the use of the DVH to compare radiation treatment plans to minimize the volume of normal lung irradiated in patients who are at risk. It is hoped that the study of mechanisms that lead to the development of radiation fibrosis will point the way to possible future therapies. Patients who are included in studies of novel irradiation treatments for lung cancer need, in particular, to be monitored for late radiation lung toxicity.

The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies.

AIMS: The debate on the funding and availability of cytotoxic drugs raises questions about the contribution of curative or adjuvant cytotoxic chemotherapy to survival in adult cancer patients. MATERIALS AND METHODS: We undertook a literature search for randomised clinical trials reporting a 5-year survival benefit attributable solely to cytotoxic chemotherapy in adult malignancies. The total number of newly diagnosed cancer patients for 22 major adult malignancies was determined from cancer registry data in Australia and from the Surveillance Epidemiology and End Results data in the USA for 1998. For each malignancy, the absolute number to benefit was the product of (a) the total number of persons with that malignancy; (b) the proportion or subgroup(s) of that malignancy showing a benefit; and (c) the percentage increase in 5-year survival due solely to cytotoxic chemotherapy. The overall contribution was the sum total of the absolute numbers showing a 5-year survival benefit expressed as a percentage of the total number for the 22 malignancies. RESULTS: The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA. CONCLUSION: As the 5-year relative survival rate for cancer in Australia is now over 60%, it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.

Clinicopathological correlates of GpIbalpha expression in human breast cancers.

BACKGROUND: GPIbalpha is the von Willebrand factor binding subunit of the GPIb/VI/IX receptor of platelets. We have recently demonstrated that GPIbalpha and the other receptor subunits of this platelet complex are aberrantly expressed on the surface of breast cancer cell lines in a functional form. The current study examines the clinicopathological correlates of GPIbalpha expression in human breast cancer. MATERIALS AND METHODS: GPIbalpha expression was examined in a retrospective series of human breast cancers using immunohistochemistry. RESULTS: We found that of 98 primary breast cancers, 61 (62.2%) expressed GPIbalpha. The presence of the receptor did not correlate with any known prognostic variables including age, tumour size, or number of involved lymph nodes. GPIbalpha expression was not related to overall survival when the group was considered as a whole. However, it was prognostically important when considered in relation to the menopausal status of patients. CONCLUSION: We conclude that GPIbalpha immunoreactivity does not appear to be of prognostic significance overall, but may be important in a subset of breast cancer patients.