Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders

Background: IgG4-related systemic fibrosclerosis is a recently defined disorder characterised by a diffuse or tumefactive inflammatory reaction rich in IgG4-positive plasma cells associated with sclerosis and obliterative phlebitis. Although characteristic histopathological features are essential for the diagnosis of these disorders, to date there exists no consensus regarding the cut-off values used to define a ‘significant IgG4-positive plasma cell count,’ and data regarding the distribution of IgG4-positive plasma cells under common (non-specific) inflammatory conditions are lacking. Methods: The authors analysed 121 randomly selected histopathological specimens containing prominent lymphoplasmacytic infiltrates (11 obstructive sialadenitis, 27 inflammatory lesions of the oral cavity, 24 inflammatory gastrointestinal lesions, 15 rheumatoid synovitis, 15 non-specific synovitis, eight non-specific dermatitis and 21 primary carcinomas with a peritumoral inflammatory response). For comparison, seven cases of sclerosing sialadenitis (Küttner tumour) were examined. Results: High counts of IgG4 plasma cells were found in sclerosing sialadenitis (mean 40/high-power field (hpf)), contrasting sharply with sialadenitis caused by sialolithiasis (mean 3/hpf). Greatly varied but generally high counts of IgG4-positive plasma cells were also seen in several of the other lesions, particularly in rheumatoid synovitis (mean 55/hpf), oral cavity lesions (mean 79/hpf) and carcinoma-associated inflammatory response (mean 24/hpf). The mean IgG4/IgG ratios for all lesions varied between 0 and 0.4. Conclusions: The results demonstrate the ubiquitous occurrence of variably high numbers of IgG4-positive plasma cells under diverse non-specific inflammatory conditions, indicating that high IgG4-positive plasma cell counts and high IgG4/IgG ratios per se do not reliably distinguish IgG4-associated systemic disease from non-specific conditions, and that the IgG4 counts must be cautiously interpreted in the context of appropriate clinical and histopathological features

Invasive Breast Cancer: Recognition of Molecular Subtypes

Molecular profiling has fundamentally changed our understanding of breast cancer in the last 10 years, by creating a new taxonomy of breast cancers based on the expression patterns of so-called ‘intrinsic genes’. Hierarchical clustering analyses performed on microarray-based gene expression profiles of breast cancers defined distinct breast cancer subgroups (luminal type A/B, HER2-enriched type, basal-like type). Since the initial landmark study by Perou et al., the concept of intrinsic breast cancer subtypes has been corroborated and expanded by several independent research groups. Further studies revealed individual properties of the intrinsic subgroups regarding the clinical course and the responsiveness to chemotherapy. The new gene expression profile-based taxonomy of breast cancer has been enthusiastically embraced by the scientific community and hailed as a major breakthrough on the way to individually tailored therapies. However, validation of the gene signatures in prospective studies is necessary before accepting these new technologies in daily clinical practice. In this review, the current data regarding the intrinsic subtypes and the associated clinical implications as well as the methodology of molecular profiling and possible use of immunohistochemistry in identifying intrinsic subtypes are discussed

Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

<p>Abstract</p> <p>Background</p> <p>The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.</p> <p>Methods</p> <p>Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.</p> <p>Results</p> <p>Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.</p> <p>Conclusions</p> <p>Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.</p

IgG4 immune response in Churg–Strauss syndrome

Objective: T-helper type 2 responses are crucial in Churg–Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients. Methods: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia). Results: IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10−5 and p=6×10−4, respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups. Conclusions: Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity

Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases

<p>Abstract</p> <p>Background</p> <p>The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth.</p> <p>Methods</p> <p>CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired <it>t </it>test when appropriate.</p> <p>Results</p> <p>Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-β and TNF-α were increased during tumor growth whereas IFN-γ showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location.</p> <p>Conclusions</p> <p>This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the situation in human cancer.</p

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

Studies regarding the antitumor immune response and tumor neoangiogenesis in colorectal hepatic metastases in a mouse model

Das Kolonkarzinom besitzt aufgrund seiner hohen Inzidenz und der zahlreichen Möglichkeiten, mittels moderner Therapiestrategien auf den Krankheitsverlauf Einfluss zu nehmen, eine hohe Relevanz für den klinischen Alltag. Etwa die Hälfte der an einem kolorektalen Karzinom erkrankten Patienten weisen Lebermetastasen auf, welche entweder bereits bei der primären Diagnosestellung vorliegen oder sich im weiteren Krankheitsverlauf ausbilden. Bei der Mehrzahl der Patienten mit Lebermetastasen ist derzeit nur eine palliative Therapie möglich. Die genaue Analyse kolorektaler Lebermetastasen ist somit unerlässlich, um eine gezielte Entwicklung neuer, effizienter Therapiestrategien für dieses große Patientenkollektiv zu ermöglichen. Ziel dieser Arbeit war es, möglichst genau Zytokinprofil, lymphozytäres Infiltrationsmuster und Verhältnis von pro- zu antiangiogenetischen Faktoren im Lebermetastasengewebe über einen biologisch maßgeblichen Wachstumszeitraum zu charakterisieren, um zu einem besseren Verständnis von Tumorimmunologie und Wachstumsverhalten kolorektaler Lebermetastasen beizutragen. Zu diesem Zweck wurde in einem Mausmodell die Ausbildung kolorektaler Lebermetastasen nach intraportaler Injektion von Tumorzellen (CT26.WT) untersucht.Because of its high incidence and the numerous therapeutic strategies which allow the clinician to influence the course of the disease colorectal carcinoma figures prominently in the clinical daily routine. About half the patients with colorectal carcinoma suffer from hepatic metastasis, which is either already present at the primary diagnosis or develops later in the course of the disease. At present the majority of patients with hepatic metastasis can only be offered palliative therapy. A detailed analysis of hepatic metastasis is therefore essential for the specific development of new and efficient therapeutic strategies for this group of patients. The objective of this work was to characterize the cytokine profile, the lymphocytic infiltration patterns and the ratio of angiogenic and antangiogenic factors in the tissue of colorectal hepatic metastases as precisely as possible over a biologically significant timespan, thus contributing to a better understanding of tumor immunology and tumor growth. With this aim in view we analyzed the development of colorectal hepatic metastases in a mouse model after the intraportal injection of tumor cells (CT26.WT)

Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders

Background: IgG4-related systemic fibrosclerosis is a recently defined disorder characterised by a diffuse or tumefactive inflammatory reaction rich in IgG4-positive plasma cells associated with sclerosis and obliterative phlebitis. Although characteristic histopathological features are essential for the diagnosis of these disorders, to date there exists no consensus regarding the cut-off values used to define a ‘significant IgG4-positive plasma cell count,’ and data regarding the distribution of IgG4-positive plasma cells under common (non-specific) inflammatory conditions are lacking. Methods: The authors analysed 121 randomly selected histopathological specimens containing prominent lymphoplasmacytic infiltrates (11 obstructive sialadenitis, 27 inflammatory lesions of the oral cavity, 24 inflammatory gastrointestinal lesions, 15 rheumatoid synovitis, 15 non-specific synovitis, eight non-specific dermatitis and 21 primary carcinomas with a peritumoral inflammatory response). For comparison, seven cases of sclerosing sialadenitis (Küttner tumour) were examined. Results: High counts of IgG4 plasma cells were found in sclerosing sialadenitis (mean 40/high-power field (hpf)), contrasting sharply with sialadenitis caused by sialolithiasis (mean 3/hpf). Greatly varied but generally high counts of IgG4-positive plasma cells were also seen in several of the other lesions, particularly in rheumatoid synovitis (mean 55/hpf), oral cavity lesions (mean 79/hpf) and carcinoma-associated inflammatory response (mean 24/hpf). The mean IgG4/IgG ratios for all lesions varied between 0 and 0.4. Conclusions: The results demonstrate the ubiquitous occurrence of variably high numbers of IgG4-positive plasma cells under diverse non-specific inflammatory conditions, indicating that high IgG4-positive plasma cell counts and high IgG4/IgG ratios per se do not reliably distinguish IgG4-associated systemic disease from non-specific conditions, and that the IgG4 counts must be cautiously interpreted in the context of appropriate clinical and histopathological features

Immunohistochemical expression of IMP3 and p53 in inflammatory lesions and neoplastic lesions of the gastric mucosa

Aim: Expression of the oncofetal protein insulin like growth factor II messenger ribonucleic acid binding protein 3 (IMP3) has been shown to differentiate between benign and malignant lesions in several tissues. Our aim was to assess the immunohistochemical expression of IMP3 in inflammatory and neoplastic lesions of the gastric mucosa and to determine whether IMP3, alone or in combination with p53, could be used for identifying neoplasia of the gastric mucosa. Methods: IMP3 and p53 immunohistochemistry was performed on 57 cases of gastritis, 28 cases of dysplasia of the gastric mucosa and 63 cases of gastric carcinomas. Focal IMP3 positivity was detected in 86% of non-neoplastic lesions of the gastric mucosa. Using a simple product score (PS), 96% of non-neoplastic lesions of the gastric mucosa were assessed as IMP3(PS) negative. None of the low-grade dysplasia but 83% of high-grade dysplasia were IMP3(PS) positive. Gastric carcinomas showed IMP3(PS) positivity in 65%. Adding p53 to the diagnostic panel increased sensitivity significantly. Conclusion: High-grade dysplasia and gastric carcinomas can be distinguished from low-grade dysplasia and inflammatory lesions of the gastric mucosa with a high specificity and good sensitivity using a combination of the immunohistochemical markers IMP3 and p53

Case Report Juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis: case report and literature review

Abstract: The synchronous or metachronous development of Langerhans cell histiocytosis and non-Langerhans cell histiocytosis in the same patient is rare. To date, only seven cases of xanthogranulomas developing in young patients with a history of Langerhans cell histiocytosis and systemic therapy have been reported in the literature. As of yet, the pathogenesis and the clinical significance of this phenomenon are unclear. We report the case of a 3 year old boy who developed juvenile Xanthogranulomas on the forehead and right upper eye lid 1.5 years after systemic therapy for monosystemic Langerhans cell histiocytosis of the bone and complete disease remission