Social supports in patients with cancer attending an Irish cancer center: a cross-sectional study.

A positive association has been demonstrated between social supports, quality of life, and survival outcomes in cancer. This study assessed levels of social supports among patients with cancer in an Irish institution, with an age- and gender-specific stratification. The study highlights relatively low levels of perceived socio-emotional support and social connectedness, but good levels of tangible and informational support in our cohort of patients with cancer. Cancer clinicians should consider social supports as a factor when deciding upon cancer therapies and surveillance programs, and link in available support services for individuals with low levels of social supports where feasible.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Economic impact of 21-gene recurrence score testing on early-stage breast cancer in Ireland.

The 21-gene test is a validated multi-gene diagnostic test that predicts chemotherapy (CT) benefit in oestrogen receptor positive (ER+), lymph node-negative (N0) breast cancer (BC) patients (pts). Ireland was the first public health care system to reimburse this test in Europe. Study objectives were to assess the impact of this test on decision-making and to analyse the economic impact of testing. Between October 2011 and February 2013, a national, retrospective, cross-sectional observational study of ER+, N0 BC pts tested with the 21-gene test was conducted. Surveyed breast medical oncologists, provided the assumption for the decision impact analysis that grade (G) 1 pts would not have received CT before testing and G2/3 pts would have received CT before testing. Descriptive statistical analyses were performed. 592 pts were identified; Low, intermediate and high recurrence score were identified in 53, 36 and 10 % pts, respectively. 384 (70 %) pts had G2, 129 (22 %) G3 and 76 (13 %) G1 tumours. Post testing, 345 pts (59 %) experienced a change in CT decision; 339 changed to hormone therapy alone and 6 advised to receive CT. 172 (30 %) pts received CT, 12 (3.9 %) of pts with low scores, 108 (50.9 %) of intermediate risk and 50 (90.9 %) of pts with high risk scores. Net reduction in CT use was 58 % and net savings achieved were €793,565. Since public reimbursement, the introduction of the 21-gene test has resulted in a significant reduction in chemotherapy administration and cost savings for the Irish public healthcare system.

Cutaneous leiomyosarcoma in a case of hereditary leiomyomatosis and renal cell carcinoma syndrome.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal-dominant disorder that results from a germline pathogenic variant in the fumarate hydratase (FH) gene on chromosome 1, characterised by renal cell carcinoma (RCC), cutaneous leiomyoma and uterine leiomyoma. Leiomyosarcomas are reported in less than 1% of those with HLRCC. We report a case of a man in his 30s who had a long-standing plaque excised from the left upper arm after undergoing a radical nephrectomy for a fumarate-deficient RCC, with histological exam revealing a grade 1 leiomyosarcoma. Genetic testing confirmed a heterozygous pathogenic variant in the FH gene. This is a rare case of leiomyosarcoma associated with HLRCC, and our patient remains under surveillance with interval abdominal imaging and skin examination. Leiomyosarcomas are difficult to distinguish clinically from their benign counterpart; therefore, histopathological examination is paramount with a low threshold for excision.

Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

The prognostic value of the derived neutrophil-to-lymphocyte ratio (dNLR) in patients treated with immune checkpoint inhibitors.

BACKGROUND: The (derived) neutrophil-to-lymphocyte ratio (dNLR) is a potential predictive biomarker in the era of checkpoint inhibitors (CPI). An elevated dNLR is associated with worse outcomes across several malignancies. However, there is no clearly defined cut-off in the clinical setting. AIM: To compare outcomes in patients prescribed CPI with a baseline dNLR0 > 3 and dNLR0 ≤ 3. The dNLR6 was measured 6 weeks later to determine its impact on patient overall survival (OS). METHODS: Prospectively maintained pharmacy databases in a regional cancer centre were interrogated for patients who were prescribed CPI in the advanced setting between January 2017 and May 2020. RESULTS: There were 121 patients with advanced cancer and a median age of 68 (range 30 to 88) years. Forty-four percent (n = 53) received prior systemic therapy. Patients with an initial dNLR0 > 3 when compared with a dNLR0 ≤ 3 had significantly shorter median progression-free survival (PFS), 3 vs. 14 months (p = 0.001) and median OS, 6.4 vs. 30.2 months (p = 0.001). Patients with an initial dNLR0 > 3 and increased dNLR at 6 weeks (dNLR6) had significantly reduced median PFS (3.5 vs. 14.7 months, p = 0.03) and OS (5.7 vs. 16.3, p = 0.03) when compared with those whose dNLR decreased. In the dNLR0 ≤ 3 cohort, any increased dNLR when compared with decreased dNLR after 6 weeks of CPI had significantly reduced PFS (8.4 months vs. NR, p = 0.01) and OS (24.2 months vs. NR, p = 0.02). CONCLUSIONS: Lower pre-CPI treatment dNLR is associated with improved OS. A decrease in dNLR during treatment confers improved OS.

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial.

Background: In the FLIPPER trial, palbociclib/fulvestrant significantly improved progression-free survival (PFS) compared with placebo/fulvestrant in postmenopausal women with HR+/HER2- advanced breast cancer (ABC). Objective: We assessed health-related quality of life (QoL) using patient-reported outcomes (PROs). Design and methods: In this phase II double-blinded study, PROs were assessed at baseline after every three cycles and at the end of the treatment using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23. Time to deterioration (TTD) in global health status (GHS)/QoL was defined as a decrease of ⩾10 points. Changes from baseline (CFB) and TTD were analysed using linear mixed-effect and Cox regression models, respectively. Results: Of the 189 randomised (1:1) patients, 178 (94%) completed ⩾1 post-baseline assessment; 50% received ⩾22 cycles of study treatment, with a questionnaire compliance >90%. Mean baseline scores were comparable between arms. GHS/QoL scores were maintained throughout the palbociclib/fulvestrant treatment. CFB showed significant differences for GHS/QoL, appetite loss, constipation and systemic therapy side effect scores favouring placebo/fulvestrant. TTD in GHS/QoL was delayed in placebo/fulvestrant versus palbociclib/fulvestrant [30.3 versus 11.1 months; adjusted hazard ratio (aHR): 1.57, 95% CI: 1.03-2.39, p = 0.036]; this difference was not significant in patients with progressive disease (aHR: 1.2, 95% CI: 0.6-2.2, p = 0.658). No statistically significant differences in TTD were found for the other QLQ-C30 and QLQ-BR23 scales. Conclusions: Although TTD in GHS/QoL was prolonged with placebo/fulvestrant, no differences were observed on other functional or symptom scales. This finding and the improvement in PFS support the combination of palbociclib/fulvestrant as a beneficial therapeutic option for HR+/HER2- ABC. Trial registration number: Sponsor Study Code: GEICAM/2014-12EudraCT Number: 2015-002437-21ClinTrials.gov reference: NCT02690480.

Chemotherapy Toxicity in Older Adults Optimized by Geriatric Assessment and Intervention: A Non-Comparative Analysis.

The Comprehensive Geriatric Assessment (CGA) is recommended to guide treatment choices in older patients with cancer. Patients ≥ 70 years referred to our oncology service with a new cancer diagnosis are screened using the G-8. Patients with a score of ≤14 are eligible to attend the Geriatric Oncology and Liaison (GOAL) Clinic in our institution, with referral based on physician discretion. Referred patients undergo multidimensional assessments at baseline. CGA domains assessed include mobility, nutritional, cognitive, and psychological status. Chemotherapy toxicity risk is estimated using the Cancer Aging and Research Group (CARG) calculator. We undertook a retrospective analysis of patients attending the GOAL clinic over a 30-month period to April 2021. The objective was to determine rates of treatment dose modifications, delays, discontinuation, and unscheduled hospitalizations as surrogates for cytotoxic therapy toxicity in these patients. These data were collected retrospectively. Ninety-four patients received chemotherapy; the median age was 76 (70-87) and 45 were female (48%). Seventy-five (80%) had an ECOG PS of 0-1. Seventy-two (77%) had gastrointestinal cancer, and most had stage III (47%) or IV (40%) disease. Chemotherapy with curative intent was received by 51% (n = 48) and 51% received monotherapy. From the CGA, the median Timed Up and Go was 11 s (7.79-31.6), and 90% reported no falls in the prior 6 months. The median BMI was 26.93 (15.43-39.25), with 70% at risk or frankly malnourished by the Mini Nutritional Assessment. Twenty-seven (29%) patients had impaired cognitive function. Forty-three (46%) had a high risk of toxicity based on the baseline CARG toxicity calculator. Twenty-six (28%) required dose reduction, 55% (n = 52) required a dose delay, and 36% (n = 34) had a hospitalization due to toxicity. Thirty-nine patients (42%) discontinued treatment due to toxicity. Despite intensive assessment, clinical optimization and personalized treatment decisions, older adults with cancer remain at high risk of chemotherapy toxicity.

Professional burnout, work patterns and career satisfaction in medical oncologists in Ireland.

BACKGROUND: Burnout is an occupational syndrome frequently encountered within the healthcare profession. It is characterised by emotional exhaustion (EE), depersonalisation (DP) and a low sense of personal accomplishment (PA). Its negative impact extends to the physician, patient and overall service provision. AIMS: The aim of this study was to evaluate work patterns, the prevalence of burnout and its associations in medical oncology consultants and specialist registrars (SpRs) in Ireland. METHODS: Participants were invited to partake in an anonymised online survey. Burnout domains were measured using the validated Maslach Burnout Inventory. Associations between variables were evaluated using the Mann-Whitney U and Kruskal-Wallis tests (continuous), and chi-square and Fisher's exact testing (categorical). RESULTS: Seventy-four physicians were contacted to participate, 44 (59%) completed the survey. The majority (71%) work ≥ 50 h a week, with 57% having additional on-call commitments of ≥ 5 days/month. Burnout is defined by a high score in EE combined with a high DP and/or low PA was identified in 45% of consultants and 20% of SpRs. Longer working hours (≥ 60 h/ week) were found to be associated with both high EE (p = 0.049) and DP (p = 0.019). Higher EE scores were demonstrated in those ≥ 40 years (p = 0.04). The majority (86%) reported they would become an oncologist again. CONCLUSION: One or more of the symptoms of burnout is highly prevalent in medical oncologists in Ireland. With increasing pressure on resources, burnout is expected to increase. Attention to strategies for prevention needs to be prioritised within our healthcare system.

Obesity and cardiovascular risk in an oncology day ward population.

INTRODUCTION: The burden of obesity and risk of cardiovascular (CV) disease amongst an oncology population receiving active treatment is ill-defined. We performed a retrospective analysis assessing the incidence of obesity and cardiovascular (CV) risk factors in this group (grp) of patients as well as the predicted 10-year risk of a CV event. METHODS: Data from all patients (pts) receiving intravenous chemotherapy in an Irish oncology satellite unit over an 18-month period was extracted from chemotherapy prescriptions and electronic patient records. To calculate patients' 10-year risk of developing CV disease, we used QRISK, a predictive risk calculator. RESULTS: The prevalence of obesity (BMI > 30) amongst the total population was 19% (n = 21), with 26% (n = 28) overweight (BMI, 25-< 30). Information on CV risk factors was available in 93 pts. with the following rates being observed: hypertension 34%, dyslipidaemia 19%, current smoker 18% and diabetes 11%. The average 10-year risk of a CV event (stroke/MI) in this cohort was 19.2% (± 16.6), with a relative risk of 1.4 compared to their age-matched controls without CV risk factors. CONCLUSIONS: We observed similar or lower rates of obesity and CV risk factors in this cohort compared to the general adult Irish population. The average predicted risk of developing CV disease in this grp was moderate to high. This can have significant future implications with regard to cancer survivorship, disease recurrence and suitability for further oncological treatments.

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial.

BACKGROUND: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. METHODS: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). RESULTS: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. CONCLUSIONS: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911716.

Epidermal growth factor receptor mutated oligometastatic adeno-squamous lung cancer transformation to small cell lung cancer.

A 66-year-old non-smoker was diagnosed with stage IIIB, epidermal growth factor receptor (EGFR) mutated, squamous cell lung carcinoma. Treatment included chemotherapy, 35 fractions of radiotherapy and later Gefitinib for 3.5 years. On progression he developed a solitary brain and liver lesion. The brain lesion was excised and histology revealed adenocarcinoma of a lung primary. Afatanib was commenced for 1 further year. At the second time of progression re-biopsy identified small cell carcinoma. He completed four cycles of Carboplatin and Etoposide however deteriorated on completion of chemotherapy. EGFR directed treatment is associated with improved patient outcomes. It has been suggested that EGFR mutated squamous cell carcinoma more likely represent mixed morphology or poorly differentiated adenocarcinoma. Patients with oligometastatic progression can be treated beyond progression however the addition of a local therapy may be required. Small cell transformation is described as a rare mechanism of resistance to EGFR treatment as in our case.

Comparing attitudes of younger and older patients towards cancer clinical trials.

OBJECTIVES: To determine the attitudes of patients towards cancer clinical trials (CCTs) and assess the differences between older and younger patients. MATERIALS AND METHODS: Patients with cancer, receiving treatment or in follow-up in University Hospital Waterford, Ireland were eligible. Patients completed a self-administered questionnaire. To determine attitudes towards CCTs, patients indicated their preference if offered participation in three hypothetical studies (cancer prevention/screening trial; CCT comparing standard to new treatment; a trial of new drug where no standard exists). Patients' reasons to or not to participate in CCTs were explored. RESULTS: From May 2014 to March 2015, 219 patients were accrued, 119 <65years and 100 ≥65years. Twenty-two (18%) younger and 4 (4%) older patients had been/were actively enrolled on a CCT (p=0.0012). No older patient and 5 (4%) of younger patients had enquired about CCT availability. For the CCT questions, 85 (71%) younger vs 57 (57%) older patients would participate in a prevention/screening CCT (p=0.033); 60 (50%) vs 44 (44%) for standard vs new drug (p=0.415), and 83 (69%) vs 78 (78%) for a CCT where no standard exists (p=0.218). The most common reason to participate in a CCT was a recommendation from the oncologist -98% <65years vs 87% ≥65years (p=0.001), with health problems being the leading reason not to participate, 86% vs 72% (p=0.01), respectively. CONCLUSIONS: Older and younger patients in this study gave similar importance to reasons for and against participation in CCTs. Most patients did not actively seek out a CCT, which may reflect a lack of awareness and a need for better education.

Prevalence of human papillomavirus genotypes in women with cervical cancer in Papua New Guinea.

OBJECTIVE: Prophylactic human papillomavirus (HPV) vaccines are currently not available in Papua New Guinea. Prior to introducing these vaccines, knowledge about the HPV genotypes present in cervical cancer in this region is necessary to determine whether the types covered by the 2 commercially licensed vaccines are the same as those in other regions of the world. METHODS: Fresh, frozen cervical biopsies from 70 women with cervical cancer in Papua New Guinea were collected over a 3-year period from 2006-2009. HPV genotypes were detected using the Genera PapType assay. RESULTS: Overall, 100% of the specimens were HPV DNA positive, with HPV types 16 and 18 being the most prevalent at 57.1% and 25.7% (95% CI, 0.45-0.68 and 0.17-0.37) respectively, followed by HPV 33 (10%; 95% CI, 0.05-0.19) and HPV 31 (4.3%; 95% CI, 0.01-0.12). Multiple genotypes were identified in 6 women (8.6%), with all biopsies containing HPV 16 and 1 other high-risk type. CONCLUSION: The 2 most prevalent HPV types identified in women with cervical cancer in Papua New Guinea correspond to global data. This suggests that the currently available HPV vaccines could potentially reduce the burden of HPV-related cervical cancer in Papua New Guinea significantly.

Working Backs Scotland: a public and professional health education campaign for back pain.

STUDY DESIGN: Public and professional health education campaign. OBJECTIVE: To change public beliefs about the management of back pain. SUMMARY OF BACKGROUND DATA: Within the past decade, there has been a reversal in the strategy of management of back pain, from rest to staying active. There is only one previous public health education campaign on back pain, in a workers compensation setting in Australia. METHODS: A multimedia campaign was based around 1777 radio advertisements, which were heard by 60% of adults. Information leaflets were prepared for people with back pain, for all health professionals who treat back pain, and for employers. A Web site was set up: www.workingbacksscotland.com. Structured monthly samples of 1000 adults were surveyed on their beliefs about rest or staying active, professional help sought and advice received for 2 months before the campaign and over the following 3 years. Royal Mail sickness absence rates and new awards of social security benefits for back pain were compared in Scotland versus the rest of the United Kingdom, before and after the campaign. RESULTS: There was a significant (P < 0.001) change in the balance of beliefs, from about 55% rest versus 40% staying active to about 30% rest versus 60% staying active. This occurred within 1 month of the launch and was maintained over 3 years. There was a comparable change in professional advice. There was no change in advice about work or the number who said they stayed off work. There was no effect on sickness absence or new awards of social security benefits for back pain. CONCLUSION: There was a major shift in public beliefs and professional advice but no change in work-related outcomes.

Peptide-mediated inhibition of neutrophil transmigration by blocking CD47 interactions with signal regulatory protein alpha.

CD47, a cell surface transmembrane Ig superfamily member, is an extracellular ligand for signal regulatory protein (SIRPalpha). Interactions between CD47 and SIRPalpha regulate many important immune cell functions including neutrophil (PMN) transmigration. Here we report identification of a novel function-blocking peptide, CERVIGTGWVRC, that structurally mimics an epitope on CD47 and binds to SIRPalpha. The CERVIGTGWVRC sequence was identified by panning phage display libraries on the inhibitory CD47 mAb, C5D5. In vitro PMN migration assays demonstrated that peptide CERVIGTGWVRC specifically inhibited PMN migration across intestinal epithelial monolayers and matrix in a dose-dependent fashion. Further studies using recombinant proteins indicated that the peptide specifically blocks CD47 and SIRPalpha binding in a dose-dependent fashion. Protein binding assays using SIRPalpha domain-specific recombinant proteins demonstrated that this peptide directly bound to the distal-most Ig loop of SIRPalpha, the same loop where CD47 binds. In summary, these findings support the relevance of CD47-SIRPalpha interactions in regulation of PMN transmigration and provide structural data predicting the key residues involved on the surface of CD47. Such peptide reagents may be useful for studies on experimental models of inflammation and provide a template for the design of anti-inflammatory agents.

The Salmonella typhimurium flagellar basal body protein FliE is required for flagellin production and to induce a proinflammatory response in epithelial cells.

During apical colonization by Salmonella typhimurium, intestinal epithelial cells orchestrate a proinflammatory response that involves secretion of chemoattractants, predominantly interleukin-8, which coordinate neutrophil trans-epithelial migration at the site of infection. This host-pathogen interaction requires several S. typhimurium genes. To identify novel genes that participate in this pathogen-induced proinflammatory response, we created S. typhimurium Tn-10 transposon mutants and identified a single mutant with Tn-10 insertional inactivation within the fliE flagellar locus that was able to adhere to and invade intestinal epithelial cells normally but was unable to induce interleukin-8 secretion in host cells. The fliE-deficient mutant failed to secrete flagellin and lacked any surface assembly of flagellae. Unlike wild-type S. typhimurium, the fliE-deficient mutant did not activate the IkappaBalpha/NF-kappaB signaling pathway or induce the coordinated trans-epithelial migration of isolated human neutrophils. Transcomplementation of the fliE-deficient mutant with a wild-type fliE-harboring plasmid restored all defects and produced a wild-type S. typhimurium phenotype. Furthermore, functional down-regulation of basolateral TLR5 completely inhibited the monolayers' ability to respond to both wild-type S. typhimurium and purified flagellin but had no affect on tumor necrosis factor alpha-induced responses. We therefore conclude that S. typhimurium fliE is essential for flagellin secretion, flagellar assembly, and S. typhimurium-induced proinflammatory responses through basolateral TLR5 and is consistent with the emerging model of S. typhimurium flagellin-induced inflammation.