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ObjectiveNon-mass enhancement (NME) in breast MRI is the most common feature of ductal carcinoma in situ (DCIS). We sought to evaluate the interobserver variability and positive predictive value (PPV) for malignancy of NME descriptors using the fifth edition BI-RADS lexicon focusing on the newly introduced “clustered ring enhancement” pattern.Materials and methodsBreast MRIs of 129 patients who had undergone MRI-guided vacuum-assisted biopsy (VAB) in our institution were reviewed. Studies assessed as NME were classified according to the fifth edition BI-RADS lexicon by two breast radiologists. Consensus was reached by involving a third radiologist. Interobserver variability and PPV for malignancy were assessed.ResultsSeventy-two of 129 studies were assessed as NME. The disagreement rate in the first assessment step (mass vs. NME) was low at 9.3% (ĸ = 0.81, 95% confidence interval [CI] 0.71–0.91). The disagreement rate for distribution patterns was 23.6% (ĸ = 0.67, 95% CI 0.54–0.80) and 22.2% (ĸ = 0.69, 95% CI 0.56–0.81) for internal enhancement patterns. Clustered ring enhancement (PPV 53.85, p = 0.038) and segmental distribution (PPV 62.5%, p = 0.028) had the highest malignancy rates among internal enhancement and distribution patterns with a significant result; the combination of clustered ring enhancement and segmental distribution raised the malignancy rate by approximately 4% (PPV 66.67%, p = 0.049).ConclusionThere was a high agreement rate among readers when differentiating NME from mass lesions. The agreement rate was lower when assessing the distribution and internal enhancement pattern descriptors, but still substantial. The descriptors clustered ring enhancement and segmental distribution were significant predictors of malignancy.Key Points• Non-mass enhancement is a common morphological feature of non-invasive breast cancer (DCIS) in MRI. Differentiation between potentially malignant and benign changes may be very challenging.• Since clustered ring enhancement and segmental distribution are both significant predictors of malignancy, the awareness of this important finding, combined with high-quality image interpretation skills, may improve the tumor detection rate.• The combination of clustered ring enhancement and segmental distribution increases the positive predictive value for malignancy, which may be relevant for clinical practice.

Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56-0.72). However, we found very high inter-observer variabilities (Kappa 0.04-0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01-0.04) and intra-observer agreement was likewise poor (Kappa 0.00-0.35). Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas.

Extracellular matrix (ECM) remodeling plays critical roles in cancer progression and involves alterations in its composition and biophysical properties. Aggressiveness and malignancy of solid tumors are strongly correlated with tissue stiffening, mainly due to upregulated ECM production and cross‐linking. However, nothing is known about the tensional alterations that occur at the single‐fiber level during tumorigenesis in humans. The well‐validated peptide tension probe (FnBPA5) now reveals that Fibronectin fibers lose their tension as invasive tumors progress while they are stretched in healthy human breast tissue stroma and in ductal carcinoma in situ (DCIS), the non‐invasive precursor of breast cancer. In invasive carcinomas, cancer cells, cancer‐associated fibroblasts (CAFs) and infiltrating immune cells (cytotoxic T cells and regulatory T cells), are predominantly located in proximity to untensed Fibronectin fibers. This is significant, as Fibronectin fiber stretching can mechano‐regulate the reciprocal cell‐ECM crosstalk and the bioavailability of ECM‐bound molecules. Not only tissue stiffening, but also the accumulation of untensed Fibronectin fibers may serve as a mechanical biomarker that correlates with tumor grade. Loss of Fibronectin fiber tension may play a central role in regulating tumor invasiveness. This suggests that physically altered ECM fibers can be exploited for stroma‐targeted drug delivery and immunotherapy. Extracellular matrix remodeling is crucial in cancer progression. Using a peptide to probe the tension of ECM fibers, it was found that Fibronectin fibers gradually lose tension as human breast carcinoma progresses, while their tension is maintained in ductal carcinoma in situ (DCIS), the non‐invasive precursor of breast cancer. This loss of tension is associated with the presence of T cells, cancer‐associated fibroblasts(CAFs), and cancer cells, prone to be exploited for stroma‐targeted drug delivery and immunotherapy.

PurposeOvarian carcinoma (OC) is the most lethal female genital cancer. After a primary curative surgical approach followed by chemotherapy, a fraction of the patients recur with chemoresistant disease. Data indicate a favorable therapeutic effect of tumor-infiltrating neutrophils (TIN) in OC. Our aim was to investigate the prognostic role of CD66b expression, corresponding to neutrophilic infiltration for recurrence-free survival (RFS) and overall survival (OS) in patients with OC.MethodsA collective of 47 primary serous ovarian carcinoma and their matching recurrences were processed and stained with CD66b using immunohistochemistry. Tumors from patients with RFS of more than 6 months were defined as chemosensitive. Statistical analysis of CD66b expression was performed to assess the clinical endpoints.ResultsHigh density of CD66b expressing neutrophils in primary carcinoma was associated with chemosensitivity (p = 0.014) and longer RFS (p = 0.001). Univariate analysis identified high density of CD66b expressing neutrophils as a predictor for favorable RFS (HR 0.41, 95% CI 0.22–0.76, p < 0.005). Residual disease > 2 cm (HR 3.67, 95% CI 1.62–8.31, p < 0.002) and higher number of chemotherapy cycles (HR 1.28, 95% CI 1.05–1.55, p < 0.013) were associated with worse RFS. Multivariate analysis showed that high density of CD66b expressing neutrophils (HR 0.22, 95% CI 0.10–0.48, p < 0.001) and residual disease > 2 cm (HR 3.69, 95% CI 1.43–9.53, p < 0.007) were independent predictors of RFS but had no impact on OS.ConclusionHigh CD66b neutrophil density in primary high-grade OC predicts good response to initial chemotherapy and longer recurrence-free survival independent of known risk factors.

Background Ovarian carcinoma (OC) is the fifth most common female cancer and mostly diagnosed at an advanced stage. Surgical debulking is usually followed by adjuvant platinum-based chemotherapy. Only few biomarkers are known to be related to chemosensitivity. OX40 is a TNF receptor member and expressed on activated CD4+ and CD8+ T cells. It is known that OX40 signaling promotes survival and responds to various immune cells of the innate and adaptive immune system. Therefore we investigated the indicative value of OX40 expression for recurrence and survival in OC. Methods A tissue microarray of biopsies of mostly high-grade primary serous OC and matched recurrences of 47 patients was stained with OX40. Recurrence within 6 months of the completion of platinum-based chemotherapy was defined as chemoresistance. Results Chemosensitivity correlated significantly with high OX40 positive immune cell density in primary cancer biopsies ( p =  0.027). Furthermore patients with a higher OX40 expression in recurrent cancer biopsies showed a better outcome in recurrence free survival (RFS) ( p =  0.017) and high OX40 expression was associated with chemosensitivity ( p =  0.008). OX40 positive TICI in recurrent carcinomas significantly correlated with IL-17 positive tumor infiltrating immune cells in primary carcinomas ( r s  = 0.34; p  = 0.023). Univariate cox regression analysis revealed a significant longer RFS and higher numbers of chemotherapy cycles for high OX40 tumor cell expression in recurrent cancer biopsies (HR 0.39, 95%CI 0.16–0.94, p = 0.036 and 1.28, 95%CI 1.05–1.55; p = 0.013 ). Conclusion High OX40 expression in OC is correlated with chemosensitivity and improved RFS in OC. Patients might therefore benefit from a second line therapy.

Background Ovarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS). Methods A tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS. Results Patients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years ( p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years ( p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate ( p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193). Conclusions To the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy. Highlights • We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence. • High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis. • We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer.

We report a rare case of successfully conservatively treated stage III xanthogranulomatous pyelonephritis (XGP). To our knowledge, this is among the first descriptions of successfully managed extensive XGP without surgical intervention.

Background Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions. Results For our studies, we employed the preclinical radiotracer [ 111 In]In-FnBPA5, which specifically binds to relaxed fibronectin–an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [ 111 In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [ 111 In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma. Conclusion Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [ 111 In]In-FnBPA5, the matching targeting molecule is in preclinical development.

Background: In the current literature, deposits in calcific tendinitis are described as amorphous masses of hydroxyapatite with a size in the range of 5 to 20 μm. Theoretically, these are too big to be phagocytized by macrophages and induce an inflammatory reaction. Purpose: To better characterize the deposits seen in calcific tendinitis. Study Design: Case series; Level of evidence, 4. Methods: Included in the study were 6 patients with a history of at least 1 year of shoulder pain (range, 1-14 years). Shoulder arthroscopy was performed under general anesthesia, and calcium deposits from the supraspinatus tendon and biopsies from the adjacent subacromial bursa were taken. Samples were analyzed by light microscopy and immunostained for macrophages. Scanning electron microscopy and energy-dispersive x-ray (EDX) analysis were used to assess the morphology and chemical composition of the calcific deposits. Results: Light microscopy showed round and bulky calcium deposits partially surrounded by activated CD68-positive macrophages within inflammatory tissue. Some hemosiderin positive mononuclear cells, indicative for (micro-) hemorrhage, were seen. Scanning electron microscopy revealed that the large calcific deposits (1-20 μm) were composed of rod-like structures. These highly crystalline rods had a size of approximately 100 nm in length and 20 nm in width. Chemical composition by EDX analysis showed that crystals were composed of mainly calcium, oxygen, and phosphorus, equaling the chemical composition of hydroxyapatite. Conclusion: Deposits in calcific tendinitis of the rotator cuff are not amorphous but composed of highly crystalline structures. Fragmentation of these aggregates and subsequent release of the needle-like nanocrystals might initiate the strong inflammatory reaction often seen in patients with calcifying tendinitis of the rotator cuff.