A state-of-the-art review of stratified medicine in cancer: towards a future precision medicine strategy in cancer.

BACKGROUND: Building on the success of targeted therapy in certain well-defined cancer genotypes, three platform studies-NCI-MATCH, LUNG-MAP and The National Lung Matrix Trial (NLMT)-have attempted to discover new genotype-matched therapies for people with cancer. PATIENTS AND METHODS: We review the outputs from these platform studies. This review led us to propose a series of recommendations and considerations that we hope will inform future precision medicine programmes in cancer. RESULTS: The three studies collectively screened over 13 000 patients. Across 37 genotype-matched cohorts, there have been 66/875 responders, with an overall response rate of 7.5%. Targeting copy number gain yielded 5/199 responses across nine biomarker-drug matched cohorts, with a response rate of 2.5%. CONCLUSIONS: The majority of these studies used single-agent targeted therapies. Whilst preclinical data can suggest rational combination treatment to reverse adaptive resistance or block parallel activated pathways, there is an essential need for accurate modelling of the toxicity-activity trade-off of combinations. Agent selection is often suboptimal; dose expansion should only be carried out with agents with clear clinical proof of mechanism and high target selectivity. Targeting copy number change has been disappointing; it is crucial to define the drivers on shared amplicons that include the targeted aberration. Maximising outcomes with currently available targeted therapies requires moving towards a more contextualised stratified medicine acknowledging the criticality of the genomic, transcriptional and immunological context on which the targeted aberration is inscribed. Genomic complexity and instability is likely to be a leading cause of targeted therapy failure in genomically complex cancers. Preclinical models must be developed that more accurately capture the genomic complexity of human disease. The degree of attrition of studies carried out after standard-of-care therapy suggests that serious efforts be made to develop a suite of precision medicine studies in the minimal residual disease setting.

Risk factors for melanoma by anatomical site: an evaluation of aetiological heterogeneity.

BACKGROUND: Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops. OBJECTIVES: We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk. METHODS: We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case-control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA samples. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls. RESULTS: When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P-heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites. CONCLUSIONS: We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.

Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Risk of Colorectal Cancer After Solid Organ Transplantation in the United States.

Solid organ transplant recipients have increased colorectal cancer (CRC) risk. We assessed CRC risk among transplant recipients and identified factors contributing to this association. The US transplant registry was linked to 15 population-based cancer registries (1987-2010). We compared CRC risk in recipients to the general population by using standardized incidence ratios (SIRs) and identified CRC risk factors by using Poisson regression. Based on 790 cases of CRC among 224 098 transplant recipients, the recipients had elevated CRC risk (SIR 1.12, 95% confidence interval [CI] 1.04 to 1.20). The increase was driven by an excess of proximal colon cancer (SIR 1.69, 95% CI 1.53 to 1.87), while distal colon cancer was not increased (SIR 0.93, 95% CI 0.80 to 1.07), and rectal cancer was reduced (SIR 0.64, 95% CI 0.54 to 0.76). In multivariate analyses, CRC was increased markedly in lung recipients with cystic fibrosis (incidence rate ratio [IRR] 12.3, 95% CI 6.94 to 21.9, vs. kidney recipients). Liver recipients with primary sclerosing cholangitis and inflammatory bowel disease also had elevated CRC risk (IRR 5.32, 95% CI 3.73 to 7.58). Maintenance therapy with cyclosporine and azathioprine was associated with proximal colon cancer (IRR 1.53, 95% CI 1.05 to 2.23). Incidence was not elevated in a subgroup of kidney recipients treated with tacrolimus and mycophenolate mofetil, pointing to the relevance of the identified risk factors. Transplant recipients have increased proximal colon cancer risk, likely related to underlying medical conditions (cystic fibrosis and primary sclerosing cholangitis) and specific immunosuppressive regimens.

Donor surfactant protein D (SP-D) polymorphisms are associated with lung transplant outcome.

Chronic lung allograft dysfunction (CLAD) is the major factor limiting long-term success of lung transplantation. Polymorphisms of surfactant protein D (SP-D), an important molecule within lung innate immunity, have been associated with various lung diseases. We investigated the association between donor lung SP-D polymorphisms and posttransplant CLAD and survival in 191 lung transplant recipients consecutively transplanted. Recipients were prospectively followed with routine pulmonary function tests. Donor DNA was assayed by pyrosequencing for SP-D polymorphisms of two single-nucleotide variations altering amino acids in the mature protein N-terminal domain codon 11 (Met(11) Thr), and in codon 160 (Ala(160) Thr) of the C-terminal domain. CLAD was diagnosed in 88/191 patients, and 60/191 patients have died. Recipients of allografts that expressed the homozygous Met(11) Met variant of aa11 had significantly greater freedom from CLAD development and better survival compared to those with the homozygous Thr(11) Th variant of aa11. No significant association was noted for SP-D variants of aa160. Lung allografts with the SP-D polymorphic variant Thr(11) Th of aa11 are associated with development of CLAD and reduced survival. The observed genetic differences of the donor lung, potentially with their effects on innate immunity, may influence the clinical outcomes after lung transplantation.

The determination of resectability of lung cancer by fiberoptic bronchoscopy.

The usefulness of flexible fiberoptic bronchoscopy (FFB) in determining resectability of lung cancer in 152 patients was evaluated. Based on clinical and routine chest roentgenographic examinations, 66 patients (43%) had what were considered to be operable lesions greater than 3 cm in diameter or tumors associated with atelectasis or obstructive pneumonitis (but less than an entire lung), without evidence of pleural effusion or chest wall, mediastinal, or extrathoracic involvement. Forty-eight (73%) of the 66 patients were eventually found to have unresectable conditions. With FFB alone, the conditions of 32 (67%) of these 48 patients were staged as unresectable, so that more invasive procedures, eg, mediastinoscopy or thoracotomy, were required in only 12 and four patients, respectively. Early FFB should be done in potentially resectable cases in which these roentgenographic criteria are met. This procedure is easy, safe, and economical and would allow many patients with lung cancer to have the stage of their disease determined and be treated entirely as outpatients.

Interferon gamma release assay in the diagnosis of tuberculous mastitis.

Tuberculous mastitis is rare, especially in Western countries. We describe a case where the interferon gamma release assay blood test led to diagnosis and successful treatment of the disease.

Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma.

Clinical recurrences of differentiated thyroid carcinoma occur in 20% of patients after thyroid surgery. We performed a retrospective analysis of a cohort of patients undergoing routine follow-up testing to detect recurrent thyroid carcinoma over a 2-yr period. One group was prepared for testing by thyroid hormone withdrawal (THW), and the other group remained on thyroid hormone and received injections of recombinant human TSH (rhTSH) before diagnostic whole-body radioiodine scanning (DxWBS). We hypothesized that no differences in the ability to detect residual disease would exist between these 2 groups. Two hundred and eighty-nine patients were examined by both DxWBS and by measurement of the serum thyroglobulin (Tg) response to elevated TSH levels. THW was used for 161 patients, and rhTSH preparation was used for 128 patients. Based on all available testing results, we categorized patients as having metastatic disease, thyroid bed uptake only, or no evidence of disease. We examined the sensitivity, specificity, positive and negative predictive values of the DxWBS, and the stimulated Tg after preparation by THW or rhTSH. Patients with thyroid bed were not considered in accuracy testing. The sensitivity and specificity of the 2 tests were comparable between groups. No significant differences were present in the positive or negative predictive values between groups. The highest negative predictive value (97%) was in patients who had both a negative DxWBS and low stimulated Tg levels after rhTSH. In summary, we were unable to demonstrate a difference in the diagnostic accuracy of DxWBS and/or Tg between patients prepared by either THW or rhTSH. We conclude that preparing patients by rhTSH is diagnostically equivalent to preparing them by THW.

Biopsy of the main carina; staging lung cancer with the fiberoptic bronchoscope.

The efficacy of main carinal biopsy through the fiberoptic bronchoscope for evaluating resectability has not been determined. Forty-eight patients with carcinoma, but without gross neoplastic involvement of the main carina, underwent biopsy. Five (10 percent) had abnormal results on biopsy of the main carina. Three of the five patients were initially considered candidates for surgery. There were no complications from the procedure. Biopsy of the main carina through the fiberoptic bronchoscope is a valuable staging procedure in selected patients because of its simplicity and yield and the significance of abnormal findings.

Efficient cloning in Bacillus megaterium: comparison to Bacillus subtilis and Escherichia coli cloning hosts.

Quantitative cloning efficiencies for B. megaterium, B. subtilis, and E. coli were compared. Transformation of B. megaterium is less efficient than transformation of B. subtilis or E. coli. The frequency of recombinant clones was equal in E. coli and B. megaterium; both somewhat higher than in B. subtilis. Equivalent average insert sizes were found in B. megaterium and E. coli clones, but significantly smaller inserts were obtained in B. subtilis clones. Clones obtained and propagated in B. megaterium were structurally stable when grown under plasmid selection.

Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin.

Radioiodine ablation (RA) of normal thyroid remnants after thyroidectomy for differentiated thyroid carcinoma improves the sensitivity of subsequent radioiodine scans and serum thyroglobulin measurements for detection of residual thyroid carcinoma. Local cancer recurrences are also lower after RA. One standard preparation for RA involves rendering the patient hypothyroid in order to stimulate endogenous thyrotropin (TSH) secretion and sodium iodide symporter (NIS) activity. An alternative approach is to prescribe thyroxine after thyroidectomy and to stimulate NIS with exogenous recombinant human thyrotropin (rhTSH). This latter approach was used in 10 patients at our medical center. Complete resolution of all visible 131I thyroid bed uptake was achieved in all when follow-up scans were performed 5 to 13 months later. This approach has the potential to successfully ablate thyroid remnants without the need to induce hypothyroidism.

Building-associated pulmonary disease from exposure to Stachybotrys chartarum and Aspergillus versicolor.

The authors present an outbreak of disease associated with exposure to Stachybotrys chartarum and Aspergillus species. A courthouse and two associated office buildings had generated discomfort among employees for two years since initial occupancy. Multiple interventions had been unsuccessful An initial evaluation of 14 individuals identified three with potential asthma and three with symptoms consistent with interstitial lung disease. A clinical screening protocol to identify individuals who should be removed from work identified three likely and seven possible cases of building-related asthma. Detailed environmental and engineering assessments of the building identified major problems in mechanical system design, building construction, and operational strategies leading to excess moisture and elevated relative humidities. Moisture-damaged interior surfaces in both buildings were contaminated with S. chartarum, A. versicolor, and Penicillium species. Aspergillus species, especially A. versicolor, at concentrations of 10(1) to 10(4)/m3 dominated the indoor air under normal operating conditions. Bulk samples also revealed large quantities of Stachybotrys. A questionnaire survey of the three case and two control buildings documented between three- and 15-fold increases in symptoms. A nested case-control study suggested emphysematous-like disease in individuals meeting questionnaire definitions for cases. Replication of analysis strategies used in similar previous investigations suggested an association between worsening symptoms and decreased diffusing capacity of the lung. Performance on neuropsychological measures was similar for both cases and controls, although workers with symptoms reported increased levels of current but not past psychiatric symptomatology. Chemical analyses demonstrated the presence of satratoxins G and H. Cytotoxic laboratory analyses demonstrated the presence of agents with biological effectiveness in bulk materials. No association was seen between IgE or IgG antibodies and the presence of disease. This outbreak represents a likely human response to inhaled fungal toxins in indoor environments. Moisture indoors represents a public health issue currently inadequately addressed by building, health, or housing codes.

Identification of intestinofugal neurons projecting to the coeliac and superior mesenteric ganglia in the rat.

Intestinofugal neurons are parts of the afferent limbs of inhibitory intestino-intestinal reflexes. These neurons have been mapped in guinea-pigs, where they have a gradient of increasing frequency of occurrence from oral to anal, but not in other species. In the present work in the rat, a species that is more amenable to physiological study than the guinea-pig, we have used retrograde tracing to map the distribution of the cell bodies of intestinofugal neurons projecting to the coeliac-superior mesenteric ganglion complex. Labelled nerve cells were found in the myenteric, but not the submucosal plexus. They were mono-axonal neurons, most with Dogiel type I morphology, and were immunoreactive for choline acetyltransferase, implying that they are cholinergic, which is consistent with functional studies. The cells increased in number per unit area from the stomach, through the small intestine, to the caecum. The results are consistent with physiological studies that reveal distal to proximal inhibitory reflexes that are more potent from distal compared to proximal sites.

Effects of vagal and splanchnic section on food intake, weight, serum leptin and hypothalamic neuropeptide Y in rat.

Truncal vagotomy can cause reduced food intake and weight loss in humans and laboratory animals. In order to investigate some of the factors that might contribute to this effect, we studied changes in ingestive behaviour, whole body and organ weights, serum leptin and hypothalamic neuropeptide Y in rats with bilateral vagal section, bilateral splanchnic nerve section and combined vagotomy plus splanchnectomy. Pyloromyotomy was combined with vagotomy to lessen effects of vagotomy on gastric emptying. Animals with vagotomy or vagotomy plus splanchnectomy lost weight and decreased their daily food intake relative to animals with splanchnectomy alone, rats with bilateral sham exposure of one or both nerve, or rats with pyloromyotomy alone. Serum leptin and white fat mass, 4 weeks after vagotomy, were about 20% of the values in the sham-operated animals at this time. No effect for splanchnic nerve section alone was observed. Pyloromyotomy caused no reduction in weight or fat mass, but reduced serum leptin. Following vagotomy with or without splanchnic nerve section, neuropeptide Y was elevated in the arcuate nucleus relative to values for the other four groups. Changes in neuropeptide Y were inversely correlated with levels of serum leptin. It is concluded that the effect of vagotomy could be due to the loss of a feeding signal carried by vagal afferent neurons, or to changed humoral signals, for example, increased production of a satiety hormone. However, it cannot be attributed to signals that reduce feeding (for example, gastric distension) reaching the central nervous system via the splanchnic nerves. The changes were sufficient to cause weight loss even though serum leptin was decreased, a change that would be expected to increase food intake.

Food affordability in air stage communities.

In 1991 and 1992, changes were made to the rate structure and eligibility requirements of the Northern Air Stage Program. To determine the effect of these changes on the affordability of a nutritious diet, food price surveys were conducted in 20 isolated communities, staging points, and selected southern cities and used to cost a 46-item Northern Nutritious Food Basket (NFB), which meets the nutrient requirements of a reference family of four. Food affordability was calculated as the percentage of "after-shelter" social assistance income required to purchase the NFB. In the Northwest Territories (NWT), from 100% to 123% of income was required in Air Stage communities in 1990-1991 and from 86% to 125% in 1993. In the provinces, from 65% to 83% of income was needed in 1990-1991 and from 56% to 98% in 1993. In Kangiqsujuaq and Nain, the amount of "after-shelter" income needed increased by as much as 6% and 15%, respectively. Changes to the Northern Air Stage Program reduced the cost of perishable foods and improved the affordability of a nutritious diet in the NWT. Affordability is also affected by social assistance income. In most isolated communities, families would still find it difficult to afford a nutritious diet.

Inflammatory bowel disease and exercise: results of a Crohn's and Colitis UK survey.

BACKGROUND: Over 250 000 people in the UK are affected with inflammatory bowel disease (IBD) and approximately 10 000 new cases are diagnosed every year. These chronic bowel conditions have been shown to affect both work and recreational activity. In the general population, regular exercise has numerous benefits to health and well-being and there are additional benefits for those with IBD. However, people with IBD face significant challenges in trying to take regular exercise. OBJECTIVE: With the renewed focus on sport brought about by the recent London Olympics, Crohn's and Colitis UK surveyed its members to explore their sport and fitness habits. METHODS: 918 members participated in the survey, which is the largest survey of its kind, investigating the exercise habits of people with IBD. RESULTS: The survey showed widespread uptake of exercise in those with IBD, with a large number feeling better for it. However, it also identified a considerable number of respondents who reported a significant negative impact of IBD on their ability to take up, enjoy and derive benefit from sporting activities. CONCLUSION: Asking questions about sporting leisure activity in clinical consultations may identify those in need of help and support and possibly identify factors to be dealt with, in order to enable them to take part in these beneficial activities.