Dermatitis in an irritable infant.

This is the case of an infant with a persistent dermatitis affecting the perioral, acral and napkin areas, in whom a simple oral therapy provided a rapid treatment response.

Barrett's Registry Collaboration of academic centers in Ireland reveals high progression rate of low-grade dysplasia and low risk from nondysplastic Barrett's esophagus: report of the RIBBON network.

Barrett's esophagus (BE) is the main pathological precursor of esophageal adenocarcinoma (EAC). Progression to high-grade dysplasia (HGD) or EAC from nondysplastic BE (NDBE), low-grade dysplasia (LGD) and indefinite for dysplasia (IND) varies widely between population-based studies and specialized centers for many reasons, principally the rigor of the biopsy protocol and the accuracy of pathologic definition. In the Republic of Ireland, a multicenter prospective registry and bioresource (RIBBON) was established in 2011 involving six academic medical centers, and this paper represents the first report from this network. A detailed clinical, endoscopic and pathologic database registered 3,557 patients. BE was defined strictly by both endoscopic evidence of Barrett's epithelium and the presence of specialized intestinal metaplasia (SIM). A prospective web-based database was used to gather information with initial and follow-up data abstracted by a data manager at each site. A total of 2,244 patients, 1,925 with no dysplasia, were included with complete follow-up. The median age at diagnosis was 60.5 with a 2.1:1 male to female ratio and a median follow-up time of 2.7 years (IQR 1.19-4.04), and 6609.25 person years. In this time period, 125 (5.57%) progressed to HGD/EAC, with 74 (3.3%) after 1 year of follow-up and 38 (1.69%) developed EAC, with 20 (0.89%) beyond 1 year. The overall incidence of HGD/EAC was 1.89% per year; 1.16% if the first year is excluded. The risk of progression to EAC alone overall was 0.57% per year, 0.31% excluding the first year, and 0.21% in the 1,925 patients who had SIM alone at diagnosis. Low-grade dysplasia (LGD) progressed to HGD/EAC in 31% of patients, a progression rate of 12.96% per year, 6.71% with the first year excluded. In a national collaboration of academic centers in Ireland, the progression rate for NDBE was similar to recent population studies. Almost one in two who progressed was evident within 1 year. Crucially, LGD diagnosed and confirmed by specialist gastrointestinal pathologists represents truly high-risk disease, highlighting the importance of expertise in diagnosis and management, and providing indirect support for ablative therapies in this context.

Computed tomography and upper gastrointestinal series findings of esophageal bronchi in infants.

BACKGROUND: Esophageal bronchus is a rare form of communicating bronchopulmonary foregut malformation and a rare but important cause of an opaque hemithorax on chest radiography. A higher incidence of esophageal bronchus is associated with esophageal atresia, tracheo-esophageal fistula (TEF) and VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) association. In the presence of these conditions, the pediatric radiologist may be the first to consider the diagnosis of esophageal bronchus or esophageal lung. OBJECTIVE: To describe the imaging features in five children with esophageal bronchus. MATERIALS AND METHODS: We reviewed hospital records and teaching files at two large pediatric tertiary referral centers over the 24-year period from January 1992 to January 2016. We reviewed all imaging studies and tabulated findings on radiography, fluoroscopic upper gastrointestinal (GI) series and CT. We then described the imaging features of esophageal bronchi with emphasis on CT and upper GI findings in four infants and one toddler. RESULTS: Three cases were identified from one institution (cases 2, 3, 4) and two from another (cases 1, 5). All five cases occurred in association with other midline malformations: four of the five had VACTERL association and three of the five had esophageal atresia and TEF. CONCLUSION: Lung opacification, ipsilateral mediastinal shift, and an abnormal carina and anomalous vascular anatomy suggest an esophageal bronchus or an esophageal lung on CT. While esophageal bronchus is a rare cause of an opaque hemithorax, CT and upper GI imaging play key roles in its diagnosis. Associations with esophageal atresia with tracheo-esophageal fistula and VACTERL association are particularly pertinent. Early diagnosis of esophageal bronchus might prevent complications such as aspiration and infection, which can allow for parenchymal sparing surgery as opposed to pneumonectomy.

Symptoms to script: delays in tuberculosis treatment in the west of Ireland.

BACKGROUND: The first pillar of the End-TB Strategy is "early diagnosis and prompt treatment". Nevertheless, long delays in starting tuberculosis (TB) treatment are reported. We aimed to describe the demographics and clinical features of TB in the west of Ireland and better understand the delays in treatment. METHODS: We conducted a retrospective chart review of all patients diagnosed with active TB who attended the Galway University Hospital (GUH) TB clinic from 2014 to 2018. RESULTS: Eighty-five patients were diagnosed with TB and attended our clinic. Ten (12%) patients were receiving immunosuppressive therapy, 8 (9%) had drug resistance, and 41 (48%) had extra-pulmonary disease. Patients with extra-pulmonary disease had a longer length of stay before treatment (11 vs. 4 days; p = 0.006). Patients older than 55 had a longer length of stay before (16 vs. 5 days, p = 0.0001) and during (36 vs. 11 days, p = 0.004) treatment and were readmitted more frequently than younger patients. A total of 36% of patients were born outside Ireland. Non-Irish patients were younger (mean age 35 vs 48; p = 0.004) and more frequently had drug resistance (19% vs. 4%, p = 0.02). The median time from symptom onset to hospital presentation was 76 days (IQR 35-146 days) and the median time from first hospital presentation to TB treatment was 11 days (IQR 5-51 days). CONCLUSION: TB patients experienced long symptom durations in the community prior to presentation. Many TB patients experienced delays in diagnosis and treatment following presentation. Both pre-hospital and in-hospital delays need to be addressed in order to 'End-TB'.

Extramural venous invasion (EMVI) in colorectal cancer is associated with increased cancer recurrence and cancer-related death.

INTRODUCTION: Colorectal cancer (CRC) outcomes vary depending on tumour biology, with several features used to predict disease behaviour. Extramural venous invasion (EMVI) is associated with negative outcomes and its presence has been established as an indicator of more aggressive disease in CRC. METHODS: A prospectively maintained database was examined for patients undergoing curative resection for non-metastatic CRC between 2012 and 2018 in a tertiary institution. Clinicopathological factors were compared to assess their impact on recurrence, all-cause mortality and cancer-related death. Kaplan Meier analysis of the association between EMVI and these endpoints was performed, and univariable and multivariable analysis was carried out to establish the relationship of predictive factors in oncological outcomes. RESULTS: Eighty-eight (13.5%) of 654 patients developed recurrence. The mean time to recurrence was 19.8 ± 13.5 months. There were 36 (5.5%) cancer-related deaths at a mean duration of follow-up of 46.3 ± 21.6 months. Two hundred and sixty-six patients had extramural venous invasion (40.7%). EMVI was significantly associated with reduced overall recurrence-free survival, systemic recurrence-free survival, and increased cancer-related death on univariate analysis (p < 0.001 for all, Fig. 1), and multivariable analysis (OR 1.8 and 2.1 respectively, p < 0.05 for both). CONCLUSION: EMVI is associated with a poor prognosis, independent of stage, nodal status and other histopathological features. The presence of EMVI should be strongly considered as an indication for adjuvant therapy.

The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma.

Gastroesophageal junction adenocarcinomas (GEJA) have dramatically increased in incidence in the western world since the mid-20th century. Their prognosis is poor, and conventional anti-cancer therapies do not significantly improve survival outcomes. These tumours are comprised of a heterogenous population of both cancer stem cells (CSC) and non-CSCs, with the former playing a crucial role in tumorigenesis, metastasis and importantly drug resistance. Due to the ability of CSCs to self-replicate indefinitely, their resistance to anti-cancer therapies poses a significant barrier to effective treatment of GEJA. Ongoing drug development programmes aim to target and eradicate CSCs, however their characterisation and thus identification is difficult. CSC regulation is complex, involving an array of signalling pathways, which are in turn influenced by a number of entities including epithelial mesenchymal transition (EMT), microRNAs (miRNAs), the tumour microenvironment and epigenetic modifications. Identification of CSCs commonly relies on the expression of specific cell surface markers, yet these markers vary between different malignancies and indeed are often co-expressed in non-neoplastic tissues. Development of targeted drug therapies against CSCs thus requires an understanding of disease-specific CSC markers and regulatory mechanisms. This review details the current knowledge regarding CSCs in GEJA, with particular emphasis on their role in drug resistance.

Epstein-Barr virus-positive mucocutaneous ulcer: A unique case occurring in association with cholelithiasis in a gallbladder.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a lymphoproliferative disorder occurring in patients due to iatrogenic or age-related immunosuppression confined to the oropharynx, skin, and gastrointestinal tract. Here, we report the first case to our knowledge of EBV-positive mucocutaneous ulcer occurring in a gallbladder.

Modern oncological and operative outcomes in oesophageal cancer: the St. James's hospital experience.

BACKGROUND: Oesophageal cancer has a reputation for poor survival, and a relatively high risk of major postoperative morbidity and mortality. Encouragingly, a recent international cancer registry study reports a doubling of survival outcomes in Ireland over the last 20 years. This study focused on both oncologic and operative outcomes in patients treated with curative intent requiring surgery at a high-volume center. METHODS: All patients undergoing surgery or multimodal therapy with curative intent from 2009 to 2018 were studied. All data was recorded prospectively and maintained internally. The period 2009-2013 was compared with 2014-2018 to monitor any change in trends. RESULTS: Four hundred and seventy-five patients (adenocarcinoma 77%, mean age 65; 76% male; 64% neoadjuvant therapy) underwent open surgical resection, 54% via en bloc 2-stage, 19.8% en bloc 3-stage, and 26.5% by a transhiatal approach. New onset atrial fibrillation was the commonest index complication, in 108 (22.7%), 80 (18%) developed suspected pneumonia/respiratory tract infection, 20 (4.2%) an anastomotic leak, and 25 (5.2%) a chyle leak. The 90-day mortality rate was 1.2% and 0.8% at 30 days. The median survival was 77.17 months, with a 5-year survival of 56%. CONCLUSION: Consistent with registry data on population survival for oesophageal cancer, this study highlights markedly improved survival outcomes in patients treated curatively, reflecting international trends, as well as low mortality rates; however, cardiorespiratory complications remain significant.

The inhibitor profiling of the caspase family of proteases using substrate-derived peptide glyoxals.

A series of substrate-based α-keto-ß-aldehyde (glyoxal) sequences have been synthesised and evaluated as inhibitors of the caspase family of cysteine proteases. A number of potent inhibitor sequences have been identified. For example, a palmitic acid containing sequence pal-Tyr-Val-Ala-Asp-glyoxal was demonstrated to be an extremely effective inhibitor of caspase-1, inhibiting not only the action of the protease against synthetic fluorogenic substrates (K(i)=0.3 nM) but also blocking its processing of pro-interleukin-1beta (pro-IL-1ß). In addition, the peptide Ac-Asp-Glu-Val-Asp-glyoxal, which is based on the consensus cleavage sequence for caspase-3, is a potent inhibitor of this protease (K(i)=0.26 nM) yet only functions as a comparatively modest inhibitor of caspase-1 (K(i)=451 nM). Potent inhibitor sequences were also identified for caspases-6 and -8. However, the degree of discrimination between the family members is limited. The ability of Ac-Asp-Glu-Val-Asp-glyoxal to block caspase-3 like activity in whole cells and to delay the development of apoptosis was assessed. When tested against caspase-3 like activity in cell lysates, Ac-Asp-Glu-Val-Asp-glyoxal displayed effective inhibition similar to that observed against recombinant caspase-3. Treatment of whole cells with this potent caspase-3 inhibitor was however, not sufficient to significantly stall the development of apoptosis in-vitro.

Multi-century trends to wetter winters and drier summers in the England and Wales precipitation series explained by observational and sampling bias in early records.

Globally, few precipitation records extend to the 18th century. The England Wales Precipitation (EWP) series is a notable exception with continuous monthly records from 1766. EWP has found widespread use across diverse fields of research including trend detection, evaluation of climate model simulations, as a proxy for mid-latitude atmospheric circulation, a predictor in long-term European gridded precipitation data sets, the assessment of drought and extremes, tree-ring reconstructions and as a benchmark for other regional series. A key finding from EWP has been the multi-centennial trends towards wetter winters and drier summers. We statistically reconstruct seasonal EWP using independent, quality-assured temperature, pressure and circulation indices. Using a sleet and snow series for the UK derived by Profs. Gordon Manley and Elizabeth Shaw to examine winter reconstructions, we show that precipitation totals for pre-1870 winters are likely biased low due to gauge under-catch of snowfall and a higher incidence of snowfall during this period. When these factors are accounted for in our reconstructions, the observed trend to wetter winters in EWP is no longer evident. For summer, we find that pre-1820 precipitation totals are too high, likely due to decreasing network density and less certain data at key stations. A significant trend to drier summers is not robustly present in our reconstructions of the EWP series. While our findings are more certain for winter than summer, we highlight (a) that extreme caution should be exercised when using EWP to make inferences about multi-centennial trends, and; (b) that assessments of 18th and 19th Century winter precipitation should be aware of potential snow biases in early records. Our findings underline the importance of continual re-appraisal of established long-term climate data sets as new evidence becomes available. It is also likely that the identified biases in winter EWP have distorted many other long-term European precipitation series.

Reprieval from execution: the molecular basis of caspase inhibition.

The suppression of apoptosis is essential to the propagation of viruses, and to the control of development and homeostasis in insects and mammals. The central components of all apoptotic pathways are proteases of the caspase family. Therefore, it is not surprising that the processes of natural selection, as well as pharmaceutical chemists, have designed compounds that directly target caspase activity in attempts to regulate apoptosis. The mechanisms used by highly specialized naturally occurring caspase inhibitors (both host and viral) have remained obscure for some time. However, recently there has been significant progress in this field, particularly because of the structural elucidation of the complexes between caspases and an endogenous inhibitor (XIAP) and a viral inhibitor (p35). This article reviews the newly defined molecular basis for the regulation of the caspases by viral and endogenous inhibitors.

Impact and importance of a centralised review panel for lymphoma diagnostics in the WHO era: a single-centre experience.

Lymphoma diagnosis is complex, requiring a wide array of adjunctive tests to reach accurate diagnoses. We retrospectively examined the rates of concordance between referral and review lymphoma diagnoses on cases referred to St James's Hospital, Dublin for multidisciplinary team review between 2013 and 2016. Frequency and cost of adjunctive diagnostic tests performed were also analysed. The overall discordance rate was 7.8% (14/179), compared with rates of 6%-48% in the published literature. 13 discordant cases required a change in clinical management following review of the referred diagnosis. Of all referred cases, 33.5% (60/179) required extra analyses to reach a final diagnosis, costing the reference laboratory €35463.40. We conclude that establishment of centralised haematopathology diagnostic networks would help reduce the rate of revision made to lymphoma diagnoses by providing specialist haematopathologist input and access to ancillary testing.

Evaluation of Discordance in Primary Tumor and Lymph Node Response After Neoadjuvant Therapy in Breast Cancer.

BACKGROUND: Neoadjuvant therapy (NAT) offers a unique opportunity to assess tumor response to systemic agents. However, a discrepancy may exist between the response of the primary tumor and involved nodes. We report on the frequency of response discordance after NAT in breast cancer. PATIENTS AND METHODS: All consecutive node-positive patients receiving NAT in our department from 2009 to 2014 were identified. Patient demographics, and radiologic and pathologic features were tabulated. Tumor response was estimated by magnetic resonance imaging of the breast. Lymph node (LN) response was estimated from pathologic treatment response measurements. Statistical analysis was performed. RESULTS: A total of 108 node-positive patients treated with NAT were eligible for inclusion. Median age was 51.73 years (range, 20-87 years). All patients underwent axillary clearance, and 62% underwent mastectomy. A 40% mean reduction in tumor size was observed. Statistically, a positive correlation between tumor and LN response after NAT was observed (Spearman correlation coefficient, r = 0.46, P < .001). Complete pathologic response was observed in 17 patients (15.7%). However, 21 patients experienced complete LN response, with only 81% of these patients (n = 17) experiencing a complete response in tumor also. A complete response was observed in tumor in 20 patients, and this predicted complete nodal response in 85% of cases (n = 17). Fifteen percent of primary tumors with complete pathologic response had persistently positive LNs. CONCLUSION: A significant discordance exists between the primary tumor and LN response, representing a concern for the lack of response of occult regional or systemic metastases due to potential biologic heterogeneity.

Acute Lymphoblastic Leukemia Arising in CALR Mutated Essential Thrombocythemia.

The development of acute lymphoblastic leukemia in an existing myeloproliferative neoplasm is rare with historical cases unable to differentiate between concomitant malignancies or leukemic transformation. Molecular studies of coexisting JAK2 V617F-positive myeloproliferative neoplasms and mature B cell malignancies indicate distinct disease entities arising in myeloid and lymphoid committed hematopoietic progenitor cells, respectively. Mutations of CALR in essential thrombocythemia appear to be associated with a distinct phenotype and a lower risk of thrombosis yet their impact on disease progression is less well defined. The as yet undescribed scenario of pro-B cell acute lymphoblastic leukemia arising in CALR mutated essential thrombocythemia is presented. Intensive treatment for the leukemia allowed for expansion of the original CALR mutated clone. Whether CALR mutations in myeloproliferative neoplasms predispose to the acquisition of additional malignancies, particularly lymphoproliferative disorders, is not yet known.

Classical Hodgkin Lymphoma Arising Adjacent to a Breast Implant.

Breast implant-associated lymphoma has recently gained wide recognition. Anaplastic large cell lymphoma (ALCL) is the most frequently diagnosed subtype in this setting but the spectrum is broadening. A 66-year-old woman developed swelling and itch around her saline implant 6 years after its insertion. Imaging revealed a fluid collection surrounding the implant with an adjacent mass. Microscopy showed sclerotic tissue punctuated by discrete cellular nodules comprising small lymphocytes, eosinophils and interspersed large atypical Hodgkin Reed-Sternberg (HRS)-like cells. The HRS-like cells stained positively for CD30 and CD15 by immunohistochemistry. Small T-lymphocytes formed rosettes around HRS-like cells. Appearances were consistent with classical Hodgkin lymphoma (HL). Multiplex polymerase chain reaction demonstrated no clonal rearrangements of immunoglobulin or T-cell receptor genes, however, a t(14;18)(q32;q21)BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was present. Staging positron emission tomography-computed tomography scan revealed FDG-avid masses in the right axilla and pelvis. Subsequent pathological examination identified low-grade follicular lymphoma (FL) with a t(14;18) translocation at these sites. To our knowledge, this is the first case of HL arising adjacent to a breast implant. An awareness of this diagnosis is important as classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens. It is also important in the differential diagnosis for implant-associated ALCL as both contain large atypical CD30-positive cells highlighting the need for full immunohistochemical and molecular workup in such cases. This case also adds to the large body of literature regarding the association between HL and FL.

Enrichment of Inflammatory IL-17 and TNF-α Secreting CD4(+) T Cells within Colorectal Tumors despite the Presence of Elevated CD39(+) T Regulatory Cells and Increased Expression of the Immune Checkpoint Molecule, PD-1.

T cell infiltration into colorectal tumors has been shown to correlate with improved patient outcomes. However, more detailed information on the makeup and relationships between the infiltrating T cell subsets is lacking. We therefore correlated the extent of immune infiltration into colorectal tumors with the frequencies of various T cell subsets. We prospectively recruited 22 patients at the time of surgical resection for colorectal cancer. The Klintrup-Mäkinen (KM) score was used to estimate the extent of immune infiltration into colorectal tumors. The frequencies of CD4 and CD8 T cells that produced cytokines or expressed the inhibitory molecule programed cell death 1 (PD-1) were determined by flow cytometry in colorectal tumor and matched uninvolved colonic tissue. In addition, the frequency of CD4 regulatory T cell (Treg) subsets was determined. An increased frequency of CD4 T cells producing IL-17 (Th17 cells) was observed in colorectal tumor tissue compared with adjacent uninvolved tissue. These Th17 cells mostly coproduced TNF-α, but not IFN-γ. IL-17 expression correlated positively with TNF-α and IL-10. Increased expression of the immune checkpoint molecule PD-1 was found in colorectal tumors compared with adjacent uninvolved tissue. There was a negative correlation between expression of PD-1 and IFN-γ, but not IL-17, for both CD4(+) and CD8(+) T cells. CD4(+)CD25(+)CD127(lo) and CD4(+)CD25(+)CD127(lo)FoxP3(+)CD39(+) Treg cells were enriched in colorectal tumors. A positive correlation between KM score and percentage CD4(+)CD25(+)CD127(lo) Treg cells was observed in tumors, suggesting that increased immune infiltration is associated with an increased proportion of Treg cells. In addition, there was a negative correlation between the frequency of CD4(+)CD25(+)CD127(lo) Treg cells and the expression of IFN-γ and IL-2, but not IL-17, in tumors. Taken together, these data suggest that both PD-1 expressing T cells and Treg cells within the tumor may have a suppressive effect on T cells secreting IFN-γ, IL-2, or TNF-α, but not Th17 cells.

A comparison of standard and novel bronchoscopic endobronchial biopsy retrieval methods.

BACKGROUND: The targets of bronchoscopic biopsy now include not only adequate tissue for histologic diagnosis but also tissue for further analysis. We prospectively compared standard and novel bronchoscopic endobronchial biopsy (EBB) retrieval methods attempting to increase tissue yield. METHODS: EBB samples were retrieved using techniques A, B, and C using a standard forceps. Method A is routinely performed conventional method, where as in method B, biopsy forceps was left protruded from the bronchoscope and in method C, both valve and forceps were removed to prevent the loss of specimen. At least 6 EBB were retrieved per patient. Results were compared with gold standard composite of confirmatory pathological or clinic-radiologic follow up. RESULTS: A total of 42 of 43 patients completed the study. The final gold standard diagnosis was cancer [non-small cell lung cancer, metastatic, carcinoid, carcinoma in situ (24)], benign disease [sarcoid, amyloid, hamartoma, and chondroid tumor (4)], and benign/nonspecific inflammation (14). EBB retrieved using standard method A were smaller than novel methods B and C (P=0.03). However, the percentage of cases where blood was the predominant component (>50%) was less by standard methods A (4/42) than B (16/42) and C (20/42) (P=0.001). There was no difference in mean viable tumor area (n=23, sensitivity for EBB for cancer 96%) between groups A compared with B and C (P 0.27) and adequacy in benign cases by subepithelial depth (>0.3 mm) (P=0.38). CONCLUSION: Standard retrieval of endobronchial biopsies through the bronchoscope and cap does not reduce the size of viable tissue and reduces contaminating blood and necrotic material.