Complexity of PEComas : Diagnostic approach, molecular background, clinical management.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by a loss of function of the TSC1/TSC2 complex. Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified. By presenting a series of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences.

Endoscopic full-thickness resection (EFTR) in the lower gastrointestinal tract.

BACKGROUND: Endoscopic full-thickness resection (EFTR) significantly expands the spectrum of endoscopic colorectal resection methods for lesions that show no lifting sign, submucosal lesions and mucosal carcinomas. The aim of our study was to evaluate the efficacy and safety of EFTR using a commercially available full thickness resection device (FTRD) by assessing the completeness of the full-thickness resection, the technical success, as well as complications in a cohort of patients from three referral centers in Germany. Another aim was to determine which patient subpopulations benefit most in clinical practice. METHODS: This retrospective multicenter study was conducted on consecutive patients who were admitted to three referral centers in Germany between November 2014 and December 2017. The EFTR was conducted according to the standard indications using the FTRD System (OVESCO, Tübingen, Germany). Data were obtained from prospectively maintained institutional databases. RESULTS: There were 70 patients, 42 males and 25 females with a mean age of 79.5 years (range 25-89 years) who had colonoscopy for EFTR. In three patients EFTR was not feasible because the lesions were too large. Of the remaining 67 patients, 52 had recurrent adenomas, 10 had high-grade intraepithelial neoplasia or mucosal carcinoma and five had a subepithelial lesion. Resection was technically successful in 65 patients (97.0%). Histologically complete resection (R0) was achieved in 59/65 patients (90.8%). The R0 resection rate was lower for lesions > 20 mm (86.5%) versus lesions ≤ 20 mm (92.9%). The total complication rate was 14.9%: there was one major complication (perforation of sigmoid colon), while all other complications were minor. CONCLUSIONS: EFTR yields excellent resection rates for benign recurrent adenomas with non-lifting sign, advanced histopathological findings or submucosal lesions when the procedure is performed in experienced hands and for the correct indication. Thus, surgery can be avoided in many cases. For all lesions the risk of R1 resection goes up with the size of the lesion and careful patient selection is mandatory.

[Complexity of PEComas : Diagnostic approach, molecular background, clinical management (German version)]. / Komplexität von PEComen : Diagnose, Molekulargenetik, klinisches Management.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by a loss of function of the TSC1/TSC2 complex. Additionally, a distinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified. By presenting a series of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences.

[Hyponatremia in a 58-year-old female patient with EGFR-positive lung adenocarcinoma]. / Hyponatriämie bei einer 58-jährigen Patientin mit einem EGFR-positiven pulmonalen Adenokarzinom.

The case of a 58-year old female patient with epidermal growth factor-positive pulmonary adenocarcinoma treated with the tyrosine kinase inhibitor afatinib is reported. After several months of first-line therapy the patient developed severe hyponatremia and tumor reassessment revealed a progressive course of the lung cancer. Rebiopsy showed transformation of the tumor into small-cell lung cancer. Therapy with afatinib was stopped immediately and platin-based chemotherapy was started. This case shows that tumor transformation under tyrosine kinase inhibitor therapy from non-small-cell into small-cell lung cancer can occur in rare cases.

Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development.

Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. It is currently unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of profibrotic cytokines, are involved this process. We studied this question in a fully MHC-mismatched model of heart transplantation with transient depletion of CD4(+) T cells to largely prevent acute rejection. The model is characterized by myocardial infiltration of leukocytes and development of interstitial fibrosis and allograft vasculopathy. Using depletion of basophils, IL-4-deficient recipients and IL-4 receptor-deficient grafts, we showed that basophils and IL-4 play crucial roles in activation of fibroblasts and development of fibrotic organ remodeling. In the absence of CD4(+) T cells, basophils are the predominant source of IL-4 in the graft and contribute to expansion of myofibroblasts, interstitial deposition of collagen and development of allograft vasculopathy. Our results indicated that basophils trigger the production of various connective tissue elements by myofibroblasts. Basophil-derived IL-4 may be an attractive target for treatment of chronic allograft rejection.

Diagnostic performance of ultrasound strain elastography for differentiation of malignant breast lesions.

OBJECTIVE: Objective of the study was to assess the performance of ultrasound strain elastography combined with conventional B-mode ultrasound to diagnose suspicious breast lesions (BI-RADS 4 and 5). METHODS: Between January 2015 and December 2017, a total of 86 patients (55±17.9 years) with solid or unclear, non-cystic breast lesions were enrolled in the study. The breast lesions were evaluated by B-mode ultrasound and subsequent ultrasound strain elastography. Ultrasound features including echo pattern, lesion shape, marginal characteristics, calcifications, orientation and posterior features are useful for differentiating benign breast lesions from malignant ones. Malignant ultrasound features are irregular shape, hypoechoic pattern, spiculated margin, nonparallel orientation and posterior shadowing. Lesions with benign features such a circumscribed margin were classified as low conspicuous. In patients with highly conspicuous malignant masses ultrasound-guided core needle biopsy or surgical excision was performed. RESULTS: Among the 86 patients, 60 masses were histologically proven and 36 of these were malignant. Of the malignant lesions 26 invasive carcinomas were of no special type (NST), 1 invasive lobular carcinoma, 3 ductal carcinomas in situ and 6 metastases. 20 of these patients had breast density classified as ACR 3 or 4. The mean size of the masses was 1.2 cm (range: 0.5-5 cm). Based on ultrasound B-mode imaging, the lesions were classified as BI-RADS category 4 (n = 20; three 4a, nine 4b and eight 4c) and BI-RADS category 5 (n = 16). One patient had to be reclassified after strain elastographxy to BI-RADS 3.The sensitivity of ultrasound with strain elastography and additional B-Mode ultrasound for the characterization of solid breast lesions was 97%, for conventional B-mode alone 92%; the respective specificities were 82% and 73%, respectively. CONCLUSION: Ultrasound elastography can be a supplementary approach to conventional ultrasound to improve the diagnostic accuracy of malignant breast lesions.

Influence of hepatic fibrosis and inflammation: Correlation between histopathological changes and Gd-EOB-DTPA-enhanced MR imaging.

OBJECTIVE: To evaluate the influence of an active inflammatory process in the liver on Gd-EOB-DTPA-enhanced MR imaging in patients with different degrees of fibrosis/cirrhosis. MATERIAL AND METHODS: Overall, a number of 91 patients (61 men and 30 women; mean age 58 years) were included in this retrospective study. The inclusion criteria for this study were Gd-EOB-DTPA-enhanced MRI of the liver and histopathological evaluation of fibrotic and inflammatory changes. T1-weighted VIBE sequences of the liver with fat suppression were evaluated to determine the relative signal change (RE) between native and hepatobiliary phase (20min). In simple and multiple linear regression analyses, the influence of liver fibrosis/cirrhosis (Ishak score) and the histopathological degree of hepatitis (Modified Hepatic Activity Index, mHAI) on RE were evaluated. RESULTS: RE decreased significantly with increasing liver fibrosis/cirrhosis (p < 0.001) and inflammation (mHAI, p = 0.004). In particular, a correlation between RE and periportal or periseptal boundary zone hepatitis (moth feeding necrosis, mHAI A, p = 0.001) and portal inflammation (mHAI D, p < 0.001) was observed. In multiple linear regression analysis, both the degree of inflammation and the degree of fibrosis were significant predictors for RE (p < 0.01). CONCLUSION: The results of this study suggest that the MR-based hepatic enhancement index RE is not only influenced by the degree of fibrosis, but also by the degree of inflammation.

Acute administration of antibiotics modulates intestinal capillary perfusion and leukocyte adherence during experimental sepsis.

Antibiotic treatment represents a mainstay of therapy for clinical sepsis. Distinct from their antimicrobial effects, antibiotics may impact the inflammatory process in sepsis, e.g. within the intestinal microcirculation. The impact of seven antibiotics relevant to clinical sepsis on intestinal leukocyte recruitment and capillary perfusion was studied in rats with colon ascendens stent peritonitis (CASP)-induced sepsis or after endotoxin [lipopolysaccharide (LPS)] challenge. The following antibiotics were included: daptomycin; erythromycin; imipenem; linezolid; tigecycline; tobramycin; and vancomycin. The number of rolling and adherent leukocytes in intestinal submucosal venules and the functional capillary density (FCD) in three layers of the intestinal wall were assessed using intravital microscopy. CASP-induced sepsis reduces the intestinal FCD by 30-50%. Single administration of daptomycin, tigecycline or linezolid increased the intestinal FCD. CASP sepsis increased the number of rolling leukocytes by 4.5-fold, which was reduced by erythromycin but increased by vancomycin. The number of adherent leukocytes increased 3-fold in rats with CASP sepsis. It was reduced following administration of daptomycin, tigecycline (in V1 and V3 venules), erythromycin and linezolid (in V1 venules). However, following tobramycin and vancomycin, leukocyte adhesion was further enhanced. Administration of tigecycline and linezolid reduced the LPS-induced increase in the number of adherent leukocytes by 50%. However, imipenem did not affect leukocyte adherence. In conclusion, this work highlights the beneficial impact of the antibiotics daptomycin, tigecycline, erythromycin and linezolid in that they improve intestinal capillary perfusion and/or reduce leukocyte recruitment, whilst the antibiotics imipenem, tobramycin and vancomycin do not exert these properties.