Duodenal mast cells and eosinophils in children with celiac disease: occurrence and distribution pattern.

OBJECTIVE: The aim of this study was to characterize duodenal mast cell (MC) and eosinophil (EO) numbers, their distribution within the lamina propria and possible impact on disease severity of paediatric celiac patients compared to children without celiac disease (CD). METHODS: We analysed duodenal samples of 215 children (109 CD, 106 controls) who underwent esophagogastroduodenoscopy from 2010 to 2018. After immunohistochemical staining, average MC and EO counts were histologically examined in ten high-power-fields. Additionally, cell-distribution within the lamina propria was analysed. Possible influence of relevant clinical parameters was evaluated. STATISTICS: Student's-t-test, Mann-Whitney U-test, Chi-square-test, ANOVA, significance-level <.05. Trial registration-number: DRKS00024669. RESULTS: MC-density was higher in CD-patients compared to the control-group (23.7 (±12.1)/HPF versus 19.7 (±9.1)/HPF; p = .008), varying in number interindividually. Eosinophils were also increased in the duodenum of celiac patients (23.3 (±9.3)/HPF versus 12.2 (±6.3)/HPF; p= <.001). MCs were distributed more often homogenously in all parts of CD lamina propria (44 biopsies (40.4%), residing more distant from the intestinal lumen in controls (0 biopsies with homogenous distribution-pattern (0%); p= <.001). Regarding EOs no polarity was observable. Atopic diseases did not occur significantly more often in patients with elevated EO-counts. CONCLUSION: MC- and EO-numbers were increased in the duodenum of CD-patients and MCs showed a different distribution-pattern in the lamina propria of celiac patients. These findings support the concept that both cell-types contribute to disease-pathogenesis. However, functional studies highlighting both cell-types' and their mediators' role regarding mucosal alterations during the course of the inflammatory process in celiac patients are needed. TRIAL REGISTRATION NUMBER AND URL: DRKS00024669; https://www.drks.de/drks_web/.

Phenotype of histologically suspected drug-induced colitis; results of a comparative, retrospective cohort study.

Background/aims: Drug-induced colitis (DiC) is a rarely reported form of colonopathy and data about the clinical and endoscopic characteristics are scarce. The aim was to investigate the phenotype of DiC. Methods: Patients in a retrospective case control study were assigned to either DiC or one of two age- and gender-matched control groups (non-inflammatory controls and inflammatory colitis from other causes) based on histopathological findings. Patients' basic characteristics, symptoms, biochemical results and endoscopic appearance were collected. Statistical analysis included ANOVA, the chi-squared test and two-tailed t-test. Results: A total of 211 patients with DiC were included (97 males, age 62.1 ± 16.1 years, BMI 25.9 ± 6.1 kg m-2). In comparison to both control groups, DiC patients presented higher ASA and ECOG-scores and more particularly atherosclerotic comorbidities. The most abundant symptoms were abdominal pain (51.8%), diarrhoea (50.7%) and haematochezia (24.3%). The red blood cell count demarcated anaemia (12.7 ± 2.3 mg/dl) and C-reactive protein was slightly elevated (2.7 ± 5.2 mg/dl). The endoscopic features included erythema (46.9%), oedema (29.9%), erosions (29.9%) and ulcers (14.7%). The inflammation affected the rectum rarely (2.4%) but affected the rest of the colon without predilection in a segmental manner (p<.05). The severity of DiC was mostly mild (85.7%). Conclusions: The phenotype of DiC differs slightly from that of colitis from other causes. Taking the clinical features into account might help to confirm drug-induced aetiology once the pathologist has raised the suspicion.

Triggers of histologically suspected drug-induced colitis.

BACKGROUND: Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents. Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series. AIM: To investigate potential triggers of drug-induced colitis (DiC). METHODS: We conducted a retrospective, observational case control study. Patients were assigned to DiC or one of two age- and gender-matched control groups (non-inflammatory controls and inflammatory colitis of another cause) based on histopathological findings. Histopathology was reassessed in a subset of patients (28 DiC with atherosclerosis, DiC without atherosclerosis and ischaemic colitis each) for validation purposes. Medical history was collected from the electronic database and patient records. Statistical analysis included chi-squared test, t-test, logistic and multivariate regression models. RESULTS: Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa (7% of all screened colonoscopic biopsy samples); a total of 633 patients were included equally matched throughout the three groups (291 males, mean age: 62.1 ± 16.1 years). In the univariate analysis, DiC was associated with diuretics, dihydropyridines, glycosides, ASS, platelet aggregation inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), statins and fibrates, and with atherosclerosis, particularly coronary heart disease, and hyperlipoproteinaemia. Echocardiographic parameters did not show substantial differences. In the multivariate analysis only fibrates [odds ratio (OR) = 9.1], NSAIDs (OR = 6.7) and atherosclerosis (OR = 2.1) proved to be associated with DiC. Both DiC reassessment groups presented milder inflammation than ischaemic colitis. The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis. CONCLUSION: Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC. Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.

Using Fat Grafting to Treat Breast Implant Capsular Contracture.

Capsular contracture is a frequent complication of breast augmentation and reconstruction that affects up to 30% of patients. The authors describe the effect of fat grafting on capsular contracture used in cases with the primary intention of improving soft-tissue characteristics before implant to implant or implant to fat exchange. Fifteen patients (18 breasts) with capsular contracture Baker grade 4 were reviewed. Pain from capsular formation was able to be ameliorated in all cases after lipofilling sessions, with 11 of them achieving analgesia. Afterward, 4 patients underwent implant to implant and 7 patients implant to fat exchange. Four patients chose to keep the implants after the end of fat grafting procedures, due to satisfying cosmetic results and excellent pain management. Fat grafting may be a useful addition to therapies currently used to treat capsular contracture.

MicroRNA-205, a novel regulator of the anti-apoptotic protein Bcl2, is downregulated in prostate cancer.

Decreased expression of the microRNA miR-205 has been observed in multiple tumour types due to its role in the epithelial to mesenchymal transition, which promotes metastasis. We determined the expression of miR-205 in 111 archival samples of prostate carcinoma and found it to be strongly reduced in most samples, with a median expression level of 16% in comparison to benign tissue from the same patient. Lower miR-205 expression correlated significantly with tumour size and miR-205 levels decreased with increasing Gleason score from 7a=3+4 to 8=4+4. In addition, we describe the anti-apoptotic protein BCL2 as a target of miR-205, relevant for prostate cancer due to its role in prognosis of primary tumours and in the appearance of androgen independence. The repression of BCL2 by miR-205 was confirmed using reporter assays and western blotting. BCL2 mRNA expression in the same collective of prostate cancer tissue samples was associated with higher Gleason score and extracapsular extension of the tumour (pT3). Consistent with its anti-apoptotic target BCL2, miR-205 promoted apoptosis in prostate cancer cells in response to DNA damage by cisplatin and doxorubicin in the prostate cancer cell lines PC3 and LnCap. MiR-205 also inhibited proliferation in these cell lines.

Urgent resection of bleeding congenital mesenchymal chest wall hamartoma in an infant.

We report a case with prenatally diagnosed large cystic-solid mesenchymal chest wall hamartoma. An attempt of conservative management was made however repeated intralesional hemorrhage led to enlargement and severe anemia which required urgent resection at the age of 8 weeks. The infant had an unimpaired development over a follow-up of 4 years.

Pseudotumerous enlargement of the umbilical cord owing to an intra-amniotic varicosity associated with thrombocytopenia.

Herein, we describe a male infant with an antenatally diagnosed single umbilical artery and extensive varicosities of the umbilical vein with tumor-like appearances. Consumption coagulopathy occurred postnatally, and surgical resection of the umbilical cord led to a normalization of the platelet count.

Pathohistological diagnosis and differential diagnosis.

Malignant mesothelioma is a rare aggressive tumour arising from mesothelial cells of the pleural and peritoneal cavity including pericardium and tunica vaginalis testis. Malignant mesothelioma occurs predominantly in men (>90%). Asbestos exposure is the best known and evaluated risk factor with a long latency period between exposure and onset of malignant mesothelioma ranging from 15 to 60 years. Exposure to erionite leads to higher incidences of mesothelioma and play an important role in environmental exposure (Turkey). Other possible risk factors are radiation, recurrent pleuritis/peritonitis and simian virus 40 (SV 40).Malignant pleural mesothelioma is most common, whereas malignant peritoneal mesothelioma accounts only for 6-10%. Infrequent sites of origin are the pericardium and tunica vaginalis in 1-2%.Malignant mesothelioma shows either diffuse growth pattern or occurs as a localised tumour mass. Diffuse type represents an aggressive tumour with poor prognosis and is incurable in most cases.According to the WHO classification, three histological subtypes are distinguished: epithelioid, sarcomatoid and biphasic malignant mesothelioma.Rare variants are desmoplastic type, a subtype of sarcomatoid mesothelioma, undifferentiated type and deciduoid type. Epithelioid type is the most frequent one, but biphasic malignant mesothelioma occurs in 30%. Pure sarcomatoid or biphasic type is seen less frequently in malignant peritoneal mesothelioma than in its pleural counterpart.Well-differentiated papillary mesothelioma is a generally non-invasive mesothelioma with low malignant potential that arises mostly in females in the peritoneal cavity. Histological type is an important prognostic marker. Longest survival is seen in patients with epithelioid malignant mesothelioma. Sarcomatoid subtype has the worst prognosis.Malignant mesothelioma shows macroscopical and microscopical similarities to benign lesions and other malignancies. Therefore, reactive mesothelial proliferations on the one hand and secondary tumours resembling mesothelial cells as well as benign or rare mesothelial tumours on the other hand have to be distinguished. Additional immunohistochemistry is essential in histopathological assessment using a marker panel of antibodies.

The origins of colorectal carcinoma: specific nomenclature for different pathways and precursor lesions.

BACKGROUND: The widespread application of molecular methods in pathology has yielded steady advances in our understanding of the origins of colorectal carcinoma. Multiple pathways of carcinogenesis have been demonstrated on the molecular level and visualized on the histopathological level. The WHO has accordingly proposed a number of new designations and terms, particularly for precursor lesions, in order to establish a uniform standard for clinical diagnosis. These should be put into practice at once. METHODS: In this article, we explain the concept of intraepithelial neoplasia, which replaces the older concept of dysplasia. Moreover, we use this concept in describing a new mechanism of carcinogenesis for colorectal carcinoma, on the basis of a selective review of the literature. We estimate the frequency of precursor lesions according to the new concept using data from our own patient collective. Finally, we discuss the clinical consequences, which have been addressed in the German S3 guideline for colorectal carcinoma. RESULTS: The new type of precursor lesion, called "sessile serrated adenoma" (SSA), accounts for some 7% of all adenomas in our patient collective and is usually found in the right hemicolon. Traditional serrated adenomas (TSA) made up 1% to 3% of our cases and were found mainly in the left hemicolon and rectum. CONCLUSION: Our observations on the frequency and location of serrated adenomas accord with the initial findings published in the international literature. In view of the risk that serrated lesions will progress more rapidly, it is recommended that they should be completely removed, with follow-up at a short interval thereafter (three years according to the German S3 guidelines).

Herniation of the brain after conservative treatment of a large congenital skull defect in an infant with Adams-Oliver syndrome.

We report the case of a newborn baby with a large congenital skull defect owing to Adams-Oliver syndrome. An initial attempt at conservative treatment failed and led to disruption of the leptomeningeal membrane and prolapse of the brain. After local debridement, delayed and stepwise surgical closure was complicated by cerebrospinal fluid leakage, which required the insertion of a cerebrospinal fluid shunt. This case report highlights the potential serious risks of nonsurgical management of largely extended congenital skull defects.

The first description of an extramedullary plasmacytoma of the ureter.

Causes for acquired unilateral obstruction of the ureter are numerous: calculi, infections, blood clots and tumors are the most common underlying pathologies. Hematologic tumors with initial clinical manifestation in the lower urinary tract are rare. Primary localization of plasmocytoma has been described in kidney, bladder and urethra. Herein, we describe the first manifestation of a primary solitary extramedullary plasmacytoma of the ureter. The tumor was discovered upon diagnostic workup of gross hematuria and asymptomatic hydronephrosis. Thus far, after radical surgery the patient remains free of disease.

Signet-ring cell carcinoma arising in the gastric stump after duodenopancreatectomy for ductal adenocarcinoma of the pancreas: a case report.

The development of malignancy in the gastric stump following surgery for peptic ulcer disease is well recognized. There are also few reports on carcinomas occurring after surgery for malignant gastric disease. However, carcinoma of the gastric stump after duodenopancreatectomy is extremely rare. We describe what we believe to be an unusual case of signet-ring cell carcinoma of the gastric stump developing at the anastomotic site 5 years after duodenopancreatectomy for ductal adenocarcinoma of the pancreatic head. We performed remnant gastrectomy and Roux-en-Y gastrojejunostomy as a curative resection. This experience clearly underlies that g astric stump carcinoma (GSC) may mimic metastatic disease recurrence leading to diagnostic confusion after surgery for malignancy. Although an increased risk of gastric stump carcinoma after pancreatoduodenectomy for pancreatic cancer has not been established, the possibility of such a complication should be kept in mind when evaluating patients after gastric resection who present with symptoms of metastatic disease recurrence years after the primary operation. Investigations should be independent of the entity of the primary disease or its localization, since GSC may well be amenable to surgical cure as demonstrated in the presented case. Outpatient follow up results of the last four years indicated no recurrence in this case.

Cancer invasion and metastasis.

Metastasis is the transfer of malignant tumors from one organ to a distant organ. It is the most common cause of death in cancer patients. Different molecular mechanisms enable tumor cells to infiltrate the surrounding tissue, invade blood vessels and leave the blood stream at a different site. Tumor cell interaction with extracellular matrix components and epithelial-mesenchymal transition as well as angiogenesis are important factors in invasion and metastasis. Gene expression profiles of metastatic cells in various organs are different and not every tumor cell has the capacity to metastasize. The microenvironment in the organ influences formation of metastasis. Only 1% of micrometastases progress into macrometastases.

Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells.

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), the critical molecule in tumor angiogenesis, is regulated by different stimuli, such as hypoxia and oncogenes, and also by growth factors. Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor (IGF-IR) regulates VPF/VEGF expression. Insulin receptor substrate-1 and -2 (IRS-1 and IRS-2), two major downstream molecules of IGF-1R, are known to be important in the genesis of diabetes. In this study, we have defined a new role of IRS in angiogenesis. Both of the IRS proteins modulate VPF/VEGF expression in pancreatic cancer cells by different mechanistic pathways. The Sp1-dependent VPF/VEGF transcription is regulated mainly by IRS-2. Protein kinase C-zeta (PKC-zeta) plays a central role in VPF/VEGF expression and acts as a switching element. Furthermore, we have also demonstrated that the phosphatidylinositol 3-kinase pathway, but not the Ras pathway, is a downstream event of IRS proteins for VPF/VEGF expression in AsPC-1 cells. Interestingly, like renal cancer cells, in AsPC-1 cells PKC-zeta leads to direct Sp1-dependent VPF/VEGF transcription; in addition, it also promotes a negative feedback loop to IRS-2 that decreases the association of IRS-2/IGF-1R and IRS-2/p85. Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1-dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC-zeta to IRS-2. Our data also suggest that IRS proteins, which are known to play crucial roles in IGF-1R signaling, are also important mediators for tumor angiogenesis.

Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line.

Several oncogenes and growth factors are found to be mutated and overexpressed in adenocarcinoma of the pancreas, and may correlate with its highly aggressive nature. Insulin-like growth factor (IGF-I) and its receptor (IGF-IR) are highly expressed in this tumor type. We examined the IGF-IR-mediated signaling pathways in relation to cell proliferation, invasiveness, and expression pattern of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) in the pancreatic cancer line ASPC-1. Our findings show that IGF-IR is an important growth factor receptor for cell proliferation and invasion, and VPF/VEGF expression in ASPC-1. Further experiments indicate that IGF-IR mediates different signaling pathways to execute its functions. Activation of Ras by IGF-IR was found to be required for the cell invasion. On the other hand Src activation through IGF-IR is required for the cell proliferation, invasion, and also VPF/VEGF expression. Taken together, our data indicate the importance of IGF-IR in growth and invasiveness of the pancreatic cancer cell lines and also point out the multiple signaling pathways channeled through this receptor.