Patricia Mjønes

Gastrin and gastric cancer

Gastric cancer although occurring in reduced frequency is still an important disease, partly because of the bad prognosis when occurring in western countries. This decline in occurrence may mainly be due to the reduced prevalence of Helicobacter pylori (Hp) infection, which is the most important cause of gastric cancer. There exist many different pathological classifications of gastric carcinomas, but the most useful seems to be the one by Lauren into intestinal and diffuse types since these types seldom transform into the other and also have different epidemiology. During the nearly 30 years that have passed since the groundbreaking description of Hp as the cause of gastritis and gastric cancer, a continuous search for the mechanism by which Hp infection causes gastric cancer has been done. Interestingly, it is mainly atrophic gastritis of the oxyntic mucosa that predisposes to gastric cancer possibly by inducing hypoacidity and hypergastrinemia. There are many arguments in favor of an important role of gastrin and its target cell, the enterochromaffin-like cell, in gastric carcinogenesis. The role of gastrin in gastric carcinogenesis implies caution in the long-term treatment with inhibitors of gastric acid secretion inducing secondary hypergastrinemia, in a common disease like gastroesophageal reflux disease.

Impact of perioperative chemotherapy on oncological outcomes after gastric cancer surgery

Perioperative chemotherapy has become standard care for resectable gastric cancer. However, available evidence is based on a limited number of trials, and the outcomes in routine clinical practice and in unselected patients are scarcely reported.

Pre-treatment Evaluation of Basal Cell Carcinoma for Photodynamic Therapy: Comparative Measurement of Tumour Thickness in Punch Biopsy and Excision Specimens

Tumour thickness affects the outcome of photodynamic therapy in basal cell carcinoma (BCC). The aim of this study was to evaluate whether punch biopsy provides reliable information on BCC tumour thickness, by comparing corresponding measurements in biopsy and excision specimens for 48 lesions in 43 patients. BCC tumours were between 0.2 and 6.1 mm thick. The mean depth of the excisions were 0.14 mm greater than that of the biopsies. Bland-Altman 95% limits of agreement were (-1.3, 1.6) mm, but the difference between measurements increased with tumour thickness. A punch biopsy tumour thickness of 1.0 mm yielded an upper 95% predicted limit for excision depth within 2.0 mm. In conclusion, there was reasonable overall agreement between corresponding measurements. A biopsy thickness of 1.0 mm suggests that the tumour will most likely be within the current accepted limits for photodynamic therapy. With increasing tumour thickness, however, individual tumour measurements may differ considerably.

Comparison of clinical and histopathological evaluations of basal cell carcinoma thickness

DEAR EDITOR, Basal cell carcinoma (BCC) can be classified into a number of different clinical and histopathological types. The clinical diagnosis is not always consistent with the histopathological diagnosis because BCC does not have a definite clinical appearance in all cases. Accordingly, the extent of tumour infiltration may not be easily measurable as it can have subclinical extensions and deep irregular delineation against normal tissue. This may have implications for treatment, as tumour thickness is regarded as an important predictor of response to minimally invasive topical therapies. Therefore, the clinician needs reliable information on BCC thickness to identify those tumours most likely to respond. At present, biopsy to provide a sample for histopathological evaluation of the tumour thickness is considered the ‘gold standard’. Even so, BCC is treated in many cases without histopathological investigation of its thickness. We report on the comparison of corresponding clinical and histopathological measurements of BCC thickness to evaluate whether the clinical assessment of tumour thickness is accurate. In addition, we evaluated the agreement between these measurements in different BCC subtypes. This prospective study was approved by the regional committee for medical research ethics and performed at the outpatient clinic at the Department of Dermatology, St. Olavs University Hospital, Trondheim, Norway. Part of the study sample was included in a previous report that compared measurements of BCC thickness from punch biopsy and excision specimens. Consecutive patients ˃ 18 years old, neither pregnant nor breast feeding, with primary histopathologically verified BCC gave written informed consent before study entry. To ensure sufficient material for both punch and excision biopsy, only lesions ≥ 9 mm were included. Two consultants and an experienced registrar in dermatology performed the clinical examinations of 12, 17 and 24 tumours, respectively. Tumour size was defined clinically as the mean value of its extreme length and width. Tumour thickness was obtained by clinical and histopathological investigations. First, the clinical thickness (in mm) was estimated by inspection and palpation of the tumour. Second, a 3-mm disposable biopsy punch (Kai Industries Co. Ltd, Gifu, Japan) was used to obtain a small tissue sample. Third, and on the same day, an elliptical resection of the whole tumour was made. Details of the processing of tumour specimens have been described previously. A single hospital pathologist measured the BCC thickness from below the stratum corneum to the bottom of the tumour nest on haematoxylin, eosin and saffron-stained slides using an ocular micrometre to a precision of 0 1 mm. The greatest measurement from each punch biopsy specimen was defined as the punch tumour thickness. The greatest measurement from the corresponding punch biopsy and excision specimens of each tumour was defined as the ‘maximum tumour thickness’ (MTT), since the thickest part could reside within either specimen. The tumours were subclassified histopathologically into three categories: superficial, nodular or aggressive (morpheaform, infiltrative, basosquamous) growth types. IBM SPSS Statistics (v.21; IBM Corp., Armonk, NY, U.S.A.) was used, and the data were normally distributed. Possible relationships between the differences and mean thickness measurements were analysed by Bland–Altman plots with a regression approach for nonuniform differences. Simple regression analyses were used to calculate the slope of the regression line between the means and differences and the SD of the residuals (res-SD). The 95% limits of agreement were then calculated as 1 96 9 res-SD with respect to the regression line. P < 0 05 was considered statistically significant. In total, 159 tumour thickness measurements from 53 BCCs of 46 patients (18 women, mean age 71 years and 28 men, mean age 73 years) were included. Tumours were located to: head/neck (n = 20), trunk (n = 27) and extremities (n = 6) with a mean size of 18 mm (range 10–30). Histopathologically, 14were superficial, 24 nodular and 15 of aggressive growth types. The mean (SD) thickness values by the clinical, punch biopsy and MTT evaluations were 1 5 (0 9), 1 7 (1 3) and 2 0 mm (1 5), respectively. The largest mean difference (0 5 mm) was found between clinical and MTT values. Figure 1 shows the Bland–Altman plot with 95% limits of agreement for the difference between the MTT and the clinical thickness. The slope of the regression line was significant (slope 0 49, P < 0 001). The 95% limits of agreement were 1 3 mm (res-SD 0 67). Figure 2 shows the Bland–Altman plot between the punch biopsy thickness and the clinical thickness. The slope of the regression line was significant (slope 0 34, P = 0 004). The 95% limits of agreement were 1 6 mm (res-SD = 0 81). As the regression lines show, there was a systematic relationship between differences and tumour thicknesses. For tumours of approximately 1 6 mm thickness, the clinical and histological results agreed. Thinner BCCs were evaluated as thicker by clinical evaluation than by the corresponding histological examination, whereas the relationship was the opposite for thicker tumours. The scatter plots (Figs 1 and 2) also present the values of thickness for different BCC subtypes. By

Outcomes among patients treated for gastric adenocarcinoma during the last decade

To evaluate the outcomes among patients treated for gastric adenocarcinoma in a referral hospital, and to identify possible trends during the last decade.

Expression of erythropoietin and neuroendocrine markers in clear cell renal cell carcinoma

The aim of the study was to investigate the expression of erythropoietin and neuroendocrine markers in clear cell renal cell carcinoma (CCRCC). We retrospectively reviewed the medical records and re‐evaluated histopathological specimens of 33 patients with CCRCC and compared with those of 11 cases of non‐CCRCC. All patients were treated with a partial or radical nephrectomy at St. Olavs Hospital, Trondheim University Hospital, between 2010 and 2016. Thirty‐three patients who were diagnosed with CCRCC had a total of 35 tumours, where 34 of the tumours were CCRCC and one was papillary adenoma. Thirty‐three (97%) of 34 CCRCCs were positive for erythropoietin, and the same 33 (97%) tumours demonstrated strong expression for neuron‐specific enolase (NSE). Two (6%) of 34 CCRCCs had a positive reaction for synaptophysin, and three (9%) of 34 were positive for CD56. Erythropoietin and NSE were negative in non‐CCRCCs, and chromogranin A was negative in all tumours. The above findings suggest that there is a strong association between CCRCC and the expression of erythropoietin and NSE.

Cytomegalovirus infection and postoperative complications in patients with ulcerative colitis undergoing colectomy

Abstract Background. Ulcerative colitis (UC) can be complicated by reactivation of cytomegalovirus (CMV). CMV reactivation may change the course of UC and may require antiviral treatment. Some risk factors of CMV reactivation have previously been identified, whereas the association between CMV reactivation and postoperative complications has not been examined systematically. Methods. Patients with UC operated with colectomy due to active UC were studied (n = 77). Patient and disease characteristics, as well as postoperative complications were recorded and CMV was detected by immunohistochemical examination of multiple sections from the colectomy specimen. Results. CMV was found in nine (11.7%) colectomy specimens. CMV-positive patients received significantly higher doses of corticosteroids at colectomy than CMV-negative patients (61.1 ± 23 vs 32.5 ± 32 mg/day, p = 0.01). CMV-positive patients were also older, had a higher risk of severe complications, higher American Society of Anesthesiologists (ASA) score, longer preoperative stay, and a higher rate of acute surgery. Complications occurred in 30 (39%) patients after surgery, 8(10.4%) of whom were serious. Two CMV-positive patients (2.6%) died in-hospital after the colectomy. High ASA score was associated with the occurrence of serious complications. Conclusion. A relatively small proportion of patients with UC operated by colectomy were CMV positive. CMV positivity was associated with old age, high dose of corticosteroids at operation, high ASA score, acute surgery, and severe postoperative complications. Patients with such characteristics may be at risk of CMV infection and may require special management.

A population-based study on incidence rates, Lauren distribution, stage distribution, treatment, and long-term outcomes for gastric adenocarcinoma in Central Norway 2001–2011

Abstract Background: Population-based studies for gastric adenocarcinoma are scarce, particularly studies conducted within a defined geographical area with publicly available censuses that allow incidence rates to be calculated. Material and methods: Population-based study in Central Norway from 2001 to 2011, covering a population of 636 000–680 000, respectively. Patients were identified through the Cancer Registry of Norway and the Norwegian Patient Register, and were characterized by data from individual electronic patient records. Outcomes were compared across the early and the late half of the study period. Results: A total of 878 patients were identified with a median age of 76.2 years. The male to female ratio was 1.72. Annual world age-standardized incidence was 8.0/105 and 3.6/105, respectively. The Lauren diffuse type was significantly more frequent among patients below 60 years, among females and for non-cardia cancers, compared to their counterparts (p < .001). The Lauren mixed type had a stable proportion of around 13% irrespective of age, sex or tumor location. Early gastric cancers (EGC) represented 8.3% of the cases, whereas 44% of all patients were diagnosed with metastatic disease. In males, the proportion of cardia cancers increased from 29.7% to 39.1% during the study period (p = .005). The five-year overall survival was 16%, and was substantially better for the Lauren intestinal type compared to the diffuse type, log-rank p = .003. The R0-R1 resection rate was 39%, with a corresponding five-year survival of 40.9%. Conclusions: This study provides population-derived data lacking in hospital-based studies. Lauren categories with epidemiological aspects and clinical outcomes are displayed. Gastric cancer was associated with a dismal prognosis. Few patients had EGC and close to 50% had metastatic disease. Many were too old or frail to be considered for surgery.

PAI-1 deficiency increases the trophic effects of hypergastrinemia in the gastric corpus mucosa.

The gastric hormone gastrin plays a role in organizing the gastric mucosa. Gastrin also regulates the expression of genes that have important actions in extracellular matrix modelling, including plasminogen activator inhibitor (PAI)-1 which is part of the urokinase plasminogen activator (uPA) system. The uPA system (including PAI-1) is associated with cancer progression, fibrosis and thrombosis. Its biological role in the stomach and molecular mechanisms of action are not well understood. The aim of this study was to examine the effect of PAI-1 on the trophic changes observed in gastric corpus mucosa in hypergastrinemia using PAI-1 and/or HK-ATPase beta subunit knockout (KO) mice. HK-ATPase beta subunit KO mice were used as a model of hypergastrinemia. In 12 month old female mice, intragastric acidity and plasma gastrin were measured. The stomachs were examined for macroscopic and histological changes. In mice null for both PAI-1 and HK-ATPase beta (double KO), there was exaggerated hypergastrinemia, increased stomach weight and corpus mucosal thickness, and more pronounced trophic and architectural changes in the corpus compared with HK-ATPase beta KO mice. Genome-wide microarray expression data for the gastric corpus mucosa showed a distinct gene expression profile for the HK-ATPase beta KO mice; moreover, enrichment analysis revealed changes in expression of genes regulating intracellular processes including cytoskeleton remodelling, cell adhesion, signal transduction and epithelial-to-mesenchymal transition (EMT). Genes differentially expressed in the double KO compared with HK-ATPase beta KO mice included the transcription factor Barx2 and the chromatin remodeler gene Tet2, which may be involved in both normal gastric physiology and development of gastric cancer. Based on the present data, we suggest that PAI-1 plays a role in maintaining gastric mucosal organization in hypergastrinemia.

Expression of the Cholecystokinin-B Receptor in Neoplastic Gastric Cells

Gastric cancer is an important disease due to its high mortality. Despite the decline in frequency, most cases are discovered late in its course, and most of the cancer patients die within a few years of diagnosis. In addition to Helicobacter pylori gastritis, gastrin is considered an important factor in the development of this disease, and thus, cholecystokinin-B receptor (CCKBR) becomes of interest. The aim of our study was to explore whether CCKBR is expressed in stomach cancers. Thirty-seven tumors from 19 men and 18 women diagnosed with either adenocarcinoma or neuroendocrine neoplasm (NENs) were included in this study. The tumors were classified into 29 adenocarcinomas and eight NENs. Immunohistochemistry with antibodies against chromogranin A (CgA), synaptophysin and CCKBR, and in situ hybridization with probes against CgA, CCKBR and histidine decarboxylase were used to further explore these tumors. Thirty-three (89%) of the tumors expressed CCKBR protein, whereas only 20 (54%) of all tumors expressed CCKBR mRNA. Of the 20 tumors expressing CCKBR mRNA, eight were NENs and 12 were adenocarcinoma. The highest amount of CCKBR was expressed in NEN. Interestingly, a high degree of co-expression of CCKBR and CgA was observed when the two markers were examined together with in situ hybridization. In conclusion, we found that all eight NENs expressed CCKBR and neuroendocrine markers in a majority of tumor cells. The same markers were also expressed in a proportion of adenocarcinomas supporting the view that gastrin is important in the development of gastric cancer.