Familial rare EGFR-mutant lung cancer syndrome: Review of literature and description of R776H family.

BACKGROUND: Interest in hereditary lung cancer is increasing, in particular germline mutations in the Epidermal Growth Factor Receptor (EGFR) gene. We review the current literature on this topic, discuss risk of developing lung cancer, treatment and screening options and describe a family of 3 sisters with lung cancer and their unaffected mother all with a rare EGFR germline mutation (EGFR p.R776H). METHODS: We searched PubMed, Medline, Embase, the Cochrane Library, Google Scholar and scanned reference lists of articles. Search terms included "EGFR germline" and "familial lung cancer" or "EGFR familial lung cancer". We also describe our experience of managing a family with rare germline EGFR mutant lung cancer. RESULTS: Although the numbers are small, the described cases in the literature show several similarities. The patients are younger and usually have no or light smoking history. 50% of the patients were treated with a tyrosine kinase inhibitor (TKIs) with OS over six months. CONCLUSION: Although rare, germline p.R776H EGFR lung cancer mutations are over-represented in light or never smoking female patients who often also possess an additional somatic EGFR mutation. Treatment with TKIs appears suitable but further research is needed into the appropriate screening regime for unaffected carriers or light/never smokers.

Biology-guided precision medicine in rare cancers: Lessons from sarcomas and neuroendocrine tumours.

Rare cancers, which collectively account for almost 25 % of all malignancies, are poorly understood in terms of their aetiology and pathogenesis and are infrequently the focus of translational and clinical research to improve their diagnosis and treatment. Consequently, those affected have comparatively few treatment options, and their prognosis is worse than that of patients with more common entities. Here we review two relevant groups of rare cancers, bone and soft-tissue sarcomas and neuroendocrine tumours (NET), to illustrate recent efforts towards individualised, biology-guided clinical management to improve long-term outcomes. Specifically, we address how comprehensive, multi-layered molecular analyses, including the assessment of predisposing hereditary factors, and innovative imaging approaches can improve the diagnosis of these diseases, allow for better prognostic assessment, and provide new targets for pharmacologic and, in the case of NET, nuclear medicine interventions, whose clinical value must be determined in controlled trials optimally tailored to the particular patient population most likely to benefit. Furthermore, we describe the importance of multidisciplinary collaboration in dedicated reference centres for rare cancers and the increasingly acknowledged potential of networking across institutions at a national and international level. Finally, we illustrate the value of a learning health system based on the systematic collection and sharing of the biological and clinical profiles of patients with rare cancers to achieve continuous cross-fertilisation of scientific and clinical efforts, making the vision of stratified precision medicine in these long-overlooked diseases a reality.

Approach to screening for Familial Adenomatous Polyposis (FAP) in a cohort of 226 patients with Desmoid-type Fibromatosis (DF): experience of a specialist center in the UK.

INTRODUCTION: Desmoid-type fibromatosis (DF) are locally infiltrative, non-metastasizing tumours associated with significant morbidity and mortality if located intra-abdominally, retroperitoneally or in head and neck localisation. They are mostly sporadic, due to somatic CTNNB1 mutations. Alternatively, they can be associated with germline pathogenic variants in APC causing Familial Adenomatous Polyposis (FAP). Germline APC variants and somatic CTNNB1 mutations are mutually exclusive. AIMS AND METHODS: We conducted a retrospective descriptive analysis of patients with DF seen at the Royal Marsden NHS Foundation Trust Sarcoma Unit in London. We aimed to describe the methods of screening for FAP in patients with DF from a specialist unit. Patients diagnosed between 1992 and 2020 were selected from the prospectively maintained Sarcoma Unit database. RESULTS: 226 patients were identified and 67% (n = 152) were female. Median age at diagnosis was 37.5 (range 2-81) years. Tumour localisation was limbs/pelvis in 30.9% (N = 70), intra-abdominal 16.8% (N = 38), abdominal wall 23.5% (N = 53), thorax 18.6% (N = 42), head and neck 3.1% (N = 7) and vertebral/paravertebral 7.1% (N = 16). Colonoscopy was requested in 65 patients (28.8% of all cases) and was completed in forty-six (20.4%). Molecular testing of CTNNB1 testing was requested in 35 cases (15.5%). APC germline test was requested in 12 cases. Four patients in our cohort had an FAP-associated DF. CONCLUSIONS: CTNNB1 ± APC testing and colonoscopy are useful tools for the screening of patients with DF. CTNNB1 molecular testing should be performed in all cases of newly diagnosed DF. Negative CTNNB1 results, alongside clinical assessment, should prompt APC testing and/or colonoscopy.

Does Mode of Surgical Intervention Based on Oncotype DX Score Influence Disease Recurrence in Early Breast Cancer?

Introduction Routine utilization of multigene assays to inform operative decision-making in early breast cancer (EBC) treatment is yet to be established. In this pilot study, we sought to establish the potential benefits of surgical intervention in EBC based on recurrence risk quantification using the Oncotype DX (ODX) assay. Materials and Methods Consecutive ODX tests performed over a 9-year period from October 2007 to May 2016 were evaluated. Oncotype scores were classified into high (≥31), medium (18-30), or low-risk (0-17) groups. The primary outcome was breast cancer recurrence. Subgroup analysis offered assessment of the recurrence effect of mode of surgical intervention for patient groups as defined by the oncotype score. Results In total 361 patients underwent ODX testing. The mean age and follow-up were 55.25 (± 10.58) years and 38.59 (± 29.1) months, respectively. The majority of patients underwent wide local excision (86.7%) with 8.9 and 4.4% patients having a mastectomy or wide local excision with completion mastectomy, respectively. Fifty-one percent of patients fell into the low risk ODX category with a further 40.2 and 8.5% deemed to be of intermediate and high risk. Five patients (1.38%) had disease recurrence. Comparative analysis of operative groups in each oncotype group revealed no difference in recurrence scores in the low- ( p = 0.84) and high-risk groups ( p = 0.92) with a statistically significant difference identified in the intermediate risk group ( p = 0.002). Conclusion To date we have been unable to definitively identify a role for ODX in guiding surgical approach in EBC. There is, however, a need for larger studies to examine this hypothesis.

Investigating the association of rs2910164 with cancer predisposition in an Irish cohort.

INTRODUCTION: MicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA-mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort. METHODS: The study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22. RESULTS: The total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98-1.46), P = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18-2.14), P = 0.002). CONCLUSION: The rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort.

Impact of receptor phenotype on nodal burden in patients with breast cancer who have undergone neoadjuvant chemotherapy.

BACKGROUND: Optimal evaluation and management of the axilla following neoadjuvant chemotherapy (NAC) in patients with node-positive breast cancer remains controversial. The aim of this study was to examine the impact of receptor phenotype in patients with nodal metastases who undergo NAC to see whether this approach can identify those who may be suitable for conservative axillary management. METHODS: Between 2009 and 2014, all patients with breast cancer and biopsy-proven nodal disease who received NAC were identified from prospectively developed databases. Details of patients who had axillary lymph node dissection (ALND) following NAC were recorded and rates of pathological complete response (pCR) were evaluated for receptor phenotype. RESULTS: Some 284 patients with primary breast cancer and nodal metastases underwent NAC and subsequent ALND, including two with bilateral disease. The most common receptor phenotype was luminal A (154 of 286 tumours, 53·8 per cent), with lesser proportions accounted for by the luminal B-Her2 type (64, 22·4 per cent), Her2-overexpressing (38, 13·3 per cent) and basal-like, triple-negative (30, 10·5 per cent) subtypes. Overall pCR rates in the breast and axilla were 19·9 per cent (54 of 271 tumours) and 37·4 per cent (105 of 281) respectively. Axillary pCR rates were highest in the Her2-overexpressing group (27 of 35, 77 per cent) and lowest in the luminal A group (35 of 153, 22·9 per cent) (P < 0·001). Nodal burden (median number of positive nodes excised) was lower in the Her2-overexpressing group compared with the luminal A group (0 versus 3; P < 0·001). CONCLUSION: Her2 positivity was associated with increased rates of axillary pCR and reduced nodal burden following NAC.

The impact of the Biomolecular Era on breast cancer surgery.

Surgery has always played a central role in the management of breast cancer, with local control via complete tumour resection long established as the cornerstone of effective breast cancer therapy. While extensive surgical resection in the form of the Halstead radical mastectomy dominated treatment up until at least the 1970s, the advent of adjuvant loco-regional and systemic therapies has resulted in a decrease in the magnitude of surgical intervention in recent decades. The Biomolecular or "-omics" era initiated with the discovery of the DNA double helix in 1953 and intensified by the completion of the human genome project in 2003 has seen an unprecedented expansion in our understanding of the molecular and genetic heterogeneity of cancer. This review will discuss how the clinical application of this knowledge in the direction of personalised risk assessment and breast cancer treatment has significant implications for modern surgical practice.

A qualitative analysis of the attitudes of Irish patients towards participation in genetic-based research.

BACKGROUND: Progress in diagnostic and therapeutic strategies in medicine is dependent upon high-quality biomedical research. Technological advances have facilitated improved understanding of disease aetiology, and rapidly emerging data promises further progress. Translating this potential into the clinic depends on patient participation in innovative clinical trials. We investigated attitudes to genetic research in Ireland, particularly with respect to commercial and financial implications. METHODS: A multi-centre, cross-sectional survey study was performed. Consecutive out-patients attending four clinics were asked to complete paper-based questionnaires. The same questionnaire was publicly available in electronic format on www.surveymonkey.com for 72 h. Data were analysed using SPSS. RESULTS: 351 questionnaires were completed (99 paper, 252 electronic). The majority of respondents were female (n = 288, 82 %), and highly educated, with 244 (70 %) attending college/university. Most participants supported genetic research (267, 76 %), more frequently for common diseases (274, 78 %) than rare disorders (204, 58 %, p < 0.001, χ 2). 103 (29 %) had participated in scientific research, and 57 (16 %) had donated material to a bio-bank. The majority (n = 213, 61 %) would not support research with potential financial/commercial gain. 106 (30 %) would decline to participate in research if researchers would benefit financially, compared to 49 (14 %) if the research was supported by a pharmaceutical company (p < 0.001, χ 2). Respondents would provide buccal samples (258, 74 %) more readily than tissue (225, 64 %) or blood (222, 63 %). CONCLUSIONS: A high level of support for genetic research exists among the Irish population, but active participation is dependent upon a number of factors, notably, type of biological material required, frequency of the disease in question, and commercial interest of the researchers.

MUTYH-Associated Polyposis: The Irish Experience>.

MUTYH is involved in DNA damage repair. Bi-allelic MUTYH mutations predispose to polyposis and gastrointestinal malignancies, distinct genetically from autosomal dominant familial adenomatous polyposis coli. Two common European MUTYH mutations account for 90% of MUTYH-associated polyposis (MAP). We aimed to examine the incidence of MAP in Ireland. A retrospective cohort study was undertaken. Patients undergoing MUTYH testing from 2003-2016 were identified by searching electronic databases using terms "MUTYH" and "MYH". Phenotypic and genotypic details were obtained by chart review. Bi-allelic mutations were confirmed in 26 individuals (17 families), of whom 16 (62%) developed colorectal malignancies, and 22(85%) polyposis. Eleven families had bi-allelic status for one/both common European mutations. Regional variation was noted, with over-representation of bi-allelic mutation carriers in the South-west of Ireland. MAP is under-diagnosed in Ireland. Increased awareness is required to facilitate appropriate identification and surveillance of bi-allelic mutation carriers for colorectal pathology.

Medical speciality choice: does personality matter?

There has been increasing interest in the personalities of doctors. This study examined whether personality differed based upon gender, level of training or medical speciality among 200 physicians and 134 medical students. Post-internship doctors scored significantly higher on conscientiousness (p = .001) than those pursuing basic medical training. Among those pursuing basic medical training, females scored significantly higher than males on agreeableness (p < .001) and conscientiousness (p = .001). Among post-internship respondents, females scored significantly higher on agreeableness (p = .004). There were no personality differences between post-internship doctors working in different specialities. However, among those pursuing basic medical training, those interested in person-focused medical specialities scored significantly higher on extraversion (p < .001), conscientiousness (p = .001), and lower on neuroticism (p = .01) than those who had no strong preference. These results suggest that there is no unique personality profile associated with medical practice, or medical speciality. Instead, it appears that medical school may shape personality.

Targeted resequencing of the microRNAome and 3'UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer.

Ovarian cancer is a major cause of cancer deaths, yet there have been few known genetic risk factors identified, the best known of which are disruptions in protein coding sequences (BRCA1 and 2). Recent findings indicate that there are powerful genetic markers of cancer risk outside of these regions, in the noncoding mRNA control regions. To identify additional cancer-associated, functional non-protein-coding sequence germline variants associated with ovarian cancer risk, we captured DNA regions corresponding to all validated human microRNAs and the 3' untranslated regions (UTRs) of ~6000 cancer-associated genes from 31 ovarian cancer patients. Multiple single-nucleotide polymorphisms in the 3'UTR of the vascular endothelial growth factor receptor/FLT1, E2F2 and PCM1 oncogenes were highly enriched in ovarian cancer patients compared with the 1000 Genome Project. Sequenom validation in a case-control study (267 cases and 89 controls) confirmed a novel variant in the PCM1 3'UTR is significantly associated with ovarian cancer (P=0.0086). This work identifies a potential new ovarian cancer locus and further confirms that cancer resequencing efforts should not ignore the study of noncoding regions of cancer patients.

Endovascular aneurysm repair for multiple aneurysms as a sequel of hypereosinophilic syndrome.

This case represents the first report of multiple arterial aneurysms including aortic, iliac, visceral, and coronary aneurysms associated with hypereosinophilic syndrome. It presents an interesting case of epinephrine abuse and the unfortunate sequelae. This case illustrates novel approaches in emergency repair of internal iliac artery aneurysm rupture and the management of visceral artery aneurysms and exemplifies how multiple endovascular technologies can be utilized even in the high-risk polymorbid patient.

Gender differences in undergraduate medicine in Galway: a tale of two curricula.

AIMS: Medical teaching in the National University of Ireland Galway (NUIG) has undergone a shift from subject- to system-based learning. Our aims were to examine differences between genders in academic performance in medicine across two different curricula. METHODS: Results of each student graduating between 2007 and 2012 for each subject undertaken over the medical degree were obtained from the Medical School. Data were collected with respect to gender, nationality and mode of entry, and analysis completed using SPSS. RESULTS: The cohort included 360 females and 249 males. 396 students read from a subject-based curriculum and 213 a system-based course. Females outperformed males in 19/24 (79 %) subjects in the subject-based curriculum, and in 9/38 (24 %) in the system-based course. Males were more likely to fail and less likely to achieve an honours degree. Multivariate analysis showed nationality and gender to be significant predictive factors. CONCLUSION: Females outperformed males overall. Differences were most pronounced in a subject-based curriculum. Nationality and gender were found to be significant factors in determining overall results.

Familial breast cancer genetic testing in the West of Ireland.

AIMS: The majority of hereditary breast and ovarian cancers are associated with highly penetrant mutations in two genes: BRCA 1 and 2. Our aim was to investigate the prevalence and types of BRCA mutations in patients from the West of Ireland. METHODS: A retrospective cohort study was undertaken that included all patients from the counties, Mayo, Sligo, Galway, Roscommon, and Clare, who were referred to the National Centre for Medical Genetics (NCMG) for testing for mutations in BRCA 1 or 2 between 2000 and 2010. Data including age, symptoms, family history, Manchester score, and test results were recorded and analysed using SPSS. RESULTS: The NCMG received 380 referrals from the Western seaboard, including 148 for diagnostic testing and 232 for predictive evaluation. Sixty-five patients did not attend for assessment. Two hundred and fifty-six patients fulfilled criteria for genetic counselling, which was accepted by 184, of whom 127 proceeded to testing. Predictive tests were more often declined than diagnostic [41 (46 %) vs. 16 (17 %)]. Ten mutations in BRCA 1 were identified in 20 patients (15 families), including Exon 1-23del (3 families); Exon 14-20del (2 families) and E143X (2 families). Six mutations in BRCA 2 were identified in 15 patients (12 families) including 8525delC (n = 2 families) and 8205-1G>C (n = 3 families). Patients with positive results had significantly higher Manchester scores than those with negative tests [median 25.5 (12-48) vs. 20 (8-37), p = 0.042, Mann-Whitney U test]. CONCLUSION: To identify patients with highly penetrant variants, referrals should be made with strict adherence to guidelines. Counselling should be individualised to counteract intrinsic psychological barriers to testing.

Changing practices in the surgical management of hyperparathyroidism - a 10-year review.

AIM: Parathyroid surgery has undergone a paradigm shift over the last decade, with a move from traditional bilateral neck exploration to minimally invasive parathyroidectomy (MIP), and increasing reliance on pre- and intra-operative localization of overactive glands. We aimed to assess changing surgical practices and their impact on the management of parathyroid disease in a tertiary referral centre in the West of Ireland. METHODS: A retrospective cohort analysis of those patients undergoing a surgical intervention for parathyroid disease in the period between 1999 and 2009 in our centre was carried out. Data was analysed using PASW (v18) software. RESULTS: 248 procedures were performed, increasing from an annual rate of 6 in 1999 to 45 in 2009. 129 procedures were completed by minimally invasive means, following the introduction of MIP in 2003. Single-gland disease accounted for 87% of cases (n = 216) with carcinomas in 2 patients (0.8%). Pre-operative localization had disappointing diagnostic value, with high false negative rates for both ultrasound (37.3%) and Sestamibi Scanning (35.81%). Intra-operative adjuncts were more helpful, with intra-operative Parathyroid hormone monitoring facilitating curative resection of adenomas in 94.03% at 10 min. Median length of post-operative stay has significantly decreased from 6 days in 1999 to 1 night only in 2009 (p < 0.01, ANOVA). Those patients undergoing MIP had shorter stay than the open group (1.71 days -v-4.73, p = 0.003,t-test). CONCLUSION: The practice in our centre has shifted to a less invasive approach. Increased utilisation of intra-operative adjuncts has facilitated this change, and resulted in favourable changes in length of stay, extent of dissection, and number of patients treated.

The effects of intrauterine cocaine exposure on the respiratory status of the very low birth weight infant.

OBJECTIVES: This study examined the effects of intrauterine cocaine exposure on very low birth weight infants with respect to their surfactant requirement and need for ventilatory support. STUDY DESIGN: A retrospective cohort study was conducted on infants with birth weight between 750 and 1500 g admitted to the neonatal intensive care unit between January 1992 and January 1995. RESULTS: Of the 149 infants studied, 48 infants were exposed only to cocaine and 101 infants had no drug exposure. There were no significant differences between the two groups for gestational age, sex, abruptio placenta, prolonged rupture of membranes, and antenatal steroid usage. The cocaine-exposed group had a significantly greater birth weight (1190 vs. 1109, p<0.02), less prenatal care (48% vs. 14%, p<0.00007), older maternal age (30 vs. 24, p<0.00002), more black race (79% vs. 57%, p<0.01), and more rapid plasma reagin (RPR) positivity (25% vs. 2%, p<0.00006). There were no significant differences in median APGAR scores, or incidence of necrotizing enterocolitis, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), and bronchopulmonary dysplasia (BPD) between the two groups. Cocaine-exposed infants received surfactant treatment less often (73% vs. 48%, p<0.0035), received fewer mean doses of surfactant (0.4 vs. 10.0, p<0.0014), and were intubated less frequently (44% vs. 65%, p<0.012). There was no significant difference between groups for intubation at 24 and 48 hours and for the development of bronchopulmonary dysplasia. CONCLUSION: Perinatal cocaine exposure appears to have some significant short-term effects on the need for surfactant replacement therapy and need for initial intubation in respiratory distress syndrome (RDS) but no overall effect on the development of BPD.

The role of Saccharomyces cerevisiae Met1p and Met8p in sirohaem and cobalamin biosynthesis.

MET1 and MET8 mutants of Saccharomyces cerevisiae can be complemented by Salmonella typhimurium cysG, indicating that the genes are involved in the transformation of uroporphyrinogen III into sirohaem. In the present study, we have demonstrated complementation of defined cysG mutants of Sal. typhimurium and Escherichia coli, with either MET1 or MET8 cloned in tandem with Pseudomonas denitrificans cobA. The conclusion drawn from these experiments is that MET1 encodes the S-adenosyl-l-methionine uroporphyrinogen III transmethylase activity, and MET8 encodes the dehydrogenase and chelatase activities (all three functions are encoded by Sal. typhimurium and E. coli cysG). MET8 was further cloned into pET14b to allow expression of the protein with an N-terminal His-tag. After purification, the functions of the His-tagged Met8p were studied in vitro by assay with precorrin-2 in the presence of NAD+ and Co2+. The results demonstrated that Met8p acts as a dehydrogenase and chelatase in the biosynthesis of sirohaem. Moreover, despite the fact that S. cerevisiae does not make cobalamins de novo, we have shown also that MET8 is able to complement cobalamin cobaltochelatase mutants and have revealed a subtle difference in the early stages of the anaerobic cobalamin biosynthetic pathways between Sal. typhimurium and Bacillus megaterium.

Immunochemical and biochemical analysis of the polyvalent Pseudomonas aeruginosa vaccine PEV.

The Pseudomonas aeruginosa polyvalent vaccine PEV and its 16 constituent monovalent extracts from International Antigenic Typing System serotypes 1 through 13 and 15 through 17 (J. J. Miler, J. F. Spilsbury, R. J. Jones, E. A. Roe, and E. J. L. Lowbury, J. Med. Microbiol. 10:19-27, 1977) were subjected to biochemical analysis and to detailed immunochemical analysis with rabbit anti-PEV immunoglobulins. The results of chemical analysis, of analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis performed in conjunction with silver staining, and of analysis by crossed immunoelectrophoresis, sodium dodecyl sulfate-polyacrylamide gel-crossed immunoelectrophoresis, and Western blotting showed clearly that lipopolysaccharide was a major constituent of each monovalent extract and that it was probably the dominant antigen present in at least 15 of the 16 monovalent extracts. A 16.2-kilodalton protein, which was pronase resistant and nonsedimentable at 105,000 X g and which appeared to be biochemically and antigenically unrelated to pili, was a common although minor antigen for all extracts. Several other proteins, some of outer membrane origin, were also detected in unformalinized extracts, but these were also minor antigenic constituents of the vaccine. Neither pilin nor flagellin appeared to be major protein constituents of tested monovalent extracts, although anti-flagella antibodies could be demonstrated in rabbit anti-PEV by Western blotting. Preliminary analysis by crossed immunoelectrophoresis of serum raised in volunteers to PEV also indicated the presence therein of antibodies to lipopolysaccharide antigens.