Appendicitis to multivisceral transplantation: a career experience with appendiceal malignancy.

John Hunter is regarded as the father of scientific surgery. His principles involved reasoning, observation and experimentation. His most powerful saying was: "Why not try the experiment?" This manuscript charts a career in abdominal surgery ranging from the treatment of appendicitis to the development of the largest appendiceal tumour centre in the world. The journey has led to the first report of a successful multivisceral and abdominal wall transplant for patients with recurrent non-resectable pseudomyxoma peritonei. We all stand on the shoulders of giants and surgery progresses by learning from the past while being prepared to experiment into the future.

Peritoneal malignancy in the global COVID-19 pandemic: experience of recovery and restoration in a high-volume centre through NHS and independent sector collaboration.

INTRODUCTION: Treatment of peritoneal malignancy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) requires substantial critical care, theatre and nursing resources. The COVID-19 pandemic caused challenges in providing a high volume, tertiary referral service. METHODS: We reviewed data on referrals and operations performed in a tertiary referral centre in both NHS and independent sector settings. The impact of COVID-19 on activity was assessed using 2019 as a benchmark. RESULTS: New patient referrals were similar, with 891 in 2019 compared with 833 in 2020. Delivery of CRS and HIPEC operations were initially impacted by COVID-19. NHS and independent sector collaboration facilitated recovery, with 284 patients treated in 2020 compared with 280 in 2019. CONCLUSIONS: Close collaboration and structural organisation between the clinical and management teams in the NHS and independent sectors facilitated recovery and restoration of a complex tertiary referral service for peritoneal malignancy during the COVID pandemic.

Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis.

BACKGROUND AND AIMS: The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients. METHODS: Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1ß, TFGß1, PDGFB or TNF-α. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells. RESULTS: Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibroblasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1ß-treated cells. CONCLUSIONS: Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis.

Evaluating the effects of grass management technologies on the physical, environmental, and financial performance of Irish pasture-based dairy farms.

Grass management technologies (grass measuring devices and grassland management decision support tools) have been identified as important tools to improve the performance of pasture-based dairy farms. They have the potential to significantly improve the efficiency and sustainability of dairy systems by increasing milk production through enhanced pasture growth and utilization, which would reduce the need for supplementary feeds, along with increased output, therefore increasing farm profitability and environmental sustainability. Despite the several potential benefits of grass management technologies, there is a lack of empirical research around the effects of these technologies on the performance of pasture-based dairy systems. The current study aimed to fill this knowledge gap by using a 2018 nationally representative survey of Irish dairy farms and a propensity score matching approach to determine the effects of adopting grass management technologies on the physical, environmental, and financial performance of Irish pasture-based dairy farms. The findings showed that dairy farms utilizing grass management technologies had, on average, higher farm physical, environmental, and financial performance (in terms of grazed pasture use, total pasture use, length of the grazing season, milk yield, milk solids, greenhouse gas emissions per kilogram of fat- and protein-corrected milk, gross output, and gross margin) compared with dairy farms not utilizing these technologies. However, when controlling for selection bias, we can only attribute a positive causal effect of grass management technology adoption on the use of grazed pasture per cow, grazing season length, milk yield per cow, and milk solids per cow. This might be due to dairy farmers not yet using the technologies to their full potential, 2018 being an unusual year in terms of weather (and therefore not being able to capture the full range of farm performance benefits), or because grass management technologies need to be adopted in association with other technologies and practices to achieve their expected performance outcomes. Future research should include updated farm-level data to capture the weather and learning effects and so be able to determine the impact of grass management technologies on a wider range of performance indicators.

Factors associated with intensity of technology adoption and with the adoption of 4 clusters of precision livestock farming technologies in Irish pasture-based dairy systems.

Precision livestock farming (PLF) technologies have been widely promoted as important tools to improve the sustainability of dairy systems due to perceived economic, social, and environmental benefits. However, there is still limited information about the level of adoption of PLF technologies (percentage of farms with a PLF technology) and the factors (farm and farmer characteristics) associated with PLF technology adoption in pasture-based dairy systems. The current research aimed to address this knowledge gap by using a representative survey of Irish pasture-based dairy farms from 2018. First, we established the levels of adoption of 9 PLF technologies (individual cow activity sensors, rising plate meters, automatic washers, automatic cluster removers, automatic calf feeders, automatic parlor feeders, automatic drafting gates, milk meters, and a grassland management decision-support tool) and grouped them into 4 PLF technology clusters according to the level of association with each other and the area of dairy farm management in which they are used. The PLF technology clusters were reproductive management technologies, grass management technologies, milking management technologies, and calf management technologies. Additionally, we classified farms into 3 categories of intensity of technology adoption based on the number of PLF technologies they have adopted (nonadoption, low intensity of adoption, and high intensity of adoption). Second, we determined the factors associated with the intensity of technology adoption and with the adoption of the PLF technology clusters. A multinomial logistic regression model and 4 logistic regressions were used to determine the factors associated with intensity of adoption (low and high intensity of adoption compared with nonadoption) and with the adoption of the 4 PLF technology clusters, respectively. Adoption levels varied depending on PLF technology, with the most adopted PLF technologies being those related to the milking process (e.g., automatic parlor feeders and milk meters). The results of the multinomial logistic regression suggest that herd size, proportion of hired labor, agricultural education, and discussion group membership were positively associated with a high intensity of adoption, whereas age of farmer and number of household members were negatively associated with high intensity of adoption. However, when analyzing PLF technology clusters, the magnitude and direction of the influence of the factors in technology adoption varied depending on the PLF technology cluster being investigated. By identifying the PLF technologies in which pasture-based dairy farmers are investing more and by detecting potential drivers and barriers for the adoption of PLF technologies, the current study could allow PLF technology companies, practitioners, and researchers to develop and target strategies that improve future adoption of PLF technologies in pasture-based dairy settings.

The appendix "mucocoele" misnomer: radiological terminology of "likely appendix mucinous neoplasm" better reflects pathology findings.

AIM: To review the radiological terminology used to describe dilated mucin-containing appendiceal lesions with correlation to the histopathological diagnosis. MATERIALS AND METHODS: Radiology and histopathology reports for all patients with an abnormally dilated appendix referred to a tertiary peritoneal malignancy centre, between January 2021 and December 2021, were reviewed. RESULTS: Overall, 213 patients were included with a median appendiceal diameter of 25.5 mm (range 10-125 mm). Peritoneal disease was present in 109 patients, with the remaining 104 cases demonstrating a dilated appendix only. Local radiology reports were available for 201 cases with the appendix described in 168 cases as appendiceal mucocoele (n=104), appendiceal neoplasm (n=40), appendicitis (n=18), and dilated appendix (n=6). The appendix was not mentioned in 33/201 (15%), either misinterpreted as other pathology (n=15) or not reported (n=18). Peritoneal malignancy histopathology reports were available in 188 cases and reported as low-grade appendix mucinous neoplasm (LAMN, n=144), high-grade appendix mucinous neoplasm (HAMN, n=13), LAMN with foci of HAMN (n=2), LAMN with neuroendocrine tumour (n=2), LAMN with goblet cell adenocarcinoma (n=1), goblet cell adenocarcinoma (n=8), mucinous adenocarcinoma (n=14), non-mucinous adenocarcinoma (n=1), and benign histology (n=3). Only one case of a true inflammatory "mucocoele"/retention cyst was reported. CONCLUSION: In this cohort of patients, the overwhelming majority of dilated, mucin-filled appendices contained malignant cells and benign mucin-filled appendices were rare. The present authors advocate that the term "likely appendix mucinous neoplasm" should replace "appendix mucocoele" to represent the most likely pathology and facilitate less ambiguous interpretation in management decisions.

Investigating a clinically actionable BRAF mutation for monitoring low-grade serous ovarian cancer: A case report.

Low-grade serous ovarian cancer (LGSOC) poses a specific clinical challenge due to advanced presentation at diagnosis and the lack of effective systemic treatments. The aim of this study was to use a precision medicine approach to identify clinically actionable mutations in a patient with recurrent LGSOC. Primary, metastatic and recurrence tissue, and blood samples were collected from a stage IV LGSOC patient. Single-gene testing for clinically actionable mutations (BRAF V600, KRAS and NRAS) and subsequent whole-exome sequencing (WES) were performed. Droplet digital PCR was used to evaluate the presence of an identified BRAF D594G mutation in the matched plasma cell-free DNA (cfDNA). No clinically actionable mutations were identified using single-gene testing. WES identified a BRAF D594G mutation in six of seven tumor samples. The patient was commenced on a MEK inhibitor, trametinib, but with minimal clinical response. A newly designed ddPCR assay detected the BRAF alteration in the matched tissues and liquid biopsy cfDNA. The identification and sensitive plasma detection of a common "druggable" target emphasises the impact of precision medicine on the management of rare tumors and its potential contribution to novel monitoring regimens in this field.

Colorectal cancer outcomes determined by mode of presentation: analysis of population data in England between 2010 and 2014.

BACKGROUND: The purpose of this study was to investigate associations between mode of presentation; categorized as emergency, suspected cancer outpatient referral pathway (2-week wait or 2WW pathway), non-cancer suspected outpatient referral (non-2-week wait pathway) or following screening, and stage of diagnosis and survival in patients with colorectal cancer in England. METHODS: This was a retrospective cohort observational study of patients diagnosed with colorectal cancer between January 2010 and December 2014 in England using data from Public Health England collated from regional cancer registries. RESULTS: The most common route to diagnosis among 167,501 patients diagnosed with colorectal cancer was via the non-cancer suspect (non-2WW) outpatient referral pathway (35.1%) followed by the suspected cancer (2WW) referral pathway (31.6%), emergency presentation (22.8%) and most infrequently following screening (10.6%) (p < 0.01). Screening confers the greatest likelihood of early-stage diagnosis (61.6%) compared to other modes of presentation. The 5-year overall survival was 81.8%, 53.3%, 53.0% and 27.6% in those diagnosed via screening, 2WW, non-2WW pathway and emergency presentation, respectively. Patients from most deprived regions were more likely to be diagnosed following emergency presentation (27.7 vs 19.7%, p < 0.01) and less likely via screening (8.1 vs 12%, p < 0.01). CONCLUSIONS: Asymptomatic individuals diagnosed following screening have earlier stage cancers and better survival, the opposite was observed in those diagnosed following emergency presentation. Patients referred via the 2WW pathway do not have better survival outcomes when compared to those referred via the non-2WW pathway. In addition, this study has identified socio-economic groups that need to be targeted with public health campaigns to improve screening uptake.

Systematic review of classification systems for locally recurrent rectal cancer.

BACKGROUND: Classification of pelvic local recurrence (LR) after surgery for primary rectal cancer is not currently standardized and optimal imaging is required to categorize anatomical site and plan treatment in patients with LR. The aim of this review was to evaluate the systems used to classify locally recurrent rectal cancer (LRRC) and the relevant published outcomes. METHODS: A systematic review of the literature prior to April 2020 was performed through electronic searches of the Science Citation Index Expanded, EMBASE, MEDLINE and CENTRAL databases. The primary outcome was to review the classifications currently in use; the secondary outcome was the extraction of relevant information provided by these classification systems including prognosis, anatomy and prediction of R0 after surgery. RESULTS: A total of 21 out of 58 eligible studies, classifying LR in 2086 patients, were reviewed. Studies used at least one of the following eight classification systems proposed by institutions or institutional groups (Mayo Clinic, Memorial Sloan-Kettering - original and modified, Royal Marsden and Leeds) or authors (Yamada, Hruby and Kusters). Negative survival outcomes were associated with increased pelvic fixity, associated symptoms of LR, lateral compared with central LR and involvement of three or more pelvic compartments. A total of seven studies used MRI with specifically defined anatomical compartments to classify LR. CONCLUSION: This review highlights the various imaging systems in use to classify LRRC and some of the prognostic indicators for survival and oncological clearance based on these systems. Implementation of an agreed classification system to document pelvic LR consistently should provide more detailed information on anatomical site of recurrence, burden of disease and standards for comparative outcome assessment.

The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer.

BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

Outcomes of multicystic peritoneal mesothelioma treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Multicystic peritoneal mesothelioma (MCPM) is a rare neoplasm, generally considered a borderline malignancy, best treated by cytoreductive surgery (CRS) to remove macroscopic disease, combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Owing to its rarity, little has been published on clinical presentation, clinical behaviour over time, or an optimal treatment approach. METHODS: A prospectively developed peritoneal malignancy database was interrogated for the years 2001-2018. Details on all patients with MCPM as a definitive diagnosis after CRS and HIPEC were analysed, including previous interventions, mode of presentation, surgical treatment, postoperative outcomes, and late follow-up information from abdominal CT and tumour markers. RESULTS: Some 40 patients with MCPM underwent CRS and HIPEC between 2001 and 2018. Of these, 32 presented with abdominal pain, distension or bloating, six patients presented with recurrence following previous surgery at the referring hospitals, and two had coincidental diagnoses during a surgical procedure. CRS involved peritonectomy in all 40 patients. Bowel resection was required in 18 patients, and seven had a temporary stoma. Thirty-eight patients were considered to have undergone a complete macroscopic tumour removal (completeness of cytoreduction CC0), and two had residual tumour nodules less than 2.5 mm in size, classified as CC1. Median duration of follow-up was 65 (range 48-79) months. There were no deaths during follow-up. The Kaplan-Meier-predicted recurrence-free interval was 115.4 months. CONCLUSION: MCPM is a rare peritoneal neoplasm with a heterogeneous pattern of presentation. CRS and HIPEC is an effective management option for this group of patients, with favourable long-term survival.

The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma.

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.

Evaluation of Tooth Sensitivity of In-office Bleaching with Different Light Activation Sources: A Systematic Review and a Network Meta-analysis.

OBJECTIVES: A systematic review and network meta-analysis were performed to answer the following research question: Are there differences in the risk and the intensity of tooth sensitivity (TS) among eight light activation systems for in-office bleaching in adults? METHODS: Randomized controlled trials (RCTs) that compared at least two different in-office bleaching light activations were included. The risk of bias (RoB) was evaluated with the RoB tool version 1.0 from the Cochrane Collaboration tool. A random-effects Bayesian mixed treatment comparison (MTC) model was used independently for high- and low-concentration hydrogen peroxide. The certainty of the evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. A comprehensive search was performed in PubMed, Bridge Base Online (BBO), Latin American and Caribbean Health Sciences Literature database (LILACS), Cochrane Library, Scopus, Web of Science, and grey literature without date and language restrictions on April 23, 2017 (updated on September 26, 2019). Dissertations and theses, unpublished and ongoing trials registries, and IADR (International Association for Dental Research) abstracts (2001-2019) were also searched. RESULTS: After title and abstract screening and the removal of duplicates, 32 studies remained. Six were considered to be at low RoB, three had high RoB, and the remaining had an unclear RoB. The MTC analysis showed no significant differences among the treatments in each network. In general, the certainty of the evidence was graded as low due to unclear RoB and imprecision. CONCLUSION: There is no evidence that the risk and intensity of TS are affected by light activation during in-office bleaching.

Appendiceal tumours and pseudomyxoma peritonei: Literature review with PSOGI/EURACAN clinical practice guidelines for diagnosis and treatment.

Pseudomyxoma Peritonei (PMP) is a rare peritoneal malignancy, most commonly originating from a perforated epithelial tumour of the appendix. Given its rarity, randomized controlled trials on treatment strategies are lacking, nor likely to be performed in the foreseeable future. However, many questions regarding the management of appendiceal tumours, especially when accompanied by PMP, remain unanswered. This consensus statement was initiated by members of the Peritoneal Surface Oncology Group International (PSOGI) Executive Committee as part of a global advisory role in the management of uncommon peritoneal malignancies. The manuscript concerns an overview and analysis of the literature on mucinous appendiceal tumours with, or without, PMP. Recommendations are provided based on three Delphi voting rounds with GRADE-based questions amongst a panel of 80 worldwide PMP experts.

Dimethyl fumarate modulates the Treg-Th17 cell axis in patients with psoriasis.

BACKGROUND: Dimethyl fumarate (DMF) is the active ingredient of Skilarence™ and Tecfidera™, which are used for the treatment of psoriasis and multiple sclerosis, respectively. Various immunomodulatory mechanisms of action have been identified for DMF; however, it is still unclear what effects DMF exerts in vivo in patients with psoriasis. OBJECTIVES: In this study we examined the effects of DMF, both in vivo and in vitro, on T cells, which play a key role in the pathogenesis of psoriasis. METHODS: The frequency of T-cell subsets was examined by flow cytometry in untreated patients with psoriasis or those treated with DMF. The effects of DMF in vitro on T-cell survival, activation and proliferation, and cell-surface thiols were assessed by flow cytometry. RESULTS: In patients with psoriasis treated with DMF we observed an increase in the frequency of T regulatory (Treg) cells and a decrease in T helper (Th)17 lineage cells and the associated cytokines interleukin-17, interleukin-22 and granulocyte-macrophage colony-stimulating factor. T cells cultured in vitro with DMF exhibited reduced viability, and inhibition of activation and proliferation in response to stimulation due to the oxidative effects of DMF. However, the frequency of Treg cells increased in the presence of DMF due to their heightened ability to resist DMF-induced oxidative stress. CONCLUSIONS: DMF enhanced the ratio of Treg cells to Th17 cells in patients with psoriasis, in patients with multiple sclerosis and in vitro. Furthermore, our data suggest that this is at least in part as a result of the differential effects of DMF on Treg cells compared with conventional T cells.

Hartmann's procedure versus intersphincteric abdominoperineal excision (HiP Study): a multicentre prospective cohort study.

AIM: In patients with low rectal cancer it is occasionally necessary to avoid a low coloanal anastomosis due to patient frailty or poor function. In such situations there are two alternative approaches: Hartmann's procedure (HP) or intersphincteric abdominoperineal excision (IAPE). There are few data to guide surgeons as to which of these two procedures is the safest. The aim of this study was to determine the surgical complication rates associated with each procedure. METHOD: This was a multicentre, nonrandomized prospective cohort study of patients undergoing either HP or IAPE. The primary objective was to determine surgical complication rates. Secondary objectives included length of stay, time to adjuvant therapy and quality of life at 90 days. RESULTS: One hundred and seventy nine patients were recruited between April 2016 and June 2019; approximately two thirds of patients underwent HP and one third IAPE. The overall complication rate was high in both groups (54% for the HP group and 52% for the IAPE group). Surgery-specific complication rates were also high, but not significantly different: 43% for HP and 48% for IAPE. The pelvic abscess rate in HP was 11% and was significantly higher in patients with a palpable staple line (15% vs 2%). There was a higher incidence of serious medical complications following IAPE (16% vs 5%), along with a reduction in 90-day quality of life scores. CONCLUSION: This is the largest prospective study to compare HP and IAPE in patients undergoing rectal cancer surgery where primary anastomosis is not deemed appropriate. With similar complication rates, these data support the ongoing use of either HP or IAPE in this patient group.

Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment.

STUDY QUESTION: Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER: Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY: Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION: Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1ß, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S): Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER: NA.