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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. The use of fresh needle‐rinsing fluid offers better sensitivity than formalin‐fixed, paraffin‐embedded cytology samples for the detection of KRAS G12/G13 mutations using droplet digital polymerase chain reaction. The addition of KRAS G12/G13 mutation detection by droplet digital polymerase chain reaction analysis to cytologic examination improves pancreatic ductal adenocarcinoma diagnostic performance compared with cytology alone and can be proposed in cases of negative or noncontributory cytologic results. [ABSTRACT FROM AUTHOR]

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). 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). 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. 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. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) care has improved considerably, particularly since the implementation of a quality of care program centered on national evidence-based guidelines. Formal quality assessment is however still needed. The aim of this research was to identify factors associated with practice variation in CRC patient care. Methods CRC patients identified from all cancer centers in South-West France were included. We investigated variations in practices (from diagnosis to surgery), and compliance with recommended guidelines for colon and rectal cancer. We identified factors associated with three colon cancer practice variations potentially linked to better survival: examination of ≥12 lymph nodes (LN), non-use and use of adjuvant chemotherapy for stage II and stage III patients, respectively. Results We included 1,206 patients, 825 (68%) with colon and 381 (32%) with rectal cancer, from 53 hospitals. Compliance was high for resection, pathology report, LN examination, and chemotherapy use for stage III patients. In colon cancer, 26% of stage II patients received adjuvant chemotherapy and 71% of stage III patients. 84% of stage US T3T4 rectal cancer patients received pre-operative radiotherapy. In colon cancer, factors associated with examination of ≥12 LNs were: lower ECOG score, advanced stage and larger hospital volume; factors negatively associated were: left sided tumor location and one hospital district. Use of chemotherapy in stage II patients was associated with younger age, advanced stage, emergency setting and care structure (private and location); whereas under-use in stage III patients was associated with advanced age, presence of comorbidities and private hospitals. Conclusions Although some changes in practices may have occurred since this observational study, these findings represent the most recent report on practices in CRC in this region, and offer a useful methodological approach for assessing quality of care. Guideline compliance was high, although some organizational factors such as hospital size or location influence practice variation. These factors should be the focus of any future guideline implementation.

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. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the long-term results after Vecchietti’s operation. Study design: Twenty Mayer–Rokitanski–Kuster–Hauser (MRKH) syndrome patients underwent creation of a neovagina using Vecchietti’s operation by laparotomy (17 cases) and laparoscopy (3 cases). Results: The mean age of the patients was 21 years (16–34). After 66 months (24–156) of follow-up, the mean length×diameter of the neovagina was 8.2 cm×2.8 cm. The neovaginal epithelium was macroscopically similar to normal vaginal mucosa, except for one patient who had subsequently undergone insertion of skin graft. Post-operative sexual behavior revealed sexual desire and pleasure (100%), lubrication (94%), clitoral orgasm (87%) and vaginal-mediated orgasm (69%). Finally, 16 patients out of 18 (89%) were completely satisfied with the results of the operation. Conclusion: Vecchietti’s operation may be suggested as one of the choice of treatments to correct vaginal aplasia in young MRKH syndrome patients. [Copyright &y& Elsevier]

Background: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical. Results: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors. Conclusion: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 ., (©2016 American Association for Cancer Research.)

Purpose: To prospectively evaluate the utility of computed tomography (CT) for determination of tumor response and prediction of resectability after neoadjuvant combined chemotherapy and radiation therapy (CRT) in patients with nonmetastatic locally advanced pancreatic cancer., Materials and Methods: This study received institutional review board approval, and all participants provided written informed consent. Consecutive patients with cephalic locally advanced pancreatic cancer who underwent surgical exploration and/or resection following neoadjuvant CRT were prospectively enrolled from June 2009 to May 2013. Two radiologists independently analyzed the baseline and post-CRT CT scans for the size, attenuation, and circumferential vascular contacts of the tumor. Associations between the postoperative histologic grade of the tumor response (pTNM) and the clinical, biologic, and CT criteria were assessed by using Spearman correlation coefficients. CT criteria related to the presence of complete (ie, R0) resection were assessed by using logistic regression., Results: Forty-seven patients were included, 33 with an R0 resection and 14 with positive margins (ie, R1) or no resection. Variables demonstrating a significant correlation with the histologic tumor classification of tumor response were post-CRT carbohydrate antigen 19-9 level (r = 0.46), post-CRT largest tumor axis (r = 0.44), post-CRT sum of the largest and smallest tumor axes (r = 0.46), change in the largest axis (r = -0.31), change in the sum of the largest and smallest axes (r = -0.39), change in superior mesenteric vein (SMV) and/or portal vein (hereafter, SMV/portal vein) contact (r = -0.38), and post-CRT superior mesenteric artery contact (r = 0.34). Partial regression of tumor contact with the SMV/portal vein was associated in all cases with R0 resection (10 of 10 patients, positive predictive value = 100%), and partial regression of tumor contact with any peripancreatic vascular axis was associated with R0 resection in 91% of cases (20 of 22 patients, positive predictive value = 91%). Persistence of SMV/portal vein stenosis after CRT was not predictive of R1 resection., Conclusion: Partial regression of tumor-vessel contact indicates suitability for surgical exploration, irrespective of the degree of decrease in tumor size or the degree of residual vascular involvement., (© RSNA, 2014.)

Celiac disease (CD) is characterized by villous atrophy and an increase in intraepithelial lymphocytes (IEL). The IEL usually exhibit a suppressor/cytotoxic phenotype (CD3 and CD8) and display a polyclonal profile for T-cell receptor (TCR) rearrangement as opposed to the monoclonality of refractory CD (RCD) with CD8 IEL. A complication of CD is the loss of response to a gluten-free diet called RCD that may progress to an enteropathy-associated T-cell lymphoma. We reviewed 20 uncomplicated CD and 23 complicated CD (19 RCD and 4 diagnosed at the same time as enteropathy-associated T-cell lymphoma). In complicated CD, the IEL phenotype was CD8 in 9 cases and CD8 in 14 cases. In 100% of cases, IEL showed a monoclonal TCR rearrangement. All the 9 CD8 complicated CD exhibited a monoclonal TCR rearrangement and 3 of them were associated with a T-cell lymphoma (2 at the same time as CD and 1 after 43-mo follow-up) and bore the same monoclonal rearrangement in IEL and in lymphoma. Interestingly, the 13 cases (100%) of CD with a CD8 phenotype were also found monoclonal and 2 of them were associated with a T-cell lymphoma diagnosed at the same time as CD and exhibiting the same rearrangement in IEL and in lymphoma. An aberrant CD3 CD8 IEL phenotype is a good criterion for RCD diagnosis. However, cases with a normal CD3 CD8 IEL phenotype may correspond to RCD. In such cases, we suggest that molecular analysis of TCR-gamma genes is a useful method for identifying cases with RCD.

The number and status of lymph nodes examined is crucial for tumor staging. Impact of preoperative chemoradiotherapy on lymph nodes status and survival is still controversial in rectal carcinoma. The aim of this study was (i) to define the impact of preoperative chemoradiotherapy on the number of both retrieved and positive lymph nodes in rectal cancer specimen, (ii) to evaluate the influence of the number of lymph nodes retrieved on survival in patients treated by preoperative chemoradiotherapy. From 1994 to 2004, 495 patients underwent rectal excision for cancer, of which 332 received long course preoperative radiotherapy. Surgery and pathologic assessment were standardized. Multivariate analysis evaluated the influence of clinical and pathologic variables on the number of both retrieved and positive lymph nodes. Kaplan-Meier method and log-rank test assessed the relation between survival and the number of lymph nodes retrieved in patients treated by preoperative chemoradiotherapy. Compared with surgery alone, preoperative chemoradiotherapy decreased both the mean number of lymph nodes retrieved (17 vs. 13; P<0.001) and the mean number of positive lymph nodes (2.3 vs. 1.2; P=0.001). Multivariate analysis confirmed the independent impact of preoperative chemoradiotherapy on retrieved and positive lymph nodes. In patients treated by preoperative chemoradiotherapy, the 5-year overall (71%) and disease-free (60%) survival was not associated with the number of lymph nodes retrieved. Although long course preoperative chemoradiotherapy decreases by 24%, the mean number of lymph nodes retrieved and by 48% the mean number of positive lymph nodes, survival was not influenced by the number of lymph nodes retrieved in irradiated rectal specimen.

Objectives: The aim of this study was to evaluate the possibility of subsequent resection of locally advanced pancreatic adenocarcinoma after chemotherapy and external-beam radiotherapy., Patients and Methods: Between January 1996 and January 2001, 33 consecutive patients (18 males and 15 women, mean age 63 years) with locally advanced PA were treated with chemotherapy and concurrent external-beam radiotherapy. Radiotherapy delivered 45-50.4 Gy, in a classical manner (N=27) or on a split-course (N=6). Chemotherapy was made of 5FU by continuous infusion for all patients during 5 weeks and cisplatin at the 1st and 5th weeks (N=22). Tumor resectability was reassessed at the end of the chemoradiotherapy; surgical resection of tumour was attempted in patients whose tumor demonstrated reduction in size, and supplementary radiotherapy of 10 to 15 Gy was delivered to the others., Results: Thirty-nine percent of patients experienced grade 3 acute toxicity. WHO criteria response to chemoradiotherapy four weeks after the end of treatment were: 4 partial responders (12%), 6 minor responders (18%), 14 stable disease (42%), 9 progression (28%). Ten patients underwent exploratory laparotomy, in one case vascular encasement did not allow for tumor resection, and in another patient, there was peritoneal carcinomatosis. In the 8 remaining patients, surgical (R0) resection was possible. In one patient histological examination showed fibrosis with no residual tumour. After a median follow-up period of 40 months, median survival was 16 months (66% and 37% of survival at 1 and 2 years respectively). In operated and non-operated patients, survival rates at 24 months were 73% and 12.5% respectively. At 1 year, 80% of the patients treated with radiochemotherapy developed recurrence, metastatic recurrence in 88%. Initial laparotomy, split course radiotherapy were poor outcome factors whereas chemotherapy appears to be a favorable outcome factor., Conclusion: Subsequent resection of locally advanced pancreatic adenocarcinoma is possible after chemoradiotherapy allowing for a prolonged survival in some patients.