Reducing reflex first-line prescriptions in a surgical pathology laboratory: toward sustainable practice with positive economic and clinical effects.

In surgical pathology departments, reflex first-line techniques (RFLTs) are aimed at reducing workloads and addressing recent shortages of medical personnel. However, the impacts thereof on economic and diagnostic factors have been poorly addressed. Also, in the era of global warming, environmental considerations are crucial. This study assessed the economic and diagnostic efficacies of routine pathological RFLT and the quality of care and sustainability. Ten RFLTs of the Bordeaux University Hospital pathology department (six special stains, one cytology technique, and three immunohistochemical tests) were studied. First, a retrospective economic analysis evaluated the average cost of these RFLTs per slide and per year. Second, diagnostic relevance was prospectively surveyed. Third, the effects of changes made were analyzed over 2 years. The ten RFLTs were associated with average annual costs of €46,708. Diagnostic relevance analysis indicated that most stains were unnecessary; only 17% were requested as second-line techniques. Elimination of 7/10 tests afforded annual cost savings of €22,522 and reduced the workload by 5568 tests/year, without compromising the workflow or diagnostic quality. Seven of ten RFLTs could be eliminated without compromising diagnostic quality or the workflow. This afforded not only financial benefits but also positive social and environmental impacts. We offer valuable insights into appropriate practices in surgical pathology laboratories. Collaboration between the medical and technical teams was crucial; other healthcare sectors would also benefit from our approach.

Targeting metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor.

Gastric cancer's (GC) bad prognosis is usually associated with metastatic spread. Invasive cancer stem cells (CSC) are considered to be the seed of GC metastasis and not all CSCs are able to initiate metastasis. Targeting these aggressive metastasis-initiating CSC (MIC) is thus vital. Leukaemia inhibitory factor (LIF) is hereby used to target Hippo pathway oncogenic members, found to be induced in GC and associated with CSC features. LIF-treated GC cell lines, patient-derived xenograft (PDX) cells and/or CSC tumourspheres underwent transcriptomics, laser microdissection-associated proteomics, 2D and 3D invasion assays and in vivo xenograft in mice blood circulation. LIFR expression was analysed on tissue microarrays from GC patients and in silico from public databases. LIF-treated cells, especially CSC, presented decreased epithelial to mesenchymal transition (EMT) phenotype and invasion capacity in vitro, and lower metastasis initiation ability in vivo. These effects involved both the Hippo and Jak/Stat pathways. Finally, GC's high LIFR expression was associated with better clinical outcomes in patients. LIF treatment could thus represent a targeted anti-CSC strategy to fight against metastatic GC, and LIFR detection in primary tumours could constitute a potential new prognosis marker in this disease.

Droplet digital polymerase chain reaction detection of KRAS mutations in pancreatic FNA samples: Technical and practical aspects for routine clinical implementation.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is associated with a 5-year survival rate of less than 6%, and current treatments have limited efficacy. The diagnosis of PDAC is mainly based on a cytologic analysis of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples. However, the collected specimens may prove noncontributory in a significant number of cases, delaying patient management and treatment. The combination of EUS-FNA sample examination and KRAS mutation detection can improve the sensitivity for diagnosis. In this context, the material used for molecular analysis may condition performance. METHODS: The authors prospectively compared the performance of cytologic analysis combined with a KRAS droplet digital polymerase chain reaction (ddPCR) assay for PDAC diagnosis using either conventional formalin-fixed, paraffin-embedded cytologic samples or needle-rinsing fluids. RESULTS: Molecular testing of formalin-fixed, paraffin-embedded cytologic samples was easier to set up, but the authors observed that the treatment of preanalytic samples, in particular the fixation process, drastically reduced ddPCR sensitivity, increasing the risk of false-negative results. Conversely, the analysis of dedicated, fresh needle-rinsing fluid samples appeared to be ideal for ddPCR analysis; it had greater sensitivity and was easily to implement in clinical use. In particular, fluid collection by the endoscopist, transportation to the laboratory, and subsequent freezing did not affect DNA quantity or quality. Moreover, the addition of KRAS mutation detection to cytologic examination improved diagnosis performance, regardless of the source of the sample. CONCLUSIONS: Considering all of these aspects, the authors propose the use of an integrated flowchart for the KRAS molecular testing of EUS-FNA samples in clinical routine.

CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma.

BACKGROUND: Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinical significance in GC patients. METHODS: Using GC cell lines and patient-derived xenografts, we evaluated CD44+ and CD44v3+ GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues. RESULTS: CD44v3+ cells, which represented a subpopulation of CD44+ cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+ CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3- CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+ cells detected in the primary tumours of GC patients were associated with a worse prognosis. CONCLUSION: CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies.

Management of Pathogenic CDH1 Variant Carriers Within the FREGAT Network: A Multicentric Retrospective Study.

OBJECTIVE: To describe the management of pathogenic CDH1 variant carriers (pCDH1vc) within the FREGAT (FRench Eso-GAsTric tumor) network. Primary objective focused on clinical outcomes and pathological findings, Secondary objective was to identify risk factor predicting postoperative morbidity (POM). BACKGROUND: Prophylactic total gastrectomy (PTG) remains the recommended option for gastric cancer risk management in pCDH1vc with, however, endoscopic surveillance as an alternative. METHODS: A retrospective observational multicenter study was carried out between 2003 and 2021. Data were reported as median (interquartile range) or as counts (proportion). Usual tests were used for univariate analysis. Risk factors of overall and severe POM (ie, Clavien-Dindo grade 3 or more) were identified with a binary logistic regression. RESULTS: A total of 99 patients including 14 index cases were reported from 11 centers. Median survival among index cases was 12.0 (7.6-16.4) months with most of them having peritoneal carcinomatosis at diagnosis (71.4%). Among the remaining 85 patients, 77 underwent a PTG [median age=34.6 (23.7-46.2), American Society of Anesthesiologists score 1: 75%] mostly via a minimally invasive approach (51.9%). POM rate was 37.7% including 20.8% of severe POM, with age 40 years and above and low-volume centers as predictors ( P =0.030 and 0.038). After PTG, the cancer rate on specimen was 54.5% (n=42, all pT1a) of which 59.5% had no cancer detected on preoperative endoscopy (n=25). CONCLUSIONS: Among pCDH1vc, index cases carry a dismal prognosis. The risk of cancer among patients undergoing PTG remained high and unpredictable and has to be balanced with the morbidity and functional consequence of PTG.

KRAS gene mutation quantification in the resection or venous margins of pancreatic ductal adenocarcinoma is not predictive of disease recurrence.

Pancreatic ductal adenocarcinoma (PDAC) patients eligible for curative surgery undergo unpredictable disease relapse. Even patients with a good pathological response after neoadjuvant treatment (NAT) remain susceptible to recurrent PDAC. Molecular analysis of R0 margins may identify patients with a worse prognosis. The molecular status of mutant KRAS (exon 2, codon 12/13) was analysed retrospectively by digital droplet PCR in tumour areas, venous and resection margins of resected tumours, either undergoing up-front surgery (UFS) or after NAT with a good pathological response. Expectedly, tumour tissues or remnants from patients who underwent NAT presented lower KRAS mutant allele frequencies (MAF) than patients eligible for UFS. Similarly, ypT1 tumour MAFs were greater than the ypT0 tumour remnant MAFs in the NAT group. Mutant KRAS status in margins did not distinguish NAT subgroups. It was not predictive of shorter recurrence-free or overall survival within or between groups. KRAS-double negativity in both venous and resection margins did not identify patients with a better prognosis, regardless of the groups. The cohorts 'sizes were small due to limited numbers of patients meeting the inclusion criteria, but KRAS-positivity or MAFs in resection and venous margins did not carry prognostic value. Comparison of margins from good versus bad responders receiving NAT may provide better clinical value.

Neoadjuvant treatment for borderline resectable pancreatic adenocarcinoma is associated with higher R0 rate compared to upfront surgery.

BACKGROUND: Neoadjuvant treatment (NAT) is debated for borderline resectable pancreatic cancer (BRPC). This retrospective study assessed the impact of NAT on R0 rate and survival for BRPC patients in comparison with upfront surgery (US). MATERIAL AND METHODS: Between 2010 and 2017 patient records for all consecutive patients treated for BRPC according to NCCN 2017 were reviewed. The endpoints analysed were R0 rate, recurrence-free-survival (RFS) and overall survival (OS). RESULTS: Seventy-nine patients were included: 63 (79.7%) patients received NAT and 16 (20.3%) were upfront operated. NAT consisted in FOLFIRINOX (median cycles: 5, range 4-8) followed by chemoradiation (n = 55, 87.3%, median dose: 54 Gy). Thirty-nine (61.9%) patients had resection. R0 rate was higher in the NAT group considering a margin clearance of 0 mm (94.9%) or 1 mm (89.7%) compared to the US group (68.8% and 43.8% respectively). In the whole population, median RFS was 12.6 [95%CI: 10.5-22.1] in the NAT group vs 7.7 [95%CI: 4.4-14] months in the US group (p < 0.01). Median OS was 29.0 [95%CI: 23.5-63.1] and 27.2 [95%CI: 11.6-38.8] months in the NAT and US groups respectively (p = 0.06). In operated patients the NAT group achieved better RFS and OS than the US group (p < 0.01 for both). In multivariate analysis NAT, surgical resection and age <65 (p < 0.01 for both) were prognostic of RFS. NAT, surgical resection and adjuvant chemotherapy were prognostic of OS (p < 0.05 for all). In operated patients (n = 55) multivariate analysis showed that N1 status was associated with decreased RFS; age < 65 and NAT were associated with a longer RFS. Receiving a NAT, an adjuvant chemotherapy and achieving a ypT0-1N0 status were associated with better OS. NAT was well tolerated with 14.3% grade ≥ 3 toxicities. CONCLUSION: NAT permitted a high R0 rate with a 0- or 1-mm clearance margin and was associated with better RFS and OS for patients with BRPC.

The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa.

BACKGROUND & AIMS: Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context. METHODS: Hippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated. RESULTS: LATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other's expression. Loss-of-function experiments showed that LATS2 restricts H pylori-induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori-induced preneoplastic changes. CONCLUSIONS: H pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host-pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.

Prognostic Factors of Acinar Cell Carcinomas: A Study of 44 Patients.

OBJECTIVES: Acinar cell carcinoma is a rare tumor of the pancreas. Our current series aimed to assess the clinical and morphological features of pancreatic acinar cell carcinoma and to evaluate the treatment strategies and prognosis. METHODS: This retrospective study was conducted in 3 French referral centers. Clinical data were obtained from medical records, and data about survival were then calculated and compared using statistical analysis. RESULTS: Forty-four patients were included (men, 81.8%; median age, 65.5 years; range, 21-85). Tumors were localized, locally advanced, or metastatic in 48.8%, 14.0%, and 37.2% of cases, respectively. Twenty-nine patients (65.9%) underwent a curative-intent resection (R0, 79.2%). First-line chemotherapy in metastatic patients was heterogeneous but mainly consisted in 5-fluorouracil-based or gemcitabine plus oxaliplatin combinations. Median disease-free survival was 12 months (range, 0-82 months). Median overall survival was 55.5 months; it was 40 months in patients with metastatic tumor compared with 106.5 months (P = 0.1058) in those with a nonmetastatic one. Age older than 60 years and a proliferation index greater than 30% were poor prognostic factors. CONCLUSIONS: In this large series of patients with pancreatic acinar cell carcinoma, the rate of R0 resection and the prognosis of patients appeared to be much better than that of classic ductal adenocarcinomas.

Combination treatment of resveratrol and capsaicin radiosensitizes pancreatic tumor cells by unbalancing DNA repair response to radiotherapy towards cell death.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers because it is highly resistant to every available therapeutic strategy, in particular conventional chemotherapy or radiotherapy (RT). Sensitizing tumor cells to existing treatments remains a good option to obtain fast and applicable results. Considering that ionizing radiations induce radiolysis-derived reactive oxygen species (ROS), we hypothesized that ROS-inducing bioactive food components (BFCs) could exacerbate ROS-related cell damages, including DNA double stranded breaks (DSBs), leaving the cellular ROS scavenging systems overwhelmed, and precipitating tumor cell death. Combination of resveratrol and capsaicin radiosensitized radiosensitive tumor cells, but RT did not increase BFC combination toxicity in radioresistant tumor cells. BFC addition to RT increased ROS production and led to significant tumor volume reduction in xenografted mouse preclinical model. Strikingly, BFCs inhibited RT-induced DNA damage molecular response by strongly limiting the first steps of DSB repair, and by keeping cells in cell cycle, provoking exacerbated intrinsic apoptosis. This study positions BFCs as potent radiosensitizers when combined, and identifies an actionable molecular pathway by resveratrol and capsaicin combination.

Psammomatoid Calcification-Rich Oncocytic Thyroid Adenoma With Clear-Cell Change.

Abundant calcifications and clear-cell change may occur in oncocytic thyroid adenoma (OTA). We aimed to report the features of a case of OTA peculiar by the presence of extensive calcifications and of a clear-cell component. The OTA was detected on a right thyroid lobectomy specimen. Clear-cell change was observed in 15%-20% of the cells. Numerous, focally confluent psammomatoid calcifications, resulting in macrocalcifications, were identified. The nodule cells, uni- or multinucleated oncocytes, including those with clear cytoplasm, expressed heterogeneously TTF1, S100 protein, Bcl2, CD10, as well as CD138 and CD56. Lipid-droplet markers adipophilin and TIP47 were also expressed. In conclusion, we report a rare type of OTA, peculiar by the presence of numerous psammomatoid calcifications and of macrocalcification and by the presence of clear-cell change. Heterogeneity in membrane CD56 and/or CD138 expression as well as cytoplasmic heterogeneity of Bcl2 and lipid-droplet marker TIP47 might be relevant for calcification and clear-cell change, requiring further investigation.

Colonic MicroRNA Profiles, Identified by a Deep Learning Algorithm, That Predict Responses to Therapy of Patients With Acute Severe Ulcerative Colitis.

BACKGROUND & AIMS: Acute severe ulcerative colitis (ASUC) is a life-threatening condition managed with intravenous steroids followed by infliximab, cyclosporine, or colectomy (for patients with steroid resistance). There are no biomarkers to identify patients most likely to respond to therapy; ineffective medical treatment can delay colectomy and increase morbidity and mortality. We aimed to identify biomarkers of response to medical therapy for patients with ASUC. METHODS: We performed a retrospective analysis of 47 patients with ASUC, well characterized for their responses to steroids, cyclosporine, or infliximab, therapy at 2 centers in France. Fixed colonic biopsies, collected before or within the first 3 days of treatment, were used for microarray analysis of microRNA expression profiles. Deep neural network-based classifiers were used to derive candidate biomarkers for discriminating responders from non-responders to each treatment and to predict which patients would require colectomy. Levels of identified microRNAs were then measured by quantitative PCR analysis in a validation cohort of 29 independent patients-the effectiveness of the classification algorithm was tested on this cohort. RESULTS: A deep neural network-based classifier identified 9 microRNAs plus 5 clinical factors, routinely recorded at time of hospital admission, that associated with responses of patients to treatment. This panel discriminated responders to steroids from non-responders with 93% accuracy (area under the curve, 0.91). We identified 3 algorithms, based on microRNA levels, that identified responders to infliximab vs non-responders (84% accuracy, AUC = 0.82) and responders to cyclosporine vs non-responders (80% accuracy, AUC = 0.79). CONCLUSION: We developed an algorithm that identifies patients with ASUC who respond vs do not respond to first- and second-line treatments, based on microRNA expression profiles in colon tissues.

Histologic analysis has a prognostical value in colorectal biopsies assessed for suspicion of graft-versus-host disease.

Gastrointestinal (GI) graft-versus-host-disease (GVHD) is a common and severe complication of allogeneic hematopoietic stem cell transplantation, but clinical and histological features are unspecific. The aim of this study was to correlate the histological GI GVHD grade with the clinical outcomes. In a retrospective study of 112 patients with clinically suspected GI GVHD, colonic biopsies were reviewed by three pathologists without knowledge of the corresponding clinical data and classified in four scores, according to the NIH Consensus Project recommendations: no GVHD, possible, probable, and unequivocal GVHD. At the end of the study, the histological and clinical data were confronted with the following results: clinical diagnosis of GI GVHD was established for 70 patients (62.5%) and histological scores correlated well with the clinical diagnosis (p < 0.001) and particularly with the prognosis (p < 0.05).When severe lesions were observed, the 1 year overall survival declined to 9%. None of the features reported in the literature to support GVHD diagnosis, eosinophil count, endocrine cells aggregate, immunohistochemical analysis (cytomegalovirus, CD123, chromogranin), did not help us for diagnosis. So routine histopathology alone without immunohistochemistry is a strong and reproducible tool to diagnose GI GVHD with the help of clinical and biological information, and most importantly, histological grading proved to be a powerful prognostic value.

Molecular Pathology of Anaplastic Thyroid Carcinomas: A Retrospective Study of 144 Cases.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations. METHODS AND MATERIALS: One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened. RESULTS: Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest. CONCLUSION: This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.

Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.

Purpose: Gastric carcinomas are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemotherapy and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human gastric carcinoma of different histologic types.Experimental Design: The primary tumors from 37 patients with intestinal- or diffuse-type noncardia gastric carcinoma were studied, and patient-derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expressions of 10 putative cell surface markers of CSCs, as well as aldehyde dehydrogenase (ALDH) activity, were studied, and the tumorigenic properties of cells were evaluated by in vitro tumorsphere assays and in vivo xenografts by limiting dilution assays.Results: We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a high ALDH activity presented the properties to generate new heterogeneous tumorspheres in vitro and tumors in vivo CD44 and CD166 were coexpressed, representing 6.1% to 37.5% of the cells; ALDH activity was detected in 1.6% to 15.4% of the cells; and the ALDH+ cells represented a core within the CD44+/CD166+ subpopulation that contained the highest frequency of tumorigenic CSCs in vivo The ALDH+ cells possessed drug efflux properties and were more resistant to standard chemotherapy than the ALDH- cells, a process that was partially reversed by verapamil treatment.Conclusions: CD44 and ALDH are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. Clin Cancer Res; 23(6); 1586-97. ©2016 AACR.

MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Endoscopic and histologic response to cyclosporine in ulcerative colitis and their impact on disease outcome: A cohort study.

INTRODUCTION: Cyclosporine (CsA) is an effective agent for treating patients with acute steroid-refractory ulcerative colitis (UC). The aim was to assess endoscopic and histologic responses to CsA and to determine their predictive value on UC outcome. PATIENTS AND METHODS: Consecutive UC patients who received intravenous CsA for an acute refractory UC were included when they had endoscopic assessments with biopsies at entry and, at CsA interruption in responders. Mucosal healing (MH) was defined by Mayo endoscopic subscore ≤1 and, histologic response (HR) by the absence of basal plasmocytosis or a Geboes score <3.1. RESULTS: Among 21 patients who responded to CsA, MH was achieved in 81%. Survival rates without relapse at 2 years were 79% and 25% in patients with MH and without MH, respectively (p=0.04). HR was observed in 84% of patients according to basal plasmocytosis and in 68% according to Geboes score. Multivariate analysis revealed that a Mayo endoscopic subscore of 0 was the only prognostic factor associated with absence of relapse (RR=12; 95%CI: 1.05-136.79). CONCLUSION: CsA provides MH and HR in most of UC patients responding to this drug. As suggested with other UC treatments, a complete MH with CsA has a good prognostic value.