Comprehensive Genomic Characterization in Ovarian Low-Grade and chemosensitive and chemoresistant High-Grade Serous Carcinomas.

INTRODUCTION: Genomic characterization of serous ovarian carcinoma (SOC), which includes low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC), remains necessary to improve efficacy of platinum-based chemotherapy. The aim was to investigate the genomic variations in these SOC groups, also in relation to chemoresponse. METHODS: 45 samples SOC were retrospectively analyzed by Next Generation Sequencing (NGS) on DNA/RNA extracts from formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained at diagnosis. HGSCs were classified as platinum-resistant and platinum-sensitive. RESULTS: In the LGSC group, 44% of the carcinomas had mutually exclusive variants in the RAS/RAF pathway, while additional likely oncogenic variants in the CDKN2A, SMARCA4 and YAP1 genes were observed in the remaining LGSCs. Tumor mutation burden (TMB) was significantly lower in the intrinsically chemoresistant LGSC group than in the HGSC group. In the HGSC cohort, TP53 variants were found in 90% and homologous recombination repair (HRR) pathway variants in 41% of the neoplasms. HGSCs of the chemoresistant group without classic mutations in the HRR pathway were characterized by additional variants in FGFR2 and with a FGFR3::TACC3 fusion. In addition, HGSCs showed MYC, CCNE1 and AKT2 gains that were almost exclusively observed in the chemosensitive HGSC group. CONCLUSIONS: These results suggest that very low TMB and MYC, CCNE1 and AKT2 gains in SOC patients may be biomarkers related to platinum treatment efficacy. Thorough genomic characterization of SOCs prior to treatment might lead to more specific platinum-based chemotherapy therapy strategies.

Relaxed fibronectin: a potential novel target for imaging endometriotic lesions.

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 [111In]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 [111In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [111In]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 [111In]In-FnBPA5, the matching targeting molecule is in preclinical development.

High density of CXCL12-positive immune cell infiltration predicts chemosensitivity and recurrence-free survival in ovarian carcinoma.

BACKGROUND: Ovarian carcinoma is the most lethal gynecologic malignancy because of its late diagnosis, extremely high recurrence rate, and limited curative treatment options. In clinical practice, high-grade serous carcinoma (HGSC) predominates due to its frequency, high aggressiveness, and rapid development of drug resistance. Recent evidence suggests that CXCL12 is an important immunological factor in ovarian cancer progression. Therefore, we investigated the predictive and prognostic significance of the expression of this chemokine in tumor and immune cells in patients with HGSC. METHODS: We studied a cohort of 47 primary high-grade serous ovarian carcinomas and their associated recurrences. A tissue microarray was constructed to evaluate the CXCL12 immunostained tumor tissue. CXCL12 expression was evaluated and statistically analyzed to correlate clinicopathologic data, overall survival, and recurrence-free survival. RESULTS: A high proportion of CXCL12 + positive immune cells in primary ovarian serous carcinoma correlated significantly with chemosensitivity (p = 0.005), overall survival (p = 0.021), and longer recurrence-free survival (p = 0.038). In recurrent disease, high expression of CXCL12 was also correlated with better overall survival (p = 0.040). Univariate and multivariate analysis revealed that high CXCL12 + tumor-infiltrating immune cells (TICs) (HR 0.99, p = 0.042, HR 0.99, p = 0.023, respectively) and combined CXCL12 + /CD66b + infiltration (HR 0.15, p = 0.001, HR 0.13, p = 0.001, respectively) are independent favorable predictive markers for recurrence-free survival. CONCLUSION: A high density of CXCL12 + TICs predicts a good response to chemotherapy, leading to a better overall survival and a longer recurrence-free interval. Moreover, with concomitant high CXCL12/CD66b TIC density, it is an independent favorable predictor of recurrence-free survival in patients with ovarian carcinoma.

Extranodal Diffuse Large B-cell Lymphoma With Primary Clinical Presentation as Acute Cholecystitis: A Case Report.

This case describes a rare presentation of a diffuse large B-cell lymphoma not otherwise specified (DLBC NOS) in the gallbladder. We report the case of an 89-year-old male who initially presented with a two-week history of weakness and abdominal discomfort. We performed laparoscopic cholecystectomy for suspicion of acute cholecystitis. After the initial uneventful course, readmission occurred for persisting weakness a few weeks after surgery. Computed tomography revealed progressive retroperitoneal lymphadenopathy. With new emerging neurological symptoms, taking into account the histopathological findings of the gallbladder specimen, the diagnosis of DLBCL NOS was confirmed. Due to the rapid clinical deterioration and extranodal involvement, the patient opted against further therapy. When the suspicion of cholecystitis is inconclusive, rare differential diagnoses need to be considered. This analysis may improve the understanding of the presentation and course of DLBC NOS in abdominal organs and could form the basis for a systematic review to improve diagnosis and therapy.

Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II-IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial.

High ratio of pCXCR4/CXCR4 tumor infiltrating immune cells in primary high grade ovarian cancer is indicative for response to chemotherapy.

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.

The Role of New Technologies in the Diagnosis and Surveillance of Non-Muscle Invasive Bladder Carcinoma: A Prospective, Double-Blinded, Monocentric Study of the XPERT© Bladder Cancer Monitor and Narrow Band Imaging© Cystoscopy.

Follow-up is essential for the early detection of recurrent non-muscle invasive bladder cancers (NMIBC). This study investigates the clinical relevance of new diagnostic tools such as an mRNA-based urine test (XPERT© Bladder Cancer Monitor, XBCM) and Narrow Band Imaging© (NBI) and compares them with the established follow-up diagnostics (white-light cystoscopy (WLC) and urine cytology). This was a prospective, double-blind, single-center study that involved patients undergoing NMIBC screening at a tertiary care center. Enrollment occurred between January 2018 and March 2020. In addition to standard care (WLC, cytology, and ultrasound), patients underwent XBCM urine testing and NBI cystoscopy. In total, 301 WLCs were performed; through this, 49 patients demonstrated NMIBC recurrence. NBI cystoscopy was congruent with WLC in all patients. Cytology showed a sensitivity (SE) and specificity (SP) of 27% and 97% (PPV: 65%; NPV 87%), respectively, whereas XBCM showed SE and SP of 58% and 89%, respectively (PPV: 51%; NPV: 92%; AUC: 0.79 (0.716-0.871)). Subgroup analysis showed improved SE and similar SP (PPV, NPV) for high grade (HG) recurrence, with a SE of 74% and SP of 89% (39%, 97%). NBI cystoscopy does not necessarily provide additional benefit over standard WLC. However, the XBCM may provide better SE and a diagnostic advantage in instances of HG disease recurrence.

High Density of CD16+ Tumor-Infiltrating Immune Cells in Recurrent Ovarian Cancer Is Associated with Enhanced Responsiveness to Chemotherapy and Prolonged Overall Survival.

BACKGROUND: Ovarian cancer (OC) is the most aggressive and fatal malignancy of the female reproductive system. Debulking surgery with adjuvant chemotherapy represents the standard treatment, but recurrence rates are particularly high. Over the past decades, the association between the immune system and cancer progression has been extensively investigated. However, the interaction between chemotherapy and cancer immune infiltration is still unclear. In this study, we examined the prognostic role of CD16 expression in OC, as related to the effectiveness of standard adjuvant chemotherapy treatment. METHODS: We analyzed the infiltration by immune cells expressing CD16, a well-characterized natural killer (NK) and myeloid cell marker, in a tissue microarray (TMA) of 47 patient specimens of primary OCs and their matching recurrences by immunohistochemistry (IHC). We analyzed our data first in the whole cohort, then in the primary tumors, and finally in recurrences. We focused on recurrence-free survival (RFS), overall survival (OS), and chemosensitivity. Chemosensitivity was defined as RFS of more than 6 months. RESULTS: There was no significant correlation between CD16 expression and prognosis in primary carcinomas. However, interestingly, a high density of CD16-expressing tumor-infiltrating immune cells (TICs) in recurrent carcinoma was associated with better RFS (p = 0.008) and OS (p = 0.029). Moreover, high CD16 cell density in recurrent ovarian carcinoma showed a significant association with chemosensitivity (p = 0.034). Univariate Cox regression analysis revealed that the high expression of CD16+ TIC in recurrent cancer biopsies is significantly associated with an increased RFS (HR = 0.49; 95% CI 0.24-0.99; p = 0.047) and OS (HR = 0.28; 95% CI 0.10-0.77; p = 0.013). However, this was not independent of known prognostic factors such as age, FIGO stage, resection status, and the number of chemotherapy cycles. CONCLUSIONS: The high density of CD16-expressing TICs in recurrent ovarian cancer is associated with a better RFS and OS, thereby suggesting a previously unsuspected interaction between standard OC chemotherapy and immune cell infiltration.

Characterization of Deposits in Calcific Tendinitis of the Shoulder: Deposits Are Composed of Large Aggregates of Highly Crystalline, Rod-Like Crystals.

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.

Impact of Chronic Prostatitis on the PI-RADS Score 3: Proposal for the Addition of a Novel Binary Suffix.

We examined the impact of chronic prostatitis on the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI). In this retrospective study, 63 men underwent 3T mpMRI followed by MRI/ultrasound fusion biopsy to exclude/confirm clinically significant prostate cancer (csPCa). A total of 93 lesions were included for evaluation. Images were assessed by two radiologists. Prostatitis was graded visually on T2-weighted and contrast-enhanced sequences. The correlation of prostatitis features with the assigned Prostate Imaging Reporting and Data System (PI-RADS) and the presence of csPCa were assessed, and the clinical and functional imaging parameters for differentiating between prostatitis and significant tumors were examined. Histopathological analysis was used as the reference standard. The rate of PI-RADS 3 scores tended to be higher in the presence of radiologically severe prostatitis compared with no/discrete prostatitis (n = 52 vs. n = 9; p = 0.225). In severe prostatitis, csPCa was determined in only 7.7% (4/52) of PI-RADS 3 lesions. In severe chronic prostatitis, a binary prostatitis suffix (e.g., PI-RADS 3 i+ versus i-) within the radiological report may help assess the limitations of mpMRI interpretability because of severe prostatitis and avoid unnecessary biopsies. Mean apparent diffusion coefficient (ADCmean) was the best marker (cutoff 0.93 × 10-3 mm2/s) to differentiate between csPCa/non csPCa in severe prostatitis.

Deciphering the genetic landscape of pulmonary lymphomas.

Pulmonary lymphoid malignancies comprise various entities, 80% of them are pulmonary marginal zone B-cell lymphomas (PMZL). So far, little is known about point mutations in primary pulmonary lymphomas. We characterized the genetic landscape of primary pulmonary lymphomas using a customized high-throughput sequencing gene panel covering 146 genes. Our cohort consisted of 28 PMZL, 14 primary diffuse large B-cell lymphomas (DLBCL) of the lung, 7 lymphomatoid granulomatoses (LyG), 5 mature small B-cell lymphomas and 16 cases of reactive lymphoid lesions. Mutations were detected in 22/28 evaluable PMZL (median 2 mutation/case); 14/14 DLBCL (median 3 mutations/case) and 4/7 LyG (1 mutation/case). PMZL showed higher prevalence for mutations in chromatin modifier-encoding genes (44% of mutant genes), while mutations in genes related to the NF-κB pathway were less common (24% of observed mutations). There was little overlap between mutations in PMZL and DLBCL. MALT1 rearrangements were more prevalent in PMZL than BCL10 aberrations, and both were absent in DLBCL. LyG were devoid of gene mutations associated with immune escape. The mutational landscape of PMZL differs from that of extranodal MZL of other locations and also from splenic MZL. Their landscape resembles more that of nodal MZL, which also show a predominance of mutations of chromatin modifiers. The different mutational composition of pulmonary DLBCL compared to PMZL suggests that the former probably do not present transformations. DLBCL bear more mutations/case and immune escape gene mutations compared to LyG, suggesting that EBV infection in LyG may substitute for mutations.

Stereotactic Vacuum-Assisted Breast Biopsy in Ductal Carcinoma in situ: Residual Microcalcifications and Intraoperative Findings.

PURPOSE: The question of overtreatment of ductal carcinoma in situ (DCIS) was raised because a significant proportion of especially low-grade DCIS lesions never progress to invasive cancer. The rationale for the present study was to analyze the value of stereotactic vacuum-assisted biopsy (VAB) for complete removal of DCIS, focusing on the relationship between the absence of residual microcalcifications after stereotactic VAB and the histopathological diagnosis of the definitive surgical specimen. PATIENTS AND METHODS: Data of 58 consecutive patients diagnosed with DCIS by stereotactic VAB in a single breast center between 2012 and 2017 were analyzed. Patient records from the hospital information system were retrieved, and mammogram reports and images as well as histopathology reports were evaluated. The extent of microcalcifications before and after biopsy as well as the occurrence of DCIS in biopsy and definitive surgical specimens were analyzed and correlated. RESULTS: There was no correlation between the absence of residual microcalcifications in the post-biopsy mammogram and the absence of residual DCIS in the final surgical specimen (p = 0.085). Upstaging to invasive cancer was recorded in 4 cases (13%) but occurred only in the group that had high-grade DCIS on biopsy. Low-grade DCIS was never upgraded to high-grade DCIS in the definitive specimen. CONCLUSIONS: The radiological absence of microcalcifications after stereotactic biopsy does not rule out residual DCIS in the final surgical specimen. Since upstaging to invasive cancer is seen in a substantial proportion of high-grade DCIS, the surgical excision of high-grade DCIS should remain the treatment of choice.

Can grating interferometry-based mammography discriminate benign from malignant microcalcifications in fresh biopsy samples?

PURPOSE: In addition to absorption imaging, grating interferometry-based mammography (GIM) is capable of detecting differential-phase and scattering signals. In particular, the scattering signal can enable a quantifiable characterization of breast lesions. The purpose of this study was to determine if suspicious microcalcifications associated with benign or malignant lesions can be discriminated based on their absorption and scattering properties. MATERIALS AND METHODS: In this prospective, ethically approved study, 62 patients (mean age 60 y, range 39-89) with suspicious microcalcifications, who underwent stereotactic biopsies, were included. Biopsies were measured with an experimental GIM device and the ratios of the scattering and absorption signal (R-value) for microcalcifications were calculated. The mean R-values for benign and malignant lesions associated with microcalcifications were compared with the final histopathological diagnosis using a t-test. RESULTS: Twenty of the 62 participants had microcalcifications associated with malignancy. Comparing the two largest histopathological sub-groups of fibrosis (n = 23) vs. ductal carcinoma in situ (n = 15) resulted in an average R-value of 4.08 for benign and 2.80 for malignant lesions; p = 0.07. All microcalcifications associated with malignancy had an R-value below 4.71. Excluding microcalcifications with an R-value above this threshold would result in an 11 % reduction of false positives. CONCLUSION: The novel GIM modality has the potential to non-invasively characterize microcalcifications and might aid in the discrimination of benign from malignant lesions in fresh biopsy samples.

Correction to: Towards clinical grating-interferometry mammography.

The article Towards clinical grating-interferometry mammography, written by Carolina Arboleda, Zhentian Wang, Konstantins Jefimovs, Thomas Koehler, Udo Van Stevendaal, Norbert Kuhn, Bernd David, Sven Prevrhal, Kristina Lång, Serafino Forte, Rahel Antonia Kubik-Huch, Cornelia Leo.

Towards clinical grating-interferometry mammography.

OBJECTIVES: Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, as several research works have demonstrated in a pre-clinical setting, since it is able to provide attenuation, differential phase contrast, and scattering images simultaneously. In order to translate this technique to the clinics, it has to be adapted to cover a large field-of-view within a clinically acceptable exposure time and radiation dose. METHODS: We set up a grating interferometer that fits into a standard mammography system and fulfilled the aforementioned conditions. Here, we present the first mastectomy images acquired with this experimental device. RESULTS AND CONCLUSION: Our system performs at a mean glandular dose of 1.6 mGy for a 5-cm-thick, 18%-dense breast, and a field-of-view of 26 × 21 cm2. It seems to be well-suited as basis for a clinical-environment device. Further, dark-field signals seem to support an improved lesion visualization. Evidently, the effective impact of such indications must be evaluated and quantified within the context of a proper reader study. KEY POINTS: • Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, since it is sensitive to refraction and scattering and thus provides additional tissue information. • The most straightforward way to do grating-interferometry in the clinics is to modify a standard mammography device. • In a first approximation, the doses given with this technique seem to be similar to those of conventional mammography.

Interobserver variability and likelihood of malignancy for fifth edition BI-RADS MRI descriptors in non-mass breast lesions.

OBJECTIVE: Non-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 METHODS: Breast 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. RESULTS: Seventy-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). CONCLUSION: There 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.

High density of CD66b in primary high-grade ovarian cancer independently predicts response to chemotherapy.

PURPOSE: Ovarian 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. METHODS: A 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. RESULTS: High 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. CONCLUSION: High CD66b neutrophil density in primary high-grade OC predicts good response to initial chemotherapy and longer recurrence-free survival independent of known risk factors.

PD-L1 testing of non-small cell lung cancer using different antibodies and platforms: a Swiss cross-validation study.

With the approval of pembrolizumab for first- and second-line treatment of PD-L1+ non-small cell lung cancer (NSCLC), PD-L1 testing by immunohistochemistry (IHC) has become a necessity. However, the DAKO autostainer ASL48 for the FDA approved DAKO 22C3 pharmDx assay is not broadly available in Switzerland and other parts of Europe. The primary goal of this study was to cross-validate the 22C3 anti-PD-L1 antibody on Benchmark Ultra (VBMU) and Leica Bond (LBO) immunostainers. IHC protocols were developed for 22C3 on both platforms with the 22C3phDx using ASL48 as reference. A tissue microarray (TMA) was constructed from 23 NSCLC specimens with a range of PD-L1 staining results. Empty TMA sections and the 22C3 antibody were distributed to 16 participants for staining on VBMU (8 centers) and/or LBO (12 centers) using the centrally developed protocols. Additionally the performance of the Ventana SP263 assay was tested in five centers. IHC scoring was performed centrally. Categorical PD-L1 staining (0-49% vs. 50-100%) did not significantly differ between centers using VBMU, whereas data from LBO were highly variable (p < 0.001). The SP263 assay was well concordant with 22C3 on VBMU and with 22C3 pharmDx. PD-L1 IHC using a standardized 22C3 protocol on VBMU provides satisfactory results in most centers. The SP263 assay is confirmed as a valid alternative to 22C3 pharmDx. 22C3 PD-L1 IHC on LBO shows major staining variability between centers, highlighting the need for local validation and adjustment of protocols.

ALK-negative anaplastic large cell lymphoma arising in the thrombus of an aortic prosthesis preceeded by clonally related lymphomatoid papulosis.

We report on a 73-year-old male patient with recurrent thrombosis of his infrarenal aortic prosthesis. Histologically, the thrombus contained cells of an ALK-negative anaplastic large cell T cell lymphoma (ALCL). Imaging studies were negative for other lymphoma manifestations; however, 3 months before, the patient had developed skin lesions consistent with lymphomatoid papulosis type A (LypA) which were clonally related to the ALCL. Due to recurrent thrombosis of larger peripheral arteries with the presence of ALCL cells in the thrombi, the patient is now referred to systemic chemotherapy. We present the first case of ALCL manifesting in the thrombus of an aortic prosthesis. This case shows similarities to the well-established entity of breast implant-associated ALCL and anecdotal reports of ALCL occurring at the site of foreign material implants. These cells show a peculiar propensity to aggregate in vessels and thrombi, known primarily from subtypes of diffuse large B cell lymphomas associated with chronic inflammation.