Presenting symptoms and long-term survival in head and neck cancer.

OBJECTIVES: To assess how type and number of symptoms are related to survival in patients with head and neck cancer. DESIGN: Patients were followed up for over 10 years from the Scottish Audit of Head and Neck Cancer (national cohort of head and neck cancer patients in Scotland 1999-2001). September 2013, cohort was linked to national mortality data. First, second and third presenting symptoms were recorded at diagnosis. SETTING: National prospective audit-Scotland. PARTICIPANTS: A subset of 1589 patients, from the original cohort of 1895, who had cancer arising from one of the four main subsites; larynx, oropharynx, oral cavity and hypopharynx. MAIN OUTCOME MEASURES: Median survival in relation to patients' presenting symptoms. RESULTS: A total of 1146 (72%) males and 443 (28%) females, mean age at diagnosis 64 years (13-95). There was a significant difference in survival in relation to the number of the patient's presenting symptoms; one symptom had a median survival of 5.3 years compared with 1.1 years for three symptoms. Patients who presented with weight loss had a median survival of 0.8 years, compared to 4.2 years if they did not (P < .001). Patients who presented with hoarseness had a median survival of 5.9 years compared to 2.6 years without (P < .001). There was no significant difference in long-term survival for patients who presented with an ulcer, compared to those that did not (P = .105). CONCLUSIONS: This study highlights the importance of patients' presenting symptoms, giving valuable information in highlighting appropriate "red flag" symptoms and subsequent treatment planning and prognosis.

Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population.

Common genetic variants in the 9p21 region and their associations with multiple tumours.

BACKGROUND: The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers. METHODS: We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction. RESULTS: Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 × 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007). CONCLUSION: Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis.

Worldwide genetic structure in 37 genes important in telomere biology.

Telomeres form the ends of eukaryotic chromosomes and are vital in maintaining genetic integrity. Telomere dysfunction is associated with cancer and several chronic diseases. Patterns of genetic variation across individuals can provide keys to further understanding the evolutionary history of genes. We investigated patterns of differentiation and population structure of 37 telomere maintenance genes among 53 worldwide populations. Data from 898 unrelated individuals were obtained from the genome-wide scan of the Human Genome Diversity Panel (HGDP) and from 270 unrelated individuals from the International HapMap Project at 716 single-nucleotide polymorphism (SNP) loci. We additionally compared this gene set to HGDP data at 1396 SNPs in 174 innate immunity genes. The majority of the telomere biology genes had low to moderate haplotype diversity (45-85%), high ancestral allele frequencies (>60%) and low differentiation (FST<0.10). Heterozygosity and differentiation were significantly lower in telomere biology genes compared with the innate immunity genes. There was evidence of evolutionary selection in ACD, TERF2IP, NOLA2, POT1 and TNKS in this data set, which was consistent in HapMap 3. TERT had higher than expected levels of haplotype diversity, likely attributable to a lack of linkage disequilibrium, and a potential cancer-associated SNP in this gene, rs2736100, varied substantially in genotype frequency across major continental regions. It is possible that the genes under selection could influence telomere biology diseases. As a group, there appears to be less diversity and differentiation in telomere biology genes than in genes with different functions, possibly due to their critical role in telomere maintenance and chromosomal stability.

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.

BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk. METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001). CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.

The integral membrane protein, ponticulin, acts as a monomer in nucleating actin assembly.

Ponticulin, an F-actin binding transmembrane glycoprotein in Dictyostelium plasma membranes, was isolated by detergent extraction from cytoskeletons and purified to homogeneity. Ponticulin is an abundant membrane protein, averaging approximately 10(6) copies/cell, with an estimated surface density of approximately 300 per microns2. Ponticulin solubilized in octylglucoside exhibited hydrodynamic properties consistent with a ponticulin monomer in a spherical or slightly ellipsoidal detergent micelle with a total molecular mass of 56 +/- 6 kD. Purified ponticulin nucleated actin polymerization when reconstituted into Dictyostelium lipid vesicles, but not when a number of commercially available lipids and lipid mixtures were substituted for the endogenous lipid. The specific activity was consistent with that expected for a protein comprising 0.7 +/- 0.4%, by mass, of the plasma membrane protein. Ponticulin in octylglucoside micelles bound F-actin but did not nucleate actin assembly. Thus, ponticulin-mediated nucleation activity was sensitive to the lipid environment, a result frequently observed with transmembrane proteins. At most concentrations of Dictyostelium lipid, nucleation activity increased linearly with increasing amounts of ponticulin, suggesting that the nucleating species is a ponticulin monomer. Consistent with previous observations of lateral interactions between actin filaments and Dictyostelium plasma membranes, both ends of ponticulin-nucleated actin filaments appeared to be free for monomer assembly and disassembly. Our results indicate that ponticulin is a major membrane protein in Dictyostelium and that, in the proper lipid matrix, it is sufficient for lateral nucleation of actin assembly. To date, ponticulin is the only integral membrane protein known to directly nucleate actin polymerization.

Cancer waiting times: what is the value of a lymphoma waiting time?

BACKGROUND AND AIM: Waiting times for patients with lymphoma have been reported across the United Kingdom since 2005. Lymphoma however, is not a single disease but a wide spectrum of lymphoid tumours that range from the most malignant to the most indolent, from highly curable to incurable. We now question the value of the current system that reports lymphoma waiting time on a quarterly basis and makes no allowance for the different types of lymphoma. METHOD: Four hundred and sixty nine cases of lymphoma were registered in the west of Scotland in 2004. Complete datasets were available on 428. Patient demographic data, subtypes of lymphoma, biopsy site and referral urgency data were linked to the waiting times analysis for 2004 for the three subtypes, Lymphoma (HL), Diffuse Large B Cell (DLBC) and follicular Non Hodgkin Lymp (NHL). RESULTS: Patients with HL were younger, more likely to receive urgent referral and have a diagnosis made from neck node biopsy than the other two groups. Patients with DLBC NHL however had the shortest interval between presentation and the start of treatment and were subsequently more likely to receive treatment within 62 days than patients with either follicular NHL (p < 0.001) or HL (p < 0.05). CONCLUSION: Lymphoma subtype is a major factor determining the rate of progress from presentation to the start of treatment, hence the waiting time.

Cervical lymphadenopathy resulting in a diagnosis of lymphoma.

BACKGROUND AND AIMS: Currently there is no protocol in the west of Scotland for the investigation of a patient with a lymph node in the neck which might contain lymphoma. The aim of this audit was to examine the current management of these patients. METHODS: Data were collected on 112 patients diagnosed as having lymphoma from a neck node biopsy within a 12 month period from 1st November 2004 to 31st October 2005. Biopsy data were collected in combination with the first point of consultation, investigations used to arrive at diagnosis and any associated complications. RESULTS: Eighty seven percent of patients underwent excision biopsy with complications noted in 7%. Fine needle aspiration cytology (FNAC) was carried out in 60% of which 34% were ultrasound guided. Core biopsy was carried out in 17% of which 63% were ultrasound guided, Forty-five percent of patients were first referred to ear, nose and throat (ENT) surgery, 17% to general surgery, 14% to haematology, 13% to general medicine and 11% to other specialties. CONCLUSION: This audit shows that there was a wide range of first points of consultation and diagnostic procedures used. It is recommended that there should be access for all patients with cervical lymphadenopathy to a weekly neck lump clinic with standardised protocols for lymphoma diagnosis. This should ensure that patients are diagnosed accurately and treated in a timely manner.

Thinking outside the box: re-evaluating the approach to penetrating cardiac injuries.

INTRODUCTION: Penetrating cardiac injuries are infrequent but highly lethal. To address these injuries, cardiopulmonary bypass and cardiothoracic surgery availability are required for Level I trauma center verification. However, acute care surgeons are more readily available for this time-sensitive injury. The purpose of this study was to review an acute care surgery-based experience with penetrating cardiac trauma at an urban Level 1 trauma center. Our hypothesis was that care provided solely by acute care surgeons was both safe and effective for this patient population. METHODS: All patients with injuries to the 'cardiac box' following penetrating thoracic trauma were identified from 2005-2010. Demographic and injury related data were obtained. The types and location of cardiac injury, as well as patient outcomes, were determined from operative reports. RESULTS: 1701 patients with penetrating chest trauma were admitted during the study period. 260 patients were identified as having high-risk injuries and were included in the review. 37 patients underwent resuscitative thoracotomy, with a survival rate of 8 %. 76 patients (29 %) suffered a cardiac injury. 72 % of these patients had a preoperative FAST exam, which had a sensitivity and specificity of 56.5 and 82.5 % respectively. 82 % underwent a pericardial window, which had a positive predictive value of 81.4 %. 61 % (n = 46) of the patients with a cardiac injury survived, while the overall death rate in this cohort was 21 %. No patients in the cohort required cardiopulmonary bypass for emergent repair of cardiac injury and acute care surgeons performed all cases. CONCLUSION: Penetrating injury to the heart is highly lethal and time-sensitive. Increasingly, FAST and subxyphoid pericardial window are relied upon to make the diagnosis in patients arriving in varying stages of shock to the resuscitation room. Acute care surgeons are the most appropriate surgeons to care for these injuries and provide safe and effective care.

Self-help manuals for problem drinking: the relative effects of their educational and therapeutic components.

This study was concerned with the effects of a self-help manual, administered under conditions of minimal therapist contact, on the alcohol consumption of 26 media-recruited volunteers. It was found that the self-help programme was effective in bringing about a reduction in self-reported alcohol consumption. In addition, the order of presentation of the health education and self-management components of the self-help manual was important with respect to outcome. The group receiving the components in the order self-management followed by education showed a better outcome, in terms of lowered alcohol consumption, than a group receiving the same material in the reverse order. An explanation for this is advanced in terms of the model for process of change put forward by Prochaska & DiClemente (1983). Noting that the use of self-help is best documented for those with less severe alcohol dependency, a number of points for both practice and future research are made.

Breast self-examination training: a brief review.

A review of the literature on breast self-examination training indicated that any training in breast self-examination improves compliance, confidence, and proficiency; the evidence is unclear about the relative effectiveness of group or individual training; practice on breast models and on the woman's own breasts should be included in breast self-examination training; additional training sessions improve compliance and proficiency; reminders increase compliance, but the effect ceases when the reminders cease; and it is particularly important for older women to search their breasts slowly and thoroughly. Several other new approaches to breast self-examination training are discussed.

Health status and participation in a range of activities in an Australian community.

INTRODUCTION: The aim of the research was to determine the relationship between levels of participation in a community and self-assessed health status of people in a rural and regional setting. METHOD: A cross-sectional design, using a mailed, self-administered questionnaire was used. Questionnaires were mailed to a random sample of people aged 18 years and over who were registered on the electoral roll of a regional city and rural area, the Barwon and Otway regions of Victoria, Australia. The sample consisted of 1752 participants: 990 females (57%), 739 males (42%) and 23 sex undisclosed (1%). The range of participants was 18-98 years, and the mean age was 50.53 years (SD = 17.19). RESULTS: Self-assessed physical and mental health were measured using the SF-12 scale. Participants with low incomes, and those with low self-assessed physical and mental health scores, were significantly more likely than other participants to agree with one or more of the social isolation items, indicating that they experienced some social isolation. Low levels of participation in social, sports, leisure or support activities were associated with low self-assessed physical and mental health. Disengagement with the local community was associated with low levels of self-assessed mental health. While younger people were more likely than older people to participate in social, sports, leisure or support activities, they were less involved as members of their community. Females were more likely than males to have been involved in five or more sports, leisure or support activities. Participation in civic activities was associated with high income. Levels of participation in the four different types of activities were combined (social activities, sport, leisure or support activities, community and group activities, and civic activities). Participants classified as low participators were more likely to be older participants, to have a low income and to have low scores for both physical and mental health. CONCLUSION: An association was found between health and community participation in a range of activities, and between health and engagement with the community in this rural and regional population. These findings are consistent with those reported from similar research with a metropolitan population sample. The current research suggests that the groups of people of most concern in terms of low participation rates, are people who have low incomes, people aged over 65 years, people who may be defined as possessing poor physical health and people who may be defined as possessing poor mental health. The relationship between age, community participation and health is complex and needs further exploration because it is not known whether poor health reduces community participation or whether reduced community participation results in poor health. However, current research suggests that developing and implementing strategies to promote people's engagement with and involvement in their local community is one important way of promoting the health of the community as a whole.

Damage control strategies in the management of acute injury.

Traumatic injury is the leading cause of death worldwide. The rapid evaluation and correction of injuries in these patients is paramount to preventing uncontrolled decompensation and death. Damage control strategies are a compendium of techniques refined over decades of surgical care that focus on the rapid correction of deranged physiology, control of contamination and blood loss, and resuscitation of critical patients. Damage control resuscitation (DCR) focuses on the replacement of lost blood volume in a manner mimicking whole blood, control of crystalloid administration, and permissive hypotension. Damage control laparotomy controls gastrointestinal contamination and bleeding in the operative suite, allowing rapid egress to the intensive care unit for ongoing resuscitation. Pelvic packing, an adjunct to DCR, provides a means to control hemorrhage from severe pelvic fractures. Temporary vascular shunts restore perfusion, while resuscitation and reconstruction are ongoing. Taken together, these strategies provide the trauma surgeon with a powerful arsenal to preserve life in the transition from injury to the shock trauma room to the intensive care unit.

Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita.

Dyskeratosis congenita (DC) is characterized by reticular skin pigmentation, oral leukoplakia and abnormal nails. Patients with DC have very short telomeres and approximately one-half have mutations in telomere biology genes. A majority of patients with DC develop BM failure (BMF). Hematopoietic cell transplantation (HCT) represents the only known cure for BMF in DC, but poses significant toxicities. We report six patients who underwent allogeneic HCT with a novel nonmyeloablative conditioning regimen specifically designed for DC patients. Graft sources included related PBSCs (1), unrelated BM (2) and unrelated double umbilical cord blood (3). Complete donor engraftment was achieved in five of six patients. One patient had initial autologous hematopoietic recovery, which was followed by a second transplant that resulted in 88% donor chimerism. With a median follow-up of 26.5 months, four patients are alive, three of whom were recipients of unrelated grafts. We conclude with this small study that encouraging short-term survival can be achieved with HCT in patients with DC using a preparative regimen designed to promote donor engraftment and minimize life-threatening disease-specific complications such as pulmonary fibrosis. Long-term follow-up will be crucial with respect to individualized patient care with each of the transplanted individuals.

Processes and outcomes of head and neck cancer patients from geographically disparate regions of the UK. A comparison of Scottish and English cohorts.

AIM: The aim of this paper was to compare demographics, treatment and outcomes from two large prospective audits of head and neck cancer patients in two disparate regions of the UK. METHODS: In the Scottish Audit of Head and Neck Cancer (SAHNC) a total of 1910 patients with new head and neck cancers were registered in a two year period from September 1999 to August 2001. The South and West Audit of Head and Neck Cancer (SWAHN) was carried out in three phases between 1996 and 2002 with a total of 2050 cases. RESULTS: There were more men in SAHNC than SWAHN (71% vs 67%, p<0.01) and patients in SAHNC presented at a younger age (76% aged 45-74 compared with 64%, p<0.001). Significantly more patients in Scotland had advanced (stage III/IV) laryngeal cancer (44% vs 30%, p<0.001). The overall disease specific five year survival was 54.5 for SAHNC and 54.2 for SWAHN. CONCLUSION: This comparison of large head and neck cancer cohorts provides important data to base UK head and neck cancer care and hypotheses regarding pathogenesis and the effects of treatment processes. Given the heterogeneity in disease, patient and healthcare characteristics between the two regions, the similarities in survival and process outcomes are striking.

Parotid lymphoma in west Scotland: two-year 'snapshot' of diagnosis, management and core issues.

OBJECTIVES: To establish whether there is a requirement for a network policy on management of suspected intraparotid lymphoma, and to answer the question, 'Can lymphoma of the parotid region be adequately diagnosed, typed and treated on the basis of a core biopsy, within the West of Scotland?' METHOD: We identified 22 patients from the West of Scotland Managed Clinical Network database who had been diagnosed between 2003 and 2005 with lymphoma of the parotid region (nodal or extranodal). These 22 cases were reviewed, assessing specifically their investigation and diagnosis (compared with the World Health Organization classification of parotid lymphoma). RESULTS: Three of the 22 patients underwent core biopsy to diagnose and type their lymphoma. All these procedures were performed within a single centre. CONCLUSION: It is possible to successfully perform core biopsy of parotid lymphoma lesions (generally under ultrasonic guidance). This may obviate the need for open procedures. Close collaboration with haematology, pathology, radiology, and head and neck colleagues is required.

Teleconferencing in the management of head and neck cancer.

Teleconferencing can be used as part of the integrated management of head and neck cancer. An audit of the participants' views would suggest that the meeting is used in the management of complex head and neck issues.

Genetic variation in five genes important in telomere biology and risk for breast cancer.

Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT (-1381C>T, -244C>T, and Ex2-659G>A) may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer (odds ratios 0.73, 0.66, and 0.57, 95% confidence intervals 0.53-1.00, 0.46-0.95 and 0.39-0.84, respectively). In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.

Factors associated with screening mammography and breast self-examination intentions.

The factors associated with the use of two methods for the early detection of breast cancer were assessed using a theoretical framework derived from the theory of reasoned action and the Health Belief Model. Telephone interviews were conducted with 170 women aged between 50 and 70 years, randomly selected from the telephone directory of a provincial city in Victoria, Australia. The model explained 47% of the variance in intentions to have a mammogram and 22% of the variance in intentions to practise breast self-examination (BSE). The data supported the prediction that different variables would be associated with each method of early detection of breast cancer. Intentions to have a mammogram were associated with perceived susceptibility to breast cancer, knowing a woman who has had a mammogram, previous mammography history and Pap test history. Intentions to do BSE were associated with self efficacy, knowledge of breast cancer issues, concern about getting breast cancer and employment status. Both screening methods were associated with prior behaviour and concern about getting breast cancer.

Older women's illness representations of cancer: a qualitative study.

This paper investigates the role of illness representations in older women's utilization of cancer screening. Older women's own beliefs, or illness representations, of cancer and cancer screening in relation to breast cancer and cervical cancer were explored using relatively unstructured, face-to-face interviews. Twenty women aged between 45 and 70 were interviewed, half of whom were regular screeners and half under-screeners. A comparison of the illness representations of the screeners with the under-screeners indicates some differences regarding cancer in general, and substantial differences regarding the treatment and cure of cancer. The screeners expressed less concern about cancer and gave more positive examples of the successful treatment of cancer. The under-screeners were more likely to express cynicism about the medical profession, to indicate that a person would have symptoms if they had cancer, that they would not want most of the treatment available for cancer, that screening is more important for younger women and that the use of alternative therapies negates the need for cancer screening. Few differences emerged between the two groups regarding the causes of cancer.