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PurposeThis paper aims to examine the critical question of how to increase productivity without also increasing the burnout risk. A systems thinking framework was applied to explore individual perceptions of team dynamics and how they relate to morale, work–life balance (WLB) and hours worked.Design/methodology/approachUsing an online survey, data from 1,222 Australian workers were analysed using hierarchical multiple regression and principal components analysis (PCA).FindingsSelf-reported productivity was found to be predicted by engagement whereas burnout and morale had minimal impact. Burnout risk was not related to hours worked but was reduced when WLB, quality work and trust is higher. Co-worker effort impacted morale and a factor labelled as team “sense of accomplishment” (SoA) was identified.Research limitations/implicationsThe results of this research have limited generalisability to wider populations due to sampling methods, being conducted in the Australian context and respondents coming from a diverse range of occupations. The sample being skewed towards younger age groups and the acknowledged use of single-item measures may also restrict drawing broader conclusions from the results.Originality/valueA socio-technical systems thinking model to diagnose the link between workplace burnout and productivity is applied. The approach involved understanding the importance of trust and how the connection between people and systems can influence morale.

Supplementary Data from Protein Expression Profiling in Esophageal Adenocarcinoma Patients Indicates Association of Heat-Shock Protein 27 Expression and Chemotherapy Response

Purpose: To identify pretherapeutic predictive biomarkers in tumor biopsies of patients with locally advanced esophageal adenocarcinomas treated with neoadjuvant chemotherapy, we used an explorative proteomic approach to correlate pretherapeutic protein expression profiles with tumor response to neoadjuvant chemotherapy.Experimental Design: Thirty-four patients with locally advanced esophageal adenocarcinomas who received neoadjuvant platin/5-fluorouracil–based chemotherapy before surgical resection were enrolled in this study. Response to chemotherapy was determined (a) by the amount of decline of [18F]fluorodeoxyglucose tumor uptake 2 weeks after the start of chemotherapy measured by positron emission tomography and (b) by histopathologic evaluation of tumor regression after surgical resection. Explorative quantitative and qualitative protein expression analysis was done through a quantitative differential protein expression analysis that used dual-isotope radioactive labeling of protein extracts. Selected identified biomarkers were validated by immunohistochemistry and quantitative real time reverse transcription-PCR.Results: Proteomic analysis revealed four cellular stress response–associated proteins [heat-shock protein (HSP) 27, HSP60, glucose-regulated protein (GRP) 94, GRP78] and a number of cytoskeletal proteins whose pretherapeutic abundance was significantly different (P < 0.001) between responders and nonresponders. Immunohistochemistry and gene expression analysis confirmed these data, showing a significant association between low HSP27 expression and nonresponse to neoadjuvant chemotherapy (P = 0.049 and P = 0.032, respectively).Conclusions: Albeit preliminary, our encouraging data suggest that protein expression profiling may distinguish cancers with a different response to chemotherapy. Our results suggest that response to chemotherapy may be related to a different activation of stress response and inflammatory biology in general. Moreover, the potential of HSPs and GRPs as biomarkers of chemotherapy response warrants further validation.

Purpose: Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer.Experimental Design: NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)–neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined.Results: NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neurite-targeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer.Conclusion: NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer. Clin Cancer Res; 19(1); 50–61. ©2012 AACR.

PDF file - 62K, Supplementary Table with patient characteristics

Dengue is an ongoing health risk for Peace Corps Volunteers (PCVs) working in the tropics. On May 2019, the Peace Corps Office of Health Services notified the Centers for Disease Control and Prevention (CDC) of a dengue outbreak among PCVs in Timor-Leste. The purpose of this investigation was to identify the clinical, demographic, and epidemiological characteristics of PCVs with dengue and recommend dengue preventive measures. To identify PCVs with dengue and describe disease severity, the medical records of PCVs reporting fever during September 2018–June 2019 were reviewed. To identify factors associated with dengue virus (DENV) infection, we administered a questionnaire on demographics, travel history, and mosquito avoidance behaviors and collected blood specimens to detect the anti-DENV IgM antibody to diagnose recent infection. Of 35 PCVs in-country, 11 (31%) tested positive for dengue (NS1, IgM, PCR), eight requiring hospitalization and medical evacuation. Among 27 (77%) PCVs who participated in the investigation, all reported having been recently bitten by mosquitoes and 56% reported being bitten most often at home; only 16 (59%) reported having screens on bedroom windows. Nearly all (93%) PCVs reported using a bed net every night; fewer (70%) reported using mosquito repellent at least once a day. No behaviors were significantly associated with DENV infection. Raising awareness of dengue risk among PCVs and continuing to encourage mosquito avoidance behavior to prevent dengue is critical. Access to and use of measures to avoid mosquito bites should be improved or implemented. Peace Corps medical officers should continue to receive an annual refresher training on dengue clinical management.

A previous article sought to signpost papers that were considered helpful when starting on the journey of practicing evidence-based medicine (EBM).1 The lead author was invited to run a workshop at the Eighth Conference of the International Society for Evidence-Based Health Care run in collaboration with the Gruppo Italiano per la Medicina Basata sulle Evidenze from 6 November to 9 November 2019. The aim of the workshop was to challenge a group of teachers and educators to consider useful papers for the teaching of EBM/evidence-based healthcare (EBHC). The second aim was to start a database of such studies. The third aim was to share learning and foster discussion from the workshop through journal publication. EBM and EBHC are used interchangeable throughout this article. Working in eight small groups (three to five people), teachers and researchers of EBM/EBHC (n=29) first listed any articles that they considered useful for new teachers starting out their teaching journey. So that the challenge also acted as learning for the participants, they were deliberately not briefed on the full nature of the workshop (eg, the consideration and selection of specific articles). After 15 min, each group spent another 10 min selecting their top three articles from their original list (if this list had more than three papers). This was followed by another 5 min selecting their final article to put forward for this paper consensus and any disagreements resolved via discussion. Groups had to provide the following information for each paper: authors; year of publication; title; reason(s) for inclusion; link to paper/reference. Learning from previous experiences, the workshop lead (DN) instructed that a group could not select an article for which a group member was an author thus avoiding one possible source of conflict. As a group we felt that this specific rule of the article selection process …

Tumor regression following neoadjuvant treatment can be observed in lymph node (LN) metastases similar to the primary tumor in esophageal adenocarcinomas (EAC). We evaluated the prognostic significance of tumor regression in LN metastases of locally advanced EAC of 239 patients treated with neoadjuvant radiochemotherapy (RCTX) or chemotherapy (CTX) followed by esophagectomy. We examined retrospectively the LN for histopathologic signs of regression, i.e., nodular fibrosis and acellular mucin. LN classification was performed according to two parameters: presence (&minus, ) or absence (+) of residual tumor and regression characteristics in the LN, resulting in four categories: LN&minus, /REG&minus, LN&minus, /REG+, LN+/REG+, LN+/REG&minus, In total, LN metastases with residual tumor were detectable in 117/239 (49%) cases. Regression in LN were observed in 85/239 cases (35.5%). The distribution of the LN/REG categories were as follows: 97 patients (40.6%) were LN&minus, A total of 25 patients (10.5%) were LN&minus, /REG+. A total of 60 (25.1%) were LN+/REG+ and 57 (23.8%) LN+/REG&minus, The LN/Reg categorization had a significant prognostic value in univariate analysis (p &lt, 0.001) and multivariate analysis (HR = 1.326, p = 0.002) with similar results for the subgroups of patients treated with RCTX or CTX. The prognosis of LN&minus, /REG+ was worse than LN&minus, but better than both LN+ categories, which was demonstrated in the Kaplan&ndash, Meier curves but did not reach statistical significance (p = 0.104 and p = 0.090, respectively). In contrast, there was no difference between LN+/REG+ and LN+/REG&minus, (p = 0.802). In summary, regression in LN metastases of EAC can be observed in a significant number of patients after neoadjuvant therapy. Complete regression of former LN metastases in comparison to &ldquo, true&rdquo, negative LN seems to be of prognostic relevance but additional studies are needed to confirm this trend seen in our study.

On June 28, 2013, the Food Safety and Inspection Service (FSIS) was notified by the Centers for Disease Control and Prevention (CDC) of an investigation of a multistate cluster of illnesses of Salmonella enterica serovar Heidelberg. Since case-patients in the cluster reported consumption of a variety of chicken products, FSIS used a simple likelihood-based approach using traceback information to focus on intensified sampling efforts. This article describes the multiphased product sampling approach taken by FSIS when epidemiologic evidence implicated chicken products from multiple establishments operating under one corporation. The objectives of sampling were to (1) assess process control of chicken slaughter and further processing and (2) determine whether outbreak strains were present in products from these implicated establishments. As part of the sample collection process, data collected by FSIS personnel to characterize product included category (whole chicken and type of chicken parts), brand, organic or conventional product, injection with salt solutions or flavorings, and whether product was skinless or skin-on. From the period September 9, 2013, through October 31, 2014, 3164 samples were taken as part of this effort. Salmonella percent positive declined from 19.7% to 5.3% during this timeframe as a result of regulatory and company efforts. The results of intensified sampling for this outbreak investigation informed an FSIS regulatory response and corrective actions taken by the implicated establishments. The company noted that a multihurdle approach to reduce Salmonella in products was taken, including on-farm efforts such as environmental testing, depopulation of affected flocks, disinfection of affected houses, vaccination, and use of various interventions within the establishments over the course of several months.

Neoadjuvant therapy has been successfully introduced in the treatment of locally advanced gastrointestinal malignancies, particularly esophageal, gastric, and rectal cancers. The effects of preoperative chemo- or radiochemotherapy can be determined by histopathological investigation of the resection specimen following this treatment. Frequent histological findings after neoadjuvant therapy include various amounts of residual tumor, inflammation, resorptive changes with infiltrates of foamy histiocytes, foreign body reactions, and scarry fibrosis. Several tumor regression grading (TRG) systems, which aim to categorize the amount of regressive changes after cytotoxic treatment in primary tumor sites, have been proposed for gastroesophageal and rectal carcinomas. These systems primarily refer to the amount of therapy-induced fibrosis in relation to the residual tumor (e.g., the Mandard, Dworak, or AJCC systems) or the estimated percentage of residual tumor in relation to the previous tumor site (e.g., the Becker, Rödel, or Rectal Cancer Regression Grading systems). TRGs provide valuable prognostic information, as in most cases, complete or subtotal tumor regression after neoadjuvant treatment is associated with better patient outcomes. This review describes the typical histopathological findings after neoadjuvant treatment, discusses the most commonly used TRG systems for gastroesophageal and rectal carcinomas, addresses the limitations and critical issues of tumor regression grading in these tumors, and describes the clinical impact of TRG.

In the quest to devise new alternatives to password-based authentication, behavioral biometrics have become more and more appealing due to the improved usability that comes with their unobtrusiveness. One such type of biometric are brainwaves, which can be nowadays easily measured and used to prove a person's identity. Given the potential for this technology to be adopted in the near future, it is paramount to analyze its security implications. Furthermore, recent advances in brain computer interfaces make feasible the usage of brainwaves to prove users' identity. This work presents a comprehensive framework for assessing the vulnerabilities of brainwave authentication systems, incorporating new attack vectors that target specific features of brain biometrics. Resting on this theoretical groundwork, we analyze the existing literature on attacks and countermeasures, identifying gaps and providing a foundation for future research. Furthermore, we evaluated a subset of attacks identified through the framework and report our preliminary results.

BACKGROUND The cause of Napoleon Bonaparte's death remains controversial. Originally suggested to be gastric cancer, whether this was truly neoplastic or a benign lesion has been recently debated. AIMS To interpret findings of original autopsy reports in light of the current knowledge of gastric cancer and to highlight the significance of accurate macroscopy in modern-day medicine. METHODS Using original autopsy documents, endoscopic images and data from current literature, Napoleon's gastric situation was reconstructed. In a multicenter collection of 2071 gastric cancer specimens, the relationship between tumor size and features of tumor progression was assessed. RESULTS Greater tumor size was associated with advanced pT, nodal metastases and Borrmann types 3-4 (p

Introduction. The evaluation of the trimming surfaces (TS) of tissue blocks from frozen sections may serve as a supplementary examination tool for the intraoperative determination of resection margins of breast cancer specimens. This study aimed at the investigation of the feasibility and reliability of this technique, which has been described only very rarely in literature. Methods. Two observers assessed digital images from TS obtained from 57 resection margins. Findings were correlated with the diagnosis of the frozen section (FS) alone and the final diagnosis on formalin-fixed paraffin-embedded (FFPE) material. Results. The determination of the resection margin on TS was estimated as feasible for all cases. Interobserver congruence rate for TS was 96% (κ = 0.81), which was lower compared with FFPE (100%, κ = 1.0) but superior to FS (89%, κ = 0.67). Intraobserver congruence of the 2 reviewers was 96.5% and 93.0% between TS and FFPE, and 91.1% and 92.5% between FS and FFPE, respectively. The combination of both intraoperative consultation techniques showed similar congruence but a slight improvement for the sensitivity (0.75 to 0.875) for the diagnosis of tumor at the resection margin in FFPE for Reviewer 1 but was unchanged for Reviewer 2. Conclusion. The additional evaluation of TS can be a helpful additional tool for intraoperative margin assessment of breast cancer specimens, in particular, when processing artifacts of FS are encountered.

Background MicroRNAs (miRNAs) play an important role in cancer biology. Neoadjuvant radiochemotherapy followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, a subset of patients do not respond. We evaluated whether miRNA profiles can predict resistance to radiochemotherapy. Methods Formalin-fixed, paraffin-embedded pretherapeutic biopsies of patients treated by radiochemotherapy followed by esophagectomy were analyzed. The response was determined by histopathological tumor regression grading. miRNA profiling was performed by microarray analysis (Agilent platform) in 16 non-responders and 15 responders. Differentially expressed miRNAs were confirmed by real-time quantitative PCR (qRT-PCR) in an expanded cohort of 53 cases. Results The miRNA profiles within and between non-responders and responders were highly similar (r = 0.96, 0.94 and 0.95). However, 12 miRNAs were differentially expressed (> twofold; p ≤ 0.025): non-responders showed upregulation of hsa-miR-1323, hsa-miR-3678-3p, hsv2-miR-H7-3p, hsa-miR-194*, hsa-miR-3152, kshv-miR-K12-4-3p, hsa-miR-665 and hsa-miR-3659 and downregulation of hsa-miR-126*, hsa-miR-484, hsa-miR-330-3p and hsa-miR-3653. qRT-PCR analysis confirmed the microarray findings for hsa-miR-194* and hsa-miR-665 (p

Branchial cleft cysts rank among the most common differential diagnoses of cystic cervical masses. Rarely, classic cystic structures exhibit a squamous cell carcinoma differentiation that represents a bronchogenic carcinoma. The existence of bronchogenic carcinoma is controversial due to the lack of systematic immunohistologic workup. The present study aimed to identify the clinical and immunohistologic features of bronchogenic carcinoma to clearly distinguish this entity from other cystic cervical masses.Immunohistologic (epidermal growth factor receptor; cytokeratin 5, 6, 7, 13; and p16) and epidemiologic assessments were performed for branchial cleft cysts (n = 63), bronchogenic carcinomas (n = 5), cystic metastasized oropharyngeal carcinomas (n = 97), and carcinomas of unknown primary (n = 51). The study was conducted as a retrospective case series study with comparison.The patients with bronchogenic carcinomas differed significantly in age and in the number of involved lymph nodes compared with the cystic metastasized oropharyngeal carcinoma (and carcinoma of unknown primary) patients. Regular histologic wall structures were only observed in the bronchogenic carcinomas and branchial cleft cysts. Solitary cytokeratin-7 staining was only observed in the bronchogenic carcinomas, and all of the bronchogenic carcinomas were p16 negative.The existence of bronchogenic carcinoma seems to be plausible based on clinical findings. Cytokeratin-7 and p16 staining might be helpful in the diagnostic workflow.4 Laryngoscope, 126:638-642, 2016.

Histopathologic determination of tumor regression provides important prognostic information for locally advanced gastroesophageal carcinomas after neoadjuvant treatment. Regression grading systems mostly refer to the amount of therapy-induced fibrosis in relation to residual tumor or the estimated percentage of residual tumor in relation to the former tumor site. Although these methods are generally accepted, currently there is no common standard for reporting tumor regression in gastroesophageal cancers. We compared the application of these 2 major principles for assessment of tumor regression: hematoxylin and eosin-stained slides from 89 resection specimens of esophageal adenocarcinomas following neoadjuvant chemotherapy were independently reviewed by 3 pathologists from different institutions. Tumor regression was determined by the 5-tiered Mandard system (fibrosis/tumor relation) and the 4-tiered Becker system (residual tumor in %). Interobserver agreement for the Becker system showed better weighted κ values compared with the Mandard system (0.78 vs. 0.62). Evaluation of the whole embedded tumor site showed improved results (Becker: 0.83; Mandard: 0.73) as compared with only 1 representative slide (Becker: 0.68; Mandard: 0.71). Modification into simplified 3-tiered systems showed comparable interobserver agreement but better prognostic stratification for both systems (log rank Becker: P=0.015; Mandard P=0.03), with independent prognostic impact for overall survival (modified Becker: P=0.011, hazard ratio=3.07; modified Mandard: P=0.023, hazard ratio=2.72). In conclusion, both systems provide substantial to excellent interobserver agreement for estimation of tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas. A simple 3-tiered system with the estimation of residual tumor in % (complete regression/1% to 50% residual tumor/>50% residual tumor) maintains the highest reproducibility and prognostic value.

18F-FDG PET/CT is effective in the assessment of therapy response. Changes in glucose uptake or tumor size are used as a measure. Tumor heterogeneity was found to be a promising predictive and prognostic factor. We investigated textural parameters for their predictive and prognostic capability in patients with rectal cancer using histopathology as the gold standard. In addition, a comparison to clinical outcome was performed. Methods: Twenty-seven patients with rectal cancer underwent 18F-FDG PET/CT before, 2 wk after the start, and 4 wk after the completion of neoadjuvant chemoradiotherapy. In all PET/CT scans, conventional parameters (tumor volume, diameter, maximum and mean standardized uptake values, and total lesion glycolysis [TLG]) and textural parameters (coefficient of variation [COV], skewness, and kurtosis) were determined to assess tumor heterogeneity. Values on pretherapeutic PET/CT as well as changes early in the course of therapy and after therapy were compared with histopathologic response. In addition, the prognostic value was assessed by correlation with time to progression and survival time. Results: The COV showed a statistically significant capability to assess histopathologic response early in therapy (sensitivity, 68%; specificity, 88%) and after therapy (79% and 88%, respectively). Thereby, the COV had a higher area under the curve in receiver-operating-characteristic analysis than did any analyzed conventional parameter for early and late response assessment. The COV showed a statistically significant capability to evaluate disease progression and to predict survival, although the latter was not statistically significant. Conclusion: Tumor heterogeneity assessed by the COV, being superior to the investigated conventional parameters, is an important predictive factor in patients with rectal cancer. Furthermore, it can provide prognostic information. Therefore, its application is an important step for personalized treatment of rectal cancer.

BACKGROUND For esophageal adenocarcinoma treated with neoadjuvant chemotherapy, postoperative staging classifications initially developed for non-pretreated tumors may not accurately predict prognosis. We tested whether a multifactorial TNM-based histopathologic prognostic score (PRSC), which additionally applies to tumor regression, may improve estimation of prognosis compared with the current Union for International Cancer Control/American Joint Committee on Cancer (UICC) staging system. PATIENTS AND METHODS We evaluated esophageal adenocarcinoma specimens following cis/oxaliplatin-based therapy from two separate centers (center 1: n = 280; and center 2: n = 80). For the PRSC, each factor was assigned a value from 1 to 2 (ypT0-2 = 1 point; ypT3-4 = 2 points; ypN0 = 1 point; ypN1-3 = 2 points; ≤50 % residual tumor/tumor bed = 1 point; >50 % residual tumor/tumor bed = 2 points). The three-tiered PRSC was based on the sum value of these factors (group A: 3; group B: 4-5; group C: 6) and was correlated with patients' overall survival (OS). RESULTS The PRSC groups showed significant differences with respect to OS (p

Myospherulosis is a rare tumor caused by interaction of extravasated erythrocytes and exogenous or endogenous lipids. Fifty-nine articles presented 181 patients with myospherulosis since first description in 1969. Myospherulosis seems to occur in any age and in any part of the body; however, most frequent sites are paranasal sinus and subcutaneous tissue. In most cases, exogenous lipids from postoperative packing are damaging the erythrocytes, but also spontaneous cases are described. Diagnosis is made by histology but can be already suggested by radiographic imaging. Differential diagnoses include infections by fungi or algae due to histopathologic similarity. Besides that, radiographic imaging and morphology can wrongly be interpreted as carcinomas, metastases, osteofibrosis, or echinococcosis. Myospherulosis is a benign process, with symptoms deriving from the space occupying character and surgical excision can bring cure. We discuss the clinical presentation, diagnosis, and treatment and provide a systematic review of the literature on myospherulosis.

Background The role of surgery for patients with metastatic esophagogastric adenocarcinoma (EGC) is not defined. The purpose of this study was to define selection criteria for patients who may benefit from resection following systemic chemotherapy. Methods From 1987 to 2007, 160 patients presenting with synchronous metastatic EGC (cT3/4 cNany cM0/1 finally pM1) were treated with chemotherapy followed by resection of the primary tumor and metastases. Clinical and histopathological data, site and number of metastases were analyzed. A prognostic score was established and validated in a second cohort from another academic center (n = 32). Results The median survival (MS) in cohort 1 was 13.6 months. Significant prognostic factors were grading (p = 0.046), ypT- (p = 0.001), ypN- (p = 0.011) and R-category (p = 0.015), lymphangiosis (p = 0.021), clinical (p = 0.004) and histopathological response (p = 0.006), but not localization or number of metastases. The addition of grading (G1/2:0 points; G3/4:1 points), clinical response (responder: 0; nonresponder: 1) and R-category (complete:0; R1:1; R2:2) defines two groups of patients with significantly different survival (p = 0.001) [low risk group (Score 0/1), n = 22: MS 35.3 months, 3-year-survival 47.6%); high risk group (Score 2/3/4) n = 126: MS 12.0 months, 3-year-survival 14.2%]. The score showed a strong trend in the validation cohort (p = 0.063) [low risk group (MS not reached, 3-year-survival 57.1%); high risk group (MS 19.9 months, 3-year-survival 6.7%)]. Conclusion We observed long-term survival after resection of metastatic EGC. A simple clinical score may help to identify a subgroup of patients with a high chance of benefit from resection. However, the accurate estimation of achieving a complete resection, which is an integral element of the score, remains challenging.

BACKGROUND Oesophageal adenocarcinomas often show resistances to chemotherapy (CTX), therefore, it would be of high interest to better understand the mechanisms of resistance. We examined the expression of heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) in pretherapeutic biopsies of oesophageal adenocarcinomas to assess their potential role in CTX response. METHODS Ninety biopsies of locally advanced adenocarcinomas before platin/5-fluorouracil (FU)-based CTX were investigated by reverse phase protein arrays (RPPAs), immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS CTX response strongly correlated with survival (P=0.001). Two groups of tumours with specific protein expression patterns were identified by RPPA: Group A was characterised by low expression of HSP90, HSP27 and p-HSP27((Ser15, Ser78, Ser82)) and high expression of GRP78, GRP94, HSP70 and HSP60; Group B exhibited the inverse pattern. Tumours of Group A were more likely to respond to CTX, resulting in histopathological tumour regression (P=0.041) and post-therapeutic down-categorisation from cT3 to ypT0-T2 (P=0.040). High HSP60 protein (IHC) and mRNA expression were also associated with tumour down-categorisation (P=0.016 and P=0.004). CONCLUSION Our findings may enhance the understanding of CTX response mechanisms, might be helpful to predict CTX response and might have translational relevance as they highlight the role of potentially targetable cellular stress proteins in the context of CTX response.

PURPOSE: Neoadjuvant treatment is an accepted standard approach for treating locally advanced esophago-gastric adenocarcinomas. Despite a response of the primary tumor, a significant percentage dies from tumor recurrence. The aim of this retrospective exploratory study from two academic centers was to identify predictors of survival and recurrence in histopathologically responding patients. METHODS: Two hundred thirty one patients with adenocarcinomas (esophagus: n = 185, stomach: n = 46, cT3/4, cN0/+, cM0) treated with preoperative chemotherapy (n = 212) or chemoradiotherapy (n = 19) followed by resection achieved a histopathological response (regression 1a: no residual tumor (n = 58), and regression 1b

Objective: We have developed a multifactorial histopathological prognostic score (PRSC) for patients with gastric cancer treated with neoadjuvant chemotherapy before surgery for the accurate discrimination of patient subgroups with differing outcomes. Background: For patients with gastric cancer who undergo multimodal treatment, the postoperative staging classifications used for nontreated tumors may not accurately predict patient prognosis. Methods: We evaluated 428 gastric carcinoma specimens after a cisplatin-based chemotherapy. The factors for the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) ypT-category, ypN-category, and histopathological tumor regression were assigned a value from 1 to 3 as follows: ypT0 to 2 = 1 point; ypT3 = 2 points; ypT4 = 3 points; ypN0 = 1 point; ypN1 to 2 = 2 points; ypN3a to 3b = 3 points; less than 10% residual tumor per tumor bed = 1 point; 10% to 50% residual tumor per tumor bed = 2 points; and greater than 50% residual tumor per tumor bed = 3 points. A 3-tiered PRSC based on the sum value was established (group A: 3-4 points; group B: 5-7 points; group C: 8-9 points) and was found to correlate with patient prognosis. Results: The PRSC showed a clear discrimination of 3 significantly different prognostic groups (group A: 76 patients; group B: 210 patients; group C: 142 patients; P < 0.001). In multivariate analyses, including the completeness of resection, tumor diameter, lymphatic vessel invasion, tumor grading, and Lauren classification, the PRSC was the only independent prognostic factor for overall survival (hazard ratio [HR] = 2.03; 95% confidence intervals [CI], 1.49-2.78; P < 0.001). It was slightly superior to the UICC/AJCC staging system (HR = 1.66; 95% CI, 1.20-2.27; P = 0.002) when analyzed with tumor regression as an additional independent factor (HR = 1.27; 95% CI, 1.01-1.62; P = 0.044) included in the analysis. Conclusions: The proposed PRSC reveals the most accurate prediction of survival for patients with gastric carcinoma after neoadjuvant chemotherapy followed by surgery. The PRSC clearly identifies 3 subgroups with different prognoses and may be helpful for therapeutic decisions.

Issue addressed: Although many Aboriginal Australians live in cities, minimal research has addressed community-based approaches to reduce alcohol problems in that setting. Methods: We conducted a pilot study of community-based education and brief intervention. Existing Aboriginal community-based groups in an urban region were offered interactive education sessions with Aboriginal facilitators. The session was based around a World Health Organization brief intervention, with posters as visual aids. Before education, participants completed the Alcohol Use Disorders Identification Test (AUDIT) and questions on potential barriers to treatment access. After the session, feedback on AUDIT score and one-on-one brief intervention were offered. Results: Over 12 months, eight sessions were conducted and 58 individuals participated. The groups reached individuals with potential need for assistance: although 29.8% of the 47 questionnaire respondents were non-drinkers, 44.7% had an AUDIT score (of 8+) suggesting an alcohol problem, and 51.5% of drinkers reported 5+ (non-standardised) drinks per occasion. Participants showed considerable interest in the resources and most actively participated. All appeared unaware of recommended drinking limits, or of newer treatment options such as home detoxification or relapse prevention medicines. Participants were interested to receive their AUDIT score but not one-on-one intervention. Potential treatment access barriers were described. Conclusions: Interactive group education and feedback of AUDIT score is labour intensive but promoted thoughtful discussion on drinking. Methods to empower and support urban Aboriginal communities to tackle drinking problems need further exploration.

Preoperative chemotherapy has been shown to improve outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) and gastric cancer (GC), and histopathologic response has been identified as an independent prognostic parameter in these patients. A recent meta-analysis has identified patients with AEG as benefiting more from preoperative chemotherapy than patients with GC. The aim of this retrospective analysis was to prove these findings in an experienced single-center large patient cohort because there are currently no recruiting prospective clinical trials.In a single center, 551 patients underwent preoperative platin-based chemotherapy followed by oncologic surgery for locally advanced AEG and GC. Pretherapeutic clinical parameters were correlated with histopathologic response to preoperative chemotherapy.Histopathologic response (10% of residual tumor) was found in 130 patients (24%) and was significantly correlated with overall survival (P0.0001). Tumor localization at the esophagogastric junction (GE junction), lower baseline cT stage, and baseline cN0 stage were significantly associated with histopathologic response (P=0.034, P=0.015, and P=0.002, respectively). In subgroup analyses, the latter two predictive parameters were confirmed only for AEG (n=378) but not for other GC (n=173). AEG patients who were pretherapeutically staged as having cT3/4, cN0 disease (n=73) were identified as the subgroup with the highest rate of histopathologic response (48%).AEG is more likely to respond to preoperative chemotherapy than GC, a finding that might help identify patients who would benefit from preoperative chemotherapy.

Metabolic imaging of gastric cancer is limited due to the 30% of primary tumors that are not 18F-fluorodeoxyglucose (FDG) avid. In contrast, the proliferation marker 18F-fluorothymidine (FLT) has been shown to visualize also non-FDG-avid gastric tumors. In this study we tested whether FLT-positron emission tomography (PET) can improve the predictive potential of molecular imaging for assessing response to neoadjuvant therapy in gastric cancer compared with FDG-PET. 45 patients with gastric cancer underwent FDG- and FLT-PET before and 2 weeks after initiation of chemotherapy. FDG/FLT-PET findings and Ki67 immunohistochemistry were correlated with clinical and histopathological response and survival. 14 patients had non-FDG-avid tumors, whereas all tumors could be visualized by FLT-PET. No significant association of clinical or histopathological response with any of the analyzed metabolic parameters [initial standardized uptake value (SUV), SUV after 2 weeks, change of SUV for FDG/FLT] was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for FLT SUVmean day 14 (p = 0.048) and Ki67 (p = 0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and FLT SUVmean day 14) revealed Lauren type and FLT SUVmean day 14 as the only significant prognostic factors (p = 0.006, p = 0.002). FLT uptake 2 weeks after initiation of therapy was shown to be the only imaging parameter with significant prognostic impact. Neither FLT-PET nor FDG-PET were correlated with histopathological or clinical response. However, these data must be interpreted with caution due to the single-center trial study design, relatively short follow-up, poor response rates, and unfavorable prognosis.

OBJECTIVE: An increasing number of patients with locally advanced gastric carcinomas (GC) are being treated with preoperative chemotherapy before surgery. BACKGROUND: Histopathological tumor regression may have an important prognostic impact in addition to the UICC-TNM classification system. METHODS: We evaluated the histopathological tumor regression in 480 surgical resection specimens of GC after neoadjuvant cisplatin-based chemotherapy, using an established system encompassing three tumor regression grades based on the estimation of the percentage of residual tumor tissue at the primary tumor site in relation to the macroscopically identifiable former tumor bed. Tumor regression was correlated to clinicopathological characteristics and patient survival. RESULTS: Of the patients in this study, 102 (21.2%) had complete or subtotal tumor regression (50% residual tumor). Tumor regression was significantly associated with posttreatment tumor category (pT), lymph node status (pN), lymphatic invasion status (pL), and resection status (P < 0.001). Major histopathological regression was less frequent in tumors of the distal stomach and tumors of nonintestinal type (P = 0.003). Tumor regression (P = 0.009) and postoperative Lymph node status (P < 0.001) were independent prognostic factors for survival in a multivariate analysis of tumor regression, ypT/N/L category, resection status, grading and Lauren´s classification. CONCLUSIONS: Assessment of histological tumor regression after preoperative chemotherapy in GC provides objective and highly valuable prognostic information in addition to posttherapeutic lymph node status. A standardized tumor regression grading system should be implemented in pathological reports of these tumors.

Acinar cell carcinoma of pancreatic type rarely occurs at extra-pancreatic sites. We report four primary liver tumors with features of pancreatic acinar cell carcinoma. The patients were two males and two females with a mean age of 65 years (range, 49-72 years). They had upper abdominal pain, weight loss and/or an incidentally discovered liver mass. None had evidence of a primary pancreatic tumor. Grossly, the tumors were large (mean size, 12 cm), well circumscribed and showed a lobulated cut surface. Histologically, they showed a predominantly microacinar pattern, with occasional trabecular, solid and microcystic areas. Cellular atypia and mitotic activity varied within the same tumor and from tumor to tumor. Immunohistochemically, the tumor cells were positive for cytokeratin 18 and at least one acinar cell marker (ie, trypsin, amylase or lipase), but were negative for cytokeratins 7, 19 and 20, HepPar-1, AFP, CD10, carcinoembryonic antigen, CD56, Islet-1 and CDX2. Two tumors stained focally for synaptophysin and chromogranin A. Adjacent liver parenchyma displayed no evidence of cirrhosis. During a mean follow-up of 22 months (range, 3-38 months) no metastases occurred, but one patient developed local recurrence. Our study demonstrates that acinar cell carcinoma of pancreatic type may also originate from the liver and can be readily distinguished from other primary liver neoplasms by its distinct histological and immunohistochemical features. Because our cases were observed within a rather short period, it is likely that this tumor type is so far underrecognized and has been mistaken as a variant of hepatocellular carcinoma, cholangiocarcinoma or any other liver tumor.

Objective: To provide a comprehensive characterization of neural invasion (NI) in rectal adenocarcinoma (RC), to establish a novel NI-severity scoring system, and to assess the prognostic value of NI with emphasis on its localization and severity. Background: The literature merely contains small-scale studies with limited histopathological characterization of NI in RC. Methods: Neural invasion was thoroughly characterized in 296 patients with locally advanced uT3-RC (139 with primary resection and 157 with neoadjuvant radiochemotherapy [nRCTx]). To identify the precise localization of NI, we investigated the main tumor, peritumoral area, adjacent normal tissue, and all lymph nodes. To classify the clinical impact of NI, an NI severity score was established and related to patient prognosis. Results: Neural invasion was detected in 32% of patients with primary resection and in 19% (P = 0.010) receiving nRCTx. The major location of NI was found in the peritumoral area. The prevalence of NI in the main tumor within the primary resection group was 6%, whereas it was absent in the nRCTx group (P = 0.002). Increasing NI severity, but not NI localization, was associated with a significantly poorer survival and increased local recurrence rate in both groups. Multivariate analysis (including TNM-stage, grading, and Carcinoembryonic antigen (CEA)) revealed NI prevalence and severity as independent prognostic factors. Conclusions: Neural invasion in RC has a heterogeneous appearance in regard to its localization and its severity. nRCTx seems to have a suppressive effect on NI. Neural invasion severity might be applied as a novel tool to estimate accurately patient's prognosis and thus should be considered in pathology reports.

The aim of this study was to compare different analysis methods of 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) data for prediction of histopathological response (HPR) to neoadjuvant radiochemotherapy (RCTx) in patients with advanced rectal cancer.Twenty-eight patients of a previously published clinical trial underwent serial FDG-PET/computed tomography scans at baseline, 14 days after initiation, and after completion of RCTx. In addition, MRI was performed at baseline and after the end of therapy. Response prediction was correlated with different image analysis algorithms comprising pure metabolic parameters taking into account the FDG uptake, volume-based parameters measuring the lesion volume in either MRI or PET data, and integrated parameters combining metabolic and volumetric information. The established two-dimensional (2D) regions of interest (ROI; diameter 1.5 cm) served as standard of reference. Changes between the parameters at the defined time points were calculated and analyzed for their potential to predict HPR to RCTx using receiver operating characteristic (ROC) analysis. Additionally, the interobserver reliability of fixed-size algorithms was analyzed.Histopathology classified eight of 28 patients as non-responders and 20 patients as responders to RCTx. ROC analysis of the standard 2D ROI technique revealed areas under the curve (AUCs) of 0.64 and 0.71 for the early and late time points. Corresponding AUCs for three-dimensional (3D) volume of interest technique resulted in AUCs of 0.75 for both early and late time points, respectively. Volumetric parameters showed AUCs ranging from 0.52 to 0.57 (early time points) and 0.46 to 0.76 (later time points), respectively. Corresponding AUCs for the integrated parameters were ranging between 0.70 and 0.73 (early time points) and 0.66 and 0.76 (late time points). Analysis of intra-class correlation coefficients (ICC) for three different readers resulted in the best intra-class correlation values for the changes of 3D standard uptake value (SUV(3D)), for both early (ICC = 0.96) and late (ICC = 0.96) time points, respectively.Our study emphasizes that 3D-based approaches for assessing SUV values consistently belonged to the group of parameters with the highest AUC values for prediction of HPR to neoadjuvant RCTx in patients with rectal cancer. MRI was not a good predictor for therapy response; hence, the MRI information derived from combined anatomic and metabolic parameters showed unsatisfying results too.

Background The aim of this study was to determine whether pretherapeutic protein expression levels of the excision repair cross-complementing (ERCC1) enzyme, thymidylate synthetase (TS), multidrug-resistance protein 1 (MRP-1) and P-glycoprotein (P-gp) are associated with tumour response to cisplatin and fluorouracil (5-FU)-based neoadjuvant chemotherapy in oesophageal adenocarcinomas Methods The expression levels of ERCC1, TS, MDR-1 and P-gp were determined immunohistochemically in pretherapeutic tumour biopsies from 40 oesophageal adenocarcinoma patients and were correlated with histopathological tumour regression and with patient survival. Protein expression was compared to mRNA data, which was previously published for ERCC1, TS and MRP-1 and newly determined for the purpose of this study for MDR-1/P-gp. Results High-TS and -MRP-1 protein expression was correlated with tumour non-response to chemotherapy (P = 0.001 and P = 0.036, respectively). For ERCC-1 and P-gp, no association between pretherapeutic protein expression and response was found. There was no correlation between mRNA levels and protein expression for all investigated markers. Survival analysis revealed a trend towards increased survival for low-ERCC-1 expression (P = 0.079). Conclusions The pattern of pretherapeutic expression of TS and MRP-1 is related to chemotherapy response in oesophageal adenocarcinoma patients. Immunohistochemical assessment of these markers may be helpful for response prediction. J. Surg. Oncol. 2010;102:503–508. © 2010 Wiley-Liss, Inc.

Purpose We evaluated DNA polymorphisms in genes related to DNA repair, cell-cycle control and tumour microenvironment to determine possible associations with response and survival in neoadjuvant-treated gastric cancer patients. Patients and methods One hundred and seventy eight patients who received platinum/5FU-based chemotherapy were genotyped for 10 polymorphisms in nine genes ( ERCC1 : Asn118Asn, C > T ; ERCC1 : 8092C>A; TP53 : Arg72Pro, G ; cyclinD1 : Pro241Pro, G > A ; STK15 : Phe31Ile, A > T ; VEGF : 936 C > T ; TNF-α : -308 G > A ; interleukin-1b (IL-1B) : -511 C > T ; IL-1 receptor antagonist (IL-1RN) : variable tandem repeat; IL-8 : -251 T > A ). Genotypes were correlated with histopathological and clinical response and overall (OS) and progression-free survival (PFS). Results Only the cyclinD1 genotypes were associated with clinical response ( P χ 2 = 0.044 ). Significantly worse survival rates were noted in patients homozygous for the G-allele as compared to patients with the AG or AA genotypes of the cyclinD1 polymorphism (OS: P log-rank =0.024; PFS: P log-rank =0.007) and in patients homozygous for the short allele compared to all other genotypes at the IL-1RN polymorphic locus (OS: P log-rank =0.026; PFS: P log-rank =0.013). The combination of both unfavourable genotypes demonstrated strong prognostic relevance (OS: P log-rank =0.006; PFS: P log-rank =0.001). Multivariate analysis for OS in the group of completely resected patients ( n =139) revealed statistical significance for ypM ( P P cyclinD1/IL-1RN genotypes ( P =0.043). Conclusion The cyclinD1 and IL-1RN polymorphisms were associated with survival. The combination of specific cyclinD1 and IL-1RN genotypes showed a particular prognostic relevance and should be considered an independent prognostic marker for neoadjuvant-treated gastric cancer patients.

We evaluated histomorphological findings in 92 surgical resection specimens of locally advanced esophageal adenocarcinomas after neoadjuvant cisplatin-based chemotherapy. Tumor response to neoadjuvant chemotherapy was determined using a system encompassing three tumor regression grades based on the estimation of the percentage of residual tumor tissue of the primary tumor site in relation to the macroscopically identifiable previous tumor bed. The significance of this system was validated by correlation of the tumor regression grades with the corresponding clinicopathological characteristics and patient survival. Seven patients (7%) had complete tumor regression (grade tumor regression grade 1), 48 patients (52%) had subtotal or partial tumor regression (tumor regression grade 2: 1-50% residual tumor), and 37 patients (40%) had minimal or no regression (tumor regression grade 3: >50% residual tumor). Tumor regression was significantly associated with posttreatment complete tumor resection status (UICC R0 status; P=0.016), tumor category (UICC pT category; P

Purpose: To identify pretherapeutic predictive biomarkers in tumor biopsies of patients with locally advanced esophageal adenocarcinomas treated with neoadjuvant chemotherapy, we used an explorative proteomic approach to correlate pretherapeutic protein expression profiles with tumor response to neoadjuvant chemotherapy. Experimental Design: Thirty-four patients with locally advanced esophageal adenocarcinomas who received neoadjuvant platin/5-fluorouracil–based chemotherapy before surgical resection were enrolled in this study. Response to chemotherapy was determined (a) by the amount of decline of [18F]fluorodeoxyglucose tumor uptake 2 weeks after the start of chemotherapy measured by positron emission tomography and (b) by histopathologic evaluation of tumor regression after surgical resection. Explorative quantitative and qualitative protein expression analysis was done through a quantitative differential protein expression analysis that used dual-isotope radioactive labeling of protein extracts. Selected identified biomarkers were validated by immunohistochemistry and quantitative real time reverse transcription-PCR. Results: Proteomic analysis revealed four cellular stress response–associated proteins [heat-shock protein (HSP) 27, HSP60, glucose-regulated protein (GRP) 94, GRP78] and a number of cytoskeletal proteins whose pretherapeutic abundance was significantly different (P < 0.001) between responders and nonresponders. Immunohistochemistry and gene expression analysis confirmed these data, showing a significant association between low HSP27 expression and nonresponse to neoadjuvant chemotherapy (P = 0.049 and P = 0.032, respectively). Conclusions: Albeit preliminary, our encouraging data suggest that protein expression profiling may distinguish cancers with a different response to chemotherapy. Our results suggest that response to chemotherapy may be related to a different activation of stress response and inflammatory biology in general. Moreover, the potential of HSPs and GRPs as biomarkers of chemotherapy response warrants further validation.

To evaluate the value of positron emission tomography using fluorodeoxyglucose and computer tomography scan (FDG-PET/CT) for prediction of histopathological response of preoperative radiochemotherapy (RCTX) in patients with rectal carcinoma.Thirty patients with uT3 rectal carcinoma were examined by FDG-PET/CT at baseline, 14 days after initiation, and after completion of preoperative RCTX. The FDG decreases seen with PET scanning from baseline to day 14 (early metabolic response) and after completion of therapy (late metabolic response) were compared with histopathological tumor response. One patient denied surgery after RCTX.The mean (+/-SD) reduction of tumor FDG uptake in histopathologically responding compared to non-responding tumors was -44.3% (+/-20.1%) versus -29.6% (+/-13.1%) (p = 0.085) at day 14 and -66.0% (+/-20.3%) versus -48.3% (+/-23.4%) (p = 0.040) after completion of RCTX. Best differentiation of histopathological tumor response was achieved by a cut-off value of 35% reduction of initial FDG uptake at day 14 and 57.5% after completion of therapy. Applying the cut-off values as a criterion for metabolic response, histopathological response was predicted with a sensitivity of 74% (14/19) at day 14 and 79% (15/19) after completion of therapy. The positive predictive value for early metabolic response was 82% (14/17) and for late metabolic response was 83% (15/18). Histopathological evidence of accumulated peritumoral inflammation cells was associated with a minor FDG decrease in five histopathologically responding patients, and influenced the results with negative predictive values of 58% (7/12) and 64% (7/11) at the early and late time points, respectively.Metabolic response to a preoperative RCTX using FDG-PET/CT in rectal cancer patients can be correlated with histopathological response, but FDG uptake of peritumoral inflammation cells limited the results and led to false negative results.