IκB Kinase ε expression in pancreatic ductal adenocarcinoma

IκB kinase (IKKε) is a serine/threonine protein kinase that belongs to the IKK kinase family. Recent studies have shown that IKKε functions as a breast and ovarian cancer oncogene. We demonstrated frequent overexpression of IKKε in pancreatic ductal adenocarcinoma (PDA). We immunohistochemically evaluated 78 PDAs using the avidin-biotin-peroxidase method and the anti-IKKε rabbit polyclonal antibody. Elevated IKKε reactivity (immunohistochemical score, 4-9) was observed in 64% of PDAs (50/78), but in 0.0% of nonneoplastic pancreatic ductal epithelium (0/113; P < .001). Kaplan-Meier analysis of overall survival revealed that patients with high IKKε-immunohistochemical scores (4-9) had significantly shorter survival than did patients with low IKKε immunohistochemical scores (0-3; P = .023; log-rank test) independent of tumor stage or grade. These data indicate that deregulation of IKKε is a common event in PDA and might have an important role in the pathogenesis of this deadly disease. In addition, IKKε could serve as a prognostic marker and potential therapeutic target for PDA intervention.     

Is adenocarcinoma of the esophagogastric junction or cardia different from Barrett adenocarcinoma?

Over time the relative distribution of cancers of the proximal digestive tract has changed. Squamous cell carcinomas of the esophagus have become less common, while numbers of adenocarcinomas have greatly increased. This shift most likely reflects an increase in the incidence of gastroesophageal reflux. Moreover, there is a decline in the incidence of distal gastric cancer, which in turn may be related to Heliobacter pylori eradication. Simultaneously, there is a time trend toward a more proximal localization of gastric cancer. If the above-mentioned etiopathologic links are correct, this could indicate that the so-called cardia adenocarcinomas are not related to H pylori infection and that they may instead be related to gastroesophageal reflux and eventually may not be considered to be "gastric" cancers. The rapidly growing quantity of literature on this subject is, however, confounding. A major source of discordance would seem to be a Babylonian confusion of tongues concerning the terms cardia and cardiac carcinomas. Unfortunately, this confusion is also apparent in the classification systems available for staging of cancer, thus closing the "vicious" circle.     

Sinonasal tubulopapillary low-grade adenocarcinoma: a specific diagnosis or just another seromucous adenocarcinoma?

Histopathologically, sinonasal adenocarcinomas fall into four categories: the intestinal type, the conventional salivary gland type (eg, adenoid cystic carcinoma, acinic cell carcinoma), the seromucous type, and the low-grade not otherwise specified type. Recently, a new type of sinonasal adenocarcinoma has been described, called tubulopapillary low-grade adenocarcinoma. In this commentary, the histologic features of this type of tumor are compared with those of the other types of sinonasal adenocarcinoma. The clinicopathologic characteristics and probable origin of this type of adenocarcinoma are also discussed.     

The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity

The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDH^high (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDH^low/null (ALDH?) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDH^high/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the ‘difficult-to-treat’, ‘quick-to-relapse’ PDAC patients.

Graphical Abstract

Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway.

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Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation?

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.     

Chronic Psychophysiological Insomnia: Hyperarousal and/or Inhibition Deficits? An ERPs Investigation

STUDY OBJECTIVES: Chronic primary insomnia has been hypothesized to result from conditioned arousal or the inability to initiate normal sleep processes. The event-related potentials (ERPs) N1, P2, and N350 are useful indexes of arousal. The objective is to compare these ERPs in primary chronic psychophysiological insomniacs (INS) and good sleepers (GS) during multiple recordings. PARTICIPANTS: Participants were 15 INS (mean age = 46 years, SD = 7.5) and 16 GS (mean age = 37 years, SD = 10.1). METHODS AND PROCEDURE: Following a multistep clinical evaluation, INS and GS participants underwent 4 consecutive nights of PSG recordings (N1 to N4). ERPs were recorded on the 3rd and 4th nights in the sleep laboratory (N3 and N4). ERPs recordings were made during wake on both nights (in the evening and upon awakening), with the addition of sleep-onset recordings on N4. Auditory stimuli consisted of "standard" and "deviant" tones. STATISTICAL ANALYSIS: Repeated measures ANOVAs were computed for each ERP for each recording for each type of stimulus. RESULTS: The amplitude of P2 and N350 was greater for the deviant than for the standard stimulus in both groups. The amplitude of N1 was larger in INS than GS in the morning and the evening. While the amplitude of N350 was larger in GS than in INS at sleep onset, the amplitude of P2 was greater in INS than in GS at that time. CONCLUSION: Signs of greater cortical arousal in psychophysiological insomnia individuals are observed, especially upon awakening in the morning. However, at sleep onset, difficulties from disengaging from wake processes and some inability at initiating normal sleep processes appear also present in individuals with insomnia compared to good sleepers.     

Adrenocortical adenocarcinoma in an MSH2 carrier: Coincidence or causal relation?

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. H P 31:1522-1527.     

Are all ductal proliferations of the breast premalignant?

The evidence for ductal proliferations of the breast being associated with the development of breast carcinoma originally came from epidemiological studies. There have now been a variety of genetic analyses of such lesions, which have shown a range of alterations from none to 37% of hyperplasias. Alterations in growth regulatory factors (steroid receptors, proliferation and apoptosis-related proteins) can also be found in a proportion of hyperplasias. The findings to date indicate that not all hyperplasias are premalignant and that the early events in breast carcinogenesis remain elusive.     

Attitudes and Beliefs About Chronic Pain Among Nurses–Biomedical or Behavioral? A Cross-sectional Survey

Context:

Studies have documented that nurses and other health care professionals are inadequately prepared to care for patients in chronic pain. Several reasons have been identified including inadequacies in nursing education, absence of curriculum content related to pain management, and attitudes and beliefs related to chronic pain.

Aims:

The objective of this paper was to assess the chronic pain-related attitudes and beliefs among nursing professionals in order to evaluate the biomedical and behavioral dimensions of their perceptions on pain.

Settings and Design:

Cross-sectional survey of 363 nurses in a multispecialty hospital.

Materials and Methods:

The study utilized a self-report questionnaire – pain attitudes and beliefs scale (PABS) – which had 31 items (statements about pain) for each of which the person had to indicate the level at which he or she agreed or disagreed with each statement. Factor 1 score indicated a biomedical dimension while factor 2 score indicated a behavioral dimension to pain.

Statistical Analysis Used:

Comparisons across individual and professional variables for both dimensions were done using one-way ANOVA and correlations were done using the Karl–Pearson co-efficient using SPSS version 11.5 for Windows.

Results:

The overall factor 1 score was 52.95 ± 10.23 and factor 2 score was 20.93 ± 4.72 (P = 0.00). The female nurses had a higher behavioral dimension score (21.1 ± 4.81) than their male counterparts (19.55 ± 3.67) which was significant at P < 0.05 level.

Conclusions:

Nurses had a greater orientation toward the biomedical dimension of chronic pain than the behavioral dimension. This difference was more pronounced in female nurses and those nurses who reported very “good” general health had higher behavioral dimension scores than those who had good general health. The study findings have important curricular implications for nurses and practical implications in palliative care.     

Vinblastine and 5-fluorouracil sensitivity of xenografts of four pancreatic ductal adenocarcinomas: is there a correlation with histological and cytological tumour differentiation?

In a search for nuclear parameters which may predict chemosensitivity of ductal adenocarcinoma of the pancreas, the growth of four xenografted pancreatic carcinomas in response to chemotherapeutic agents was correlated with histological and cytological features of tumour differentiation. Histologically, the tumours were classified according to their ability to form glands into poorly (PaTu-2, PaTu-3), moderately (Panc-1) and well differentiated (PaTu-39) ductal adenocarcinomas. Cytologically, similar segregation of tumours was possible using the nuclear form factor, which was one of four nuclear parameters analysed by image cytometry on Feulgen stained tumour imprints. Histological and cytological differentiation correlated closely with tumour growth. One week after a single intraperitoneal injection of either vinblastine or 5-fluorouracil, both drugs inhibited the growth of PaTu-2 and PaTu-3 significantly. The growth of Panc-1 was only affected by vinblastine, while neither drug had an effect on PaTu-39. The results suggest that the response of pancreatic ductal adenocarcinoma to chemotherapeutic drugs may be, to some extent, predicted by histological and cytological differentiation features. However, within these lines, each tumour may show a specific response pattern.