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Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558_V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery. [ABSTRACT FROM AUTHOR]

Background: The two principal ways of metastases in gastrointestinal stromal tumors (GISTs) are diffuse intraabdominal spread and liver metastasis whereas lymph node metastases (LNM) are extremely rare. Accordingly, nodal dissection is generally not recommended for GISTs' surgical treatment.Methods: We present two unique cases of GIST with synchronous and metachronous extraabdominal LNM, whose clinical, macro-/microscopic, and immunohistochemical criteria, surgical and neo- or adjuvant therapy were investigated in retrospective analysis.Results: A 76-year-old man was presented with an inguinal mass and a simultaneously detected intraabdominal mass. Pathological evaluation of the core needle biopsy from the inguinal lymph node confirmed metastatic GIST. Partial resection of the ileum and inguinal lymph node dissection (LND) showed a spindle cell GIST in the ileum with inguinal LNM. Imatinib mesylate therapy was administered, which was interrupted 2 years later because of patient's intolerance. A 35-year-old man underwent extended gastrectomy, atypical liver resection, splenectomy, and LND because of a huge gastric fundus GIST. Postoperative imatinib mesylate therapy was administered. Histology showed multiple regional lymph node metastasis. Two years later, a left hemihepatectomy was performed for liver metastases. During follow-up, new axillary LNM were detected, and a sunitinib therapy was initiated. Thereafter, he developed progressive axillary, mediastinal, hepatic, abdominal, osseous, and cutaneous metastases, and he was treated by palliative cytoreductive surgery.Conclusion: These two cases demonstrate that extraabdominal node metastasis may rarely occur in GIST, either initially or in the setting of widespread disease. In selected cases with confirmed or suspected LNM, LND should be considered. Metachronous extraabdominal lymph node metastasis represents a late event in high-risk GISTs and cannot be controlled by drug therapy alone. [ABSTRACT FROM AUTHOR]

By means of the scientific description of two uncommon cases who underwent. surgical resection of multinodous goiter and following histopathological investigation revealing isolated extrapulmonary manifestation of sarcoidosis, this uncommon diagnosis including symptomatology, clinical findings, diagnostic and therapeutic management is to be illustrated. 1) Clinical findings: 61-years old patient with a multinodous goiter for 10 years characterized by an increasing size. Diagnostics: Scintigraphy of the thyroid gland with a left-thyroid cold node; ultrasound-guided puncture (cytological investigation, non-suspicious). Therapy: Elective thyroidectomy with no macroscopic anomalies und no abnormal aspects with regard to surgical tactic and technique. Histopathological investigation: Complete resection specimen of the thyroid gland with granulomatous inflammation consistent with sarcoidosis. Clinical course: Uneventful with no further manifestations of sarcoidosis in the following diagnostics. 2) Clinical finding: 30-years old female patient with soft swelling of increasing size at the right neck. Diagnostics: Ultrasound, inhomogeneous node (37×30×35 mm) of the right thyroideal gland with echo-poor parts and peripheral vascularization; scintigraphy showing marginally compensated unifocal autonomy of the thyroid gland (laboratory parameters, increased serum level of thyroglobulin [632 ng/mL]). Therapy: Planned right hemithyroidectomy with confirmed nodous structure of thyroid parenchyma, without suspicious lymph nodes. Histopathological investigation: 33-mm follicular, nodular, encapsulated structure of thyroid parenchyma (diagnosed as follicular adenoma); 2nd opinion: low-grade differentiated carcinoma of thyroid gland with angioinfiltrating growth and granulomatous inflammation of sarcoidosis type. Procedural intent: After tumor-board consultation, completing thyroidectomy was performed within a 5-weeks interval (pT2 pN0[0/1] V1 L0 G3 R0) with subsequent ablating radio'active iodine therapy; 18 F-FDG-PET-CT (several atypical infiltrates within the right upper lobe of the lung) and bronchoscopy with no detection of further manifestation of sarcoidosis. Sarcoidosis is considered a rare granulomatous multi-locular, systemic disease of not completely known etiopathogenesis with substantial heterogeneity. In most cases, it is associated with the lung, but which can become manifest in various organs. Frequently, extrapulmonary manifestations are usually detected as histological findings by coincidence, which require further investigation to find out additional manifestations as well as to exclude florid infection or other granulomatous processes (clarifying competently differential diagnosis). Therapy is only indicated in symptomatic organ manifestations, taking into account the high rate of spontaneous healing and possible side effects. [ABSTRACT FROM AUTHOR]

Summary Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment. [ABSTRACT FROM AUTHOR]

Summary: Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2+Ly6Chi monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2+ endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2−/− mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis. [Copyright &y& Elsevier]

Abstract: Purpose: Cyclin-dependent kinase 2 (cdc2) controls the G2–M checkpoint and, therefore, the entrance of cells into mitosis. It might play a crucial role during tumour progression in colon carcinomas (CCA). Thus, the prognostic value of cdc2 expression and connected markers relevant for proliferation and apoptosis has to be evaluated. Experimental design: Punch biopsies from the tumour centre and the invasion front of 0.6mm diameter from 392 CCA stage UICC II–IV were integrated in 14 recipient paraffin blocks. After immunohistochemical staining for cdc2, p53, caspase 3 and ki-67, a present (+) and absent (–) scoring was performed in the tissue arrays. The logrank test was used to compare distant metastasis and cancer-related survival. Multivariate Cox regression analysis was done to identify independent prognostic factors for parameters with significant influence on cancer-related survival (CRS) and distant metastasis (DM). Results: The pT-category (p =0.007), nodal status (p <0.001), extramural venous infiltration (p <0.001) and lymphatic vessel invasion (p =0.003) were identified as independent histological parameters for CRS. Univariate analysis relating to stage UICC II–IV CCA showed caspase 3 in the tumour centre (p =0.047) to be a prognostic marker for CRS. In stage UICC II cdc2 (p =0.041) and caspase 3 in the invasion front (p =0.026) could be identified as independent prognostic factors for CRS and DM by multivariate analysis. Conclusions: Cdc2 and caspase 3 could be identified as independent prognostic markers in stage UICC II CCA. They might be of value to select patients who should receive adjuvant treatment. [Copyright &y& Elsevier]

Abstract: Methylation of promoter regions and frameshift mutations in microsatellites of the coding sequence (CDS) of genes are frequently associated with loss of expression in microsatellite instable (MSI) colorectal carcinoma. In a panel of 40 MSI and 24 microsatellite stable (MSS) colorectal tumours as well as six cultured colorectal carcinoma cell lines hypermethylation of the TIMP3-promoter was found in 28% of MSI and 25% of MSS tumours, respectively. Additionally, three MSI tumours and one cell line displayed instability of a C7-repeat located in the CDS of the TIMP-3 gene. TIMP-3 fulfils all important criteria for being a target gene in the mutator pathway. Thus, TIMP-3 might be a factor of general importance for colorectal carcinogenesis. [Copyright &y& Elsevier]

Adenocarcinoma of the small intestine (ACSI) is a rare condition with few studies addressing follow-up and prognosis. Tumors of 35 patients with curative resection of an ACSI were retrospectively analyzed by immunohistochemistry: p53, hMLH1, hMSH2 and hMSH6 and microsatellite instability (MSI): BAT-26, BAX, TGF-β RII. With a median follow up of 6.1 years, the median cancer-specific survival (CSS) was 36.2 months. Patients who were highly instable (MSI-H) (n=10) had a CSS of 49.6 months in contrast to patients with stable tumors (23.2 months) (P=0.010). Additionally, a low tumor stage according to UICC and MSI-H were shown to be independent factors (P=0.005 and P<0.001) for an increased survival in multivariate analysis. Therefore, it is suggested that analysis of the MSI status might prove useful in discerning prognosis within cancers of the same stage. [Copyright &y& Elsevier]