Myoid gonadal stromal tumor of the testis-the novel subtype of testicular gonadal stromal tumors: a case report and review of the literature.

BACKGROUND: Sex cord gonadal stromal tumors compose less than 10% of all testicular neoplasms and consist of a variety of histological subtypes. In 2016, the World Health Organization introduced a novel subtype, the myoid gonadal stromal tumor, that consists of spindle-shaped cells with immunohistologic features of muscle cells. Only few cases have been reported to date. Due to its rarity and owing to its only recent introduction, the current knowledge about myoid gonadal stromal tumor is limited, and particularly, appropriate clinical management is still ill-defined. CASE PRESENTATION: A 47-year-old man of Caucasian descent presented with nonspecific scrotal discomfort. A roundish and well demarcated hypoechoic mass of 8.5 mm in diameter was detected in the cranial region of the left testis. Serum tumor marker levels were within normal ranges. Testis-sparing surgery revealed a 9-mm whitish, hard mass with sharp surgical margin. Histologically, the neoplasm consisted of microfibrillar tissue with spindle-shaped cells harboring elongated nuclei. Immunohistochemical work-up disclosed expression of desmin, small muscle actin, and S100 protein giving evidence for the myogenic nature of the neoplastic cells. There was no indication of malignancy, neither histologically nor clinically. Follow-up of 1 year was uneventful. CONCLUSION: A literature survey revealed 22 previous cases of myoid gonadal stromal tumor. The median age was 37 years, the median size of the neoplasm was 20 mm, and there was no side-preponderance. Myoid gonadal stromal tumor is not much different from other subtypes of gonadal stromal tumors nor from testicular gem cell tumors regarding age and laterality; however, tumor size is smaller in myoid gonadal stromal tumors than in germ cell tumors. Although rarely performed so far, testis-sparing surgery probably constitutes an appropriate treatment of this neoplasm. Myoid gonadal stromal tumor represents an emerging novel entity of benign testicular new growths that caregivers of patients with testicular tumors should be aware of.

Unilateral, Small, Benign, Late-Onset, Large-Cell Calcifying Sertoli Cell Tumor: A Case Report.

Large-cell calcifying Sertoli cell tumor (LCCST) is a rare, testicular sex cord, gonadal stromal tumor that belongs to the histological subgroup of Sertoli cell tumors. LCCSTs may involve malignant potential. However, metastasis is a rare phenomenon. We describe a case of benign late-onset LCCST with testis-sparing surgery. Modern imaging techniques were useful for considering organ-sparing surgery. The ultrasound of a 37-year-old man disclosed a sharp demarcated and strong hyper-echoic lesion sized 1.5 cm, with broad dorsal acoustic shadowing. Testicular tumor markers, including lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and Beta-human chorionic gonadotropin (ß-HCG) did not reveal any pathological finding. Contrast-enhanced MRI of the pelvis showed a ring-shaped tumor with a strong contrast medium enhancement. Sections of the tumor showed a hard mass with a white calcified ring. A frozen section examination of the testicular tumor did not indicate malignancy. Histologic examination revealed a prominent and noticeable calcification of approximately 3 mm thickness. Tumor cells presented in the form of solid nests, tubules, and cords. Our present case differs from previously reported LCCST cases because the tumor was unilateral, smaller in size, and presented in an older patient.

Data infrastructures for AI in medical imaging: a report on the experiences of five EU projects.

Artificial intelligence (AI) is transforming the field of medical imaging and has the potential to bring medicine from the era of 'sick-care' to the era of healthcare and prevention. The development of AI requires access to large, complete, and harmonized real-world datasets, representative of the population, and disease diversity. However, to date, efforts are fragmented, based on single-institution, size-limited, and annotation-limited datasets. Available public datasets (e.g., The Cancer Imaging Archive, TCIA, USA) are limited in scope, making model generalizability really difficult. In this direction, five European Union projects are currently working on the development of big data infrastructures that will enable European, ethically and General Data Protection Regulation-compliant, quality-controlled, cancer-related, medical imaging platforms, in which both large-scale data and AI algorithms will coexist. The vision is to create sustainable AI cloud-based platforms for the development, implementation, verification, and validation of trustable, usable, and reliable AI models for addressing specific unmet needs regarding cancer care provision. In this paper, we present an overview of the development efforts highlighting challenges and approaches selected providing valuable feedback to future attempts in the area.Key points• Artificial intelligence models for health imaging require access to large amounts of harmonized imaging data and metadata.• Main infrastructures adopted either collect centrally anonymized data or enable access to pseudonymized distributed data.• Developing a common data model for storing all relevant information is a challenge.• Trust of data providers in data sharing initiatives is essential.• An online European Union meta-tool-repository is a necessity minimizing effort duplication for the various projects in the area.

Cellular dissociation grading on biopsies of pulmonary squamous cell carcinoma provides prognostic information across all stages and is congruent with resection specimen grading.

Grading of squamous cell carcinomas (SCCs) based on tumour budding and cell nest size has been termed cellular dissociation grading (CDG) and was suggested as a robust outcome predictor when assessed in biopsies and resections of various extrapulmonary SCCs. In pulmonary SCC (pSCC), this has so far been shown only for resected cancers. As most lung cancers are inoperable, it is of utmost importance to clarify whether the prognostic impact of CDG is retained in the biopsy setting. Two independent pSCC biopsy cohorts from Munich (n = 134, non-resected) and Heidelberg (n = 135, resected) were assessed. Tumour budding and cell nest size measures were assembled into the three-tiered CDG system (G1-G3). Data were correlated with clinicopathological parameters and overall- (OS), disease-specific- (DSS), and disease-free survival (DFS). Interobserver variability and concordance between biopsy and resection specimen were also investigated. CDG was highly congruent between biopsy and resection specimens (κ = 0.77, p < 0.001). In both pSCC cohorts, biopsy-derived CDG strongly impacted on OS, DSS, and DFS (e.g. DFS: p < 0.001). In multivariate survival analyses, CDG remained a stage independent predictor of survival in both cohorts (DFS: p < 0.001 respectively; hazard ratio Munich cohort: CDG-G2: 4.31, CDG-G3; 5.14; Heidelberg cohort: CDG-G2: 5.87, CDG-G3: 9.07). Interobserver agreement for CDG was almost perfect (κ = 0.84, p < 0.001). We conclude that assessment of CDG based on tumour budding and cell nest size is feasible on pSCC biopsies and harbours stage independent prognostic information in resectable as well as non-resectable pSCC. Integration of this grading approach into clinicopathological routine should be considered.

Antiviral death punch by ADP-ribosylating bacterial toxins.

Toxin-antitoxin systems can defend bacteria against phages by shutting down infected cells, but the links between their molecular mechanisms and biological functions have remained underexplored. LeRoux et al. now show how the DNA-targeting ADP-ribosylation activity of DarTG impairs phage replication but is overcome by dedicated viral inhibitors and evolved tolerance.

Conventional and semi-automatic histopathological analysis of tumor cell content for multigene sequencing of lung adenocarcinoma.

BACKGROUND: Targeted genetic profiling of tissue samples is paramount to detect druggable genetic aberrations in patients with non-squamous non-small cell lung cancer (NSCLC). Accurate upfront estimation of tumor cell content (TCC) is a crucial pre-analytical step for reliable testing and to avoid false-negative results. As of now, TCC is usually estimated on hematoxylin-eosin (H&E) stained tissue sections by a pathologist, a methodology that may be prone to substantial intra- and interobserver variability. Here we the investigate suitability of digital pathology for TCC estimation in a clinical setting by evaluating the concordance between semi-automatic and conventional TCC quantification. METHODS: TCC was analyzed in 120 H&E and thyroid transcription factor 1 (TTF-1) stained high-resolution images by 19 participants with different levels of pathological expertise as well as by applying two semi-automatic digital pathology image analysis tools (HALO and QuPath). RESULTS: Agreement of TCC estimations [intra-class correlation coefficients (ICC)] between the two software tools (H&E: 0.87; TTF-1: 0.93) was higher compared to that between conventional observers (0.48; 0.47). Digital TCC estimations were in good agreement with the average of human TCC estimations (0.78; 0.96). Conventional TCC estimators tended to overestimate TCC, especially in H&E stainings, in tumors with solid patterns and in tumors with an actual TCC close to 50%. CONCLUSIONS: Our results determine factors that influence TCC estimation. Computer-assisted analysis can improve the accuracy of TCC estimates prior to molecular diagnostic workflows. In addition, we provide a free web application to support self-training and quality improvement initiatives at other institutions.

Effect of moderate elevated intra-abdominal pressure on lung mechanics and histological lung injury at different positive end-expiratory pressures.

INTRODUCTION: Intra-abdominal hypertension (IAH) is a well-known phenomenon in critically ill patients. Effects of a moderately elevated intra-abdominal pressure (IAP) on lung mechanics are still not fully analyzed. Moreover, the optimal positive end-expiratory pressure (PEEP) in elevated IAP is unclear. METHODS: We investigated changes in lung mechanics and transformation in histological lung patterns using three different PEEP levels in eighteen deeply anesthetized pigs with an IAP of 10 mmHg. After establishing the intra-abdominal pressure, we randomized the animals into 3 groups. Each of n = 6 (Group A = PEEP 5, B = PEEP 10 and C = PEEP 15 cmH2O). End-expiratory lung volume (EELV/kg body weight (bw)), pulmonary compliance (Cstat), driving pressure (ΔP) and transpulmonary pressure (ΔPL) were measured for 6 hours. Additionally, the histological lung injury score was calculated. RESULTS: Comparing hours 0 and 6 in group A, there was a decrease of EELV/kg (27±2 vs. 16±1 ml/kg; p<0.05) and of Cstat (42±2 vs. 27±1 ml/cmH2O; p<0.05) and an increase of ΔP (11±0 vs. 17±1 cmH2O; p<0.05) and ΔPL (6±0 vs. 10±1 cmH2O; p<0.05). In group B, there was no significant change in EELV/kg (27±3 vs. 24±3 ml/kg), but a decrease in Cstat (42±3 vs. 32±1 ml/cmH20; p<0.05) and an increase in ΔP (11±1 vs. 15±1 cmH2O; p<0.05) and ΔPL (5±1 vs. 7±0 cmH2O; p<0.05). In group C, there were no significant changes in EELV/kg (27±2 vs. 29±3 ml/kg), ΔP (10±1 vs. 12±1 cmH2O) and ΔPL (5±1 vs. 7±1 cmH2O), but a significant decrease of Cstat (43±1 vs. 37±1 ml/cmH2O; p<0.05). Histological lung injury score was lowest in group B. CONCLUSIONS: A moderate elevated IAP of 10 mmHg leads to relevant changes in lung mechanics during mechanical ventilation. In our study, a PEEP of 10 cmH2O was associated with a lower lung injury score and was able to overcome the IAP induced alterations of EELV.

A Bartonella Effector Acts as Signaling Hub for Intrinsic STAT3 Activation to Trigger Anti-inflammatory Responses.

Chronically infecting pathogens avoid clearance by the innate immune system by promoting premature transition from an initial pro-inflammatory response toward an anti-inflammatory tissue-repair response. STAT3, a central regulator of inflammation, controls this transition and thus is targeted by numerous chronic pathogens. Here, we show that BepD, an effector of the chronic bacterial pathogen Bartonella henselae targeted to infected host cells, establishes an exceptional pathway for canonical STAT3 activation, thereby impairing secretion of pro-inflammatory TNF-α and stimulating secretion of anti-inflammatory IL-10. Tyrosine phosphorylation of EPIYA-related motifs in BepD facilitates STAT3 binding and activation via c-Abl-dependent phosphorylation of Y705. The tyrosine-phosphorylated scaffold of BepD thus represents a signaling hub for intrinsic STAT3 activation that is independent from canonical STAT3 activation via transmembrane receptor-associated Janus kinases. We anticipate that our findings on a molecular shortcut to STAT3 activation will inspire new treatment options for chronic infections and inflammatory diseases.

Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts.

BACKGROUND: Tumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB. METHODS: TMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients. RESULTS: On average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node-derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound. CONCLUSIONS: Our data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample-based TMB estimations in a clinical context.

Variant classification in precision oncology.

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.

NUT carcinoma in a nutshell: A diagnosis to be considered more frequently.

NUT carcinoma is a rarely diagnosed, poorly differentiated subtype of squamous cell carcinoma, defined by chromosomal rearrangements of the gene encoding nuclear protein of the testis (NUT). It is characterized by extremely aggressive clinical behavior resulting in a dismal prognosis, with a median survival of 6.7 months. Though most frequently detected along the body midline, NUT carcinoma can arise in any organ. Fewer than 100 cases have been reported in medical literature with the majority of patients being children or young adults. Here we present a case of sinonasal NUT in a 48-year-old male who came to our hospital due to progressive cephalalgia. Radiographically, an irregular mass in the left sphenoidal sinus suspicious for a malignant process was detected, and biopsies were taken. Histopathologically, a tumor of highly mitotic, predominantly small to middle-sized cells with a focal abrupt transition to mature-appearing, squamous epithelium was noted. Of critical importance for the diagnosis, the undifferentiated tumor cell population robustly expressed NUT. The diagnosis of NUT carcinoma was confirmed by the identification of BRD4-NUT fusion. This case integrates typical morphological, immunohistochemical and molecular characteristics of NUT carcinoma and highlights the need to consider this entity in cases of poorly differentiated squamous carcinoma.

Agreement of CK5/6, p40, and p63 immunoreactivity in non-small cell lung cancer.

Histological subtyping of non-small cell lung cancer (NSCLC) is of utmost importance for therapy stratification. Common immunohistochemical markers to identify squamous lineage are CK5/6, p40, and p63. Although p40 is considered the gold standard by current guidelines, the agreement of all three markers is an important aspect for tumours more difficult to classify. A total of 1244 NSCLC including 569 squamous cell carcinomas (SqCC) and 675 adenocarcinomas were assembled on a tissue microarray and stained with CK5/6, p40, p63, TTF-1, and Napsin-A. Sensitivity and specificity for squamous lineage markers as well as agreement of CK5/6, p40 and p63 were calculated. Sensitivity of CK5/6, p40, and p63 for SqCC was 93%, 94%, and 94% and specificity was 98%, 97%, and 84%, respectively. Positivity for two of these markers was found in at least in 90% of SqCC. Highest agreement was observed for p40 and p63 (Cohen's kappa 0.80). We report a similar sensitivity of CK5/6, p40, and p63, but a decreased specificity of p63 as compared to CK5/6 and p40 for the identification of squamous lineage. Our results support the use of either CK5/6 or p40 over p63 in the routine diagnostic setting.

Combined Immunohistochemistry after Mass Spectrometry Imaging for Superior Spatial Information.

OBJECTIVE: Tissue slides analyzed by MS imaging (MSI) are stained by H&E (Haematoxylin and Eosin) to identify regions of interest. As it can be difficult to identify specific cells of interest by H&E alone, data analysis may be impaired. Immunohistochemistry (IHC) can highlight cells of interest but single or combined IHC on tissue sections analyzed by MSI have not been performed. METHODS: We performed MSI on bone marrow biopsies from patients with multiple myeloma and stained different antibodies (CD38, CD138, MUM1, kappa- and lambda). A combination of CK5/6/TTF1 and Napsin-A/p40 is stained after MSI on adenocarcinoma and squamous cell carcinoma of the lung. Staining intensities of p40 after MSI and on a serial section are quantified on a tissue microarray (n = 44) by digital analysis. RESULTS: Digital evaluation reveals weaker staining intensities after MSI as compared to serial sections. Staining quality and quantity after MSI enables to identify cells of interest. On the tissue microarray, one out of 44 tissue specimens shows no staining of p40 after MSI, but weak nuclear staining on a serial section. CONCLUSION: We demonstrated that single and double IHC staining is feasible on tissue sections previously analyzed by MSI, with decreased staining intensities.

Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas.

Lung adenocarcinoma (ADC) is the most prevalent subtype of lung cancer and characterized by considerable morphological and mutational heterogeneity. However, little is known about the epigenomic intratumor variability between spatially separated histological growth patterns of ADC. In order to reconstruct the clonal evolution of histomorphological patterns, we performed global DNA methylation profiling of 27 primary tumor regions, seven matched normal tissues and six lymph node metastases from seven ADC cases. Additionally, we investigated the methylation data from 369 samples of the TCGA ADC cohort. All regions showed varying degrees of methylation changes between segments of different, but also of the same growth patterns. Similarly, copy number variations were seen between spatially distinct segments of each patient. Hierarchical clustering of promoter methylation revealed extensive heterogeneity within and between the cases. Intratumor DNA methylation heterogeneity demonstrated a branched clonal evolution of ADC regions driven by genomic instability with subclonal copy number changes. Notably, methylation profiles within tumors were not more similar to each other than to those from other individuals. In two cases, different tumor regions of the same individuals were represented in distant clusters of the TCGA cohort, illustrating the extensive epigenomic intratumor heterogeneity of ADCs. We found no evidence for the lymph node metastases to be derived from a common growth pattern. Instead, they had evolved early and separately from a particular pattern in each primary tumor. Our results suggest that extensive variation of epigenomic features contributes to the molecular and phenotypic heterogeneity of primary ADCs and lymph node metastases.

Subclonal evolution of pulmonary adenocarcinomas delineated by spatially distributed somatic mitochondrial mutations.

OBJECTIVES: The potential role of cancer associated somatic mutations of the mitochondrial genome (mtDNA) is controversial and still poorly understood. Our group and others recently challenged a direct tumorigenic impact and suggested a passenger-like character. In combination with the known increased mutation rate, somatic mtDNA mutations account for an interesting tool to delineate tumor evolution. Here, we comprehensively analyzed the spatial distribution of somatic mtDNA mutations throughout whole tumor sections of pulmonary adenocarcinoma (ADC). MATERIALS AND METHODS: Central sections of 19 ADC were analyzed in a segmented manner (11-34 segments/tumor) together with non-neoplastic tissue samples and lymph node metastasis, if present. We performed whole mtDNA sequencing and real-time PCR based quantification of mtDNA copy numbers for all samples. Further, histological growth patterns were determined on H&E sections and the tumor cell content was quantified by digital pathology analyses. RESULTS: Somatic mtDNA mutations were present in 96% (18/19) of the analyzed tumors, either ubiquitously or restricted to specific tumor regions. Spatial and histological mapping of the mutations enabled the identification of subclonal structures and phylogenetic relations within a tumor section indicating different progression levels. In this regard, lymph node metastases seem to be related to early events in ADC development. There was no concurrence between histological and mtDNA mutation based clusters. However, micropapillary patterns occurred only in tumors with ubiquitous mutations. ADC with more than two ubiquitous mutations were associated with shorter disease-free survival (p < 0.01). CONCLUSION: Cancer related mtDNA mutations are interesting candidates for the understanding of subclonal ADC evolution and perspectively for monitoring tumor progression. Our data reveal a potential prognostic relevance of somatic mtDNA mutations.

Expression of HMB45, MelanA and SOX10 is rare in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) and melanoma are frequent entities in routine diagnostics. Whereas the differential diagnosis is usually straight forward based on histomorphology, it can be challenging in poorly differentiated tumors as melanoma may mimic various histological patterns. Distinction of the two entities is of outmost importance as both are treated differently. HMB45 and MelanA are recommended immunohistological markers for melanoma in this scenario. SOX10 has been described as an additional marker for melanoma. However, comprehensive large-scale data about the expression of melanoma markers in NSCLC tumor tissue specimen are lacking so far. METHODS: Therefore, we analyzed the expression of these markers in 1085 NSCLC tumor tissue samples. Tissue microarrays of NSCLC cases were immunohistochemically stained for HMB45, MelanA, and SOX10. Positivity of a marker was defined as ≥1% positive tumor cells. RESULTS: In 1027 NSCLC tumor tissue samples all melanoma as well as conventional immunohistochemical markers for NSCLC could be evaluated. HMB45, MelanA, and SOX10 were positive in 1 (< 1%), 0 (0%) and 5 (< 1%) cases. The HMB45 positive case showed co-expression of SOX10 and was classified as large cell carcinoma. Three out of five SOX10 positive cases were SqCC and one case was an adenosquamous carcinoma. CONCLUSIONS: Expression of HMB45, MelanA and SOX10 is evident but exceedingly rare in NSCLC cases. Together with conventional immunomarkers a respective marker panel allows a clear-cut differential diagnosis even in poorly differentiated tumors.

Molecular dissection of large cell carcinomas of the lung with null immunophenotype.

The aim of this study was to subcategorise large cell carcinoma (LCC) with null immunophenotype according to the World Health Organization (WHO) Classification of 2015 into the existing groups of adenocarcinoma and squamous cell carcinoma by further molecular genetic analysis. Lineage-specific molecular alterations of these tumours could depict additional therapeutic approaches. We analysed a cohort of 35 LCC diagnosed according to the 2004 WHO classification and reclassified them according to the criteria of the 2015 WHO classification. Subsequently, tumours with a null immunophenotype were analysed by targeted next generation sequencing (42 marker genes including TP53, EGFR, KRAS, STK11 and SMARC4A) and fluorescence in situ hybridisation (ROS1, ALK). By applying the criteria of the 2015 WHO classification and subsequent molecular subtyping we could show that out of 35 previously diagnosed LCC, 16 cases could be reclassified into specific NSCLC subtypes using immunohistochemistry. Additionally, based on their mutational pattern, eight of the remaining 19 cases with null immunophenotype could be assigned as 'favour adenocarcinoma'. We demonstrate that molecular subtyping is helpful to further categorise LCC with null immunophenotype. Our findings argue for an algorithm including stratified molecular analysis of all respective cases.

Computed tomography and histopathological findings after embolization with inherently radiopaque 40µm-microspheres, standard 40µm-microspheres and iodized oil in a porcine liver model.

PURPOSE: The present study compared standard computed tomography (CT) and histopathological findings after endovascular embolization using a prototype of inherently radiopaque 40µm-microspheres with both standard 40µm-microspheres and iodized oil in a porcine liver model. MATERIALS AND METHODS: Twelve pigs were divided into six study groups, of two pigs each. Four pigs were embolized with iodized oil alone and four with radiopaque microspheres; two animals in each group were sacrificed at 2 hours and two at 7 days. Two pigs were embolized with radiopaque microspheres and heparin and sacrificed at 7 days. Two pigs were embolized with standard microspheres and sacrificed at 2 hours. CT was performed before and after segmental embolization and before sacrifice at 7 days. The distribution of embolic agent, inflammatory response and tissue necrosis were assessed histopathologically. RESULTS: Radiopaque microspheres and iodized oil were visible on standard CT 2 hours and 7 days after embolization, showing qualitatively comparable arterial and parenchymal enhancement. Quantitatively, the enhancement was more intense for iodized oil. Standard microspheres, delivered without contrast, were not visible by imaging. Radiopaque and standard microspheres similarly occluded subsegmental and interlobular arteries and, to a lesser extent, sinusoids. Iodized oil resulted in the deepest penetration into sinusoids. Necrosis was always observed after embolization with microspheres, but never after embolization with iodized oil. The inflammatory response was mild to moderate for microspheres and moderate to severe for iodized oil. CONCLUSION: Radiopaque 40µm-microspheres are visible on standard CT with qualitatively similar but quantitatively less intense enhancement compared to iodized oil, and with a tendency towards less of an inflammatory reaction than iodized oil. These microspheres also result in tissue necrosis, which was not observed after embolization with iodized oil. Both radiopaque and standard 40µm-microspheres are found within subsegmental and interlobar arteries, as well as in hepatic sinusoids.

Impact of Computer-Aided CT and PET Analysis on Non-invasive T Staging in Patients with Lung Cancer and Atelectasis.

PURPOSE: Tumor delineation within an atelectasis in lung cancer patients is not always accurate. When T staging is done by integrated 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG)-positron emission tomography (PET)/X-ray computer tomography (CT), tumors of neuroendocrine differentiation and slowly growing tumors can present with reduced FDG uptake, thus aggravating an exact T staging. In order to further exhaust information derived from [18F]FDG-PET/CT, we evaluated the impact of CT density and maximum standardized uptake value (SUVmax) for the classification of different tumor subtypes within a surrounding atelectasis, as well as possible cutoff values for the differentiation between the primary tumor and atelectatic lung tissue. PROCEDURES: Seventy-two patients with histologically proven lung cancer and adjacent atelectasis were investigated. Non-contrast-enhanced [18F]FDG-PET/CT was performed within 2 weeks before surgery/biopsy. Boundaries of the primary within the atelectasis were determined visually on the basis of [18F]FDG uptake; CT density was quantified manually within each primary and each atelectasis. RESULTS: CT density of the primary (36.4 Hounsfield units (HU) ± 6.2) was significantly higher compared to that of atelectatic lung (24.3 HU ± 8.3; p < 0.01), irrespective of the histological subtype. The discrimination between different malignant tumors using density analysis failed. SUVmax was increased in squamous cell carcinomas compared to adenocarcinomas. Irrespective of the malignant subtype, a possible cutoff value of 24 HU may help to exclude the presence of a primary in lesions below 24 HU, whereas a density above a threshold of 40 HU can help to exclude atelectatic lung. CONCLUSION: Density measurements in patients with lung cancer and surrounding atelectasis may help to delineate the primary tumor, irrespective of the specific lung cancer subtype. This could improve T staging and radiation treatment planning (RTP) without additional application of a contrast agent in CT, or an additional magnetic resonance imaging (MRI), even in cases of lung tumors of neuroendocrine differentiation or in slowly growing tumors with less avidity to [18F]FDG.

Analysis of the proliferative activity in lung adenocarcinomas with specific driver mutations.

In the last decade it became evident that many lung adenocarcinomas (ADC) harbor key genetic alterations such as KRAS, EGFR or BRAF mutations as well as rearrangements of ROS1 or ALK that drive these tumors. In the present study we investigated whether different driver mutations of ADC result in different proliferation rates, which might have clinical impact, including resistance to therapy, recurrence and prognosis. We analyzed the proliferation index (PI) on full slides of surgically resected ADC (n = 230) with known genetic aberrations by means of immunohistochemistry and subsequent digital image analysis and correlated the results with clinicopathological variables including overall (OS) and disease free survival (DFS). We did not observe significant differences in OS or DFS regarding the KRAS or EGFR mutational status (P = 0.56). However, KRAS mutated ADC showed an increased PI compared to EGFR mutated ADC, and ADC with ALK translocations (P < 0.01). Subgroup analysis of EGFR mutated ADC showed a higher PI for tumors harboring a mutation in exon 18 and 20, compared to tumors with a mutation in exon 19 or 21. A PI of 11.5% was the best possible prognostic stratificator for OS (P = 0.01 in KRAS mutated and P < 0.01 in EGFR mutated ADC). In conclusion, the PI differs significantly among ADC with distinct driver mutations. This might explain the varying indications for a prognostic relevance of the PI observed in prior studies. Our study provides a basis for the establishment of a reliable and clinically meaningful PI threshold.