Multicenter Multireader Evaluation of an Artificial Intelligence-Based Attention Mapping System for the Detection of Prostate Cancer With Multiparametric MRI.

OBJECTIVE. The purpose of this study was to evaluate in a multicenter dataset the performance of an artificial intelligence (AI) detection system with attention mapping compared with multiparametric MRI (mpMRI) interpretation in the detection of prostate cancer. MATERIALS AND METHODS. MRI examinations from five institutions were included in this study and were evaluated by nine readers. In the first round, readers evaluated mpMRI studies using the Prostate Imaging Reporting and Data System version 2. After 4 weeks, images were again presented to readers along with the AI-based detection system output. Readers accepted or rejected lesions within four AI-generated attention map boxes. Additional lesions outside of boxes were excluded from detection and categorization. The performances of readers using the mpMRI-only and AI-assisted approaches were compared. RESULTS. The study population included 152 case patients and 84 control patients with 274 pathologically proven cancer lesions. The lesion-based AUC was 74.9% for MRI and 77.5% for AI with no significant difference (p = 0.095). The sensitivity for overall detection of cancer lesions was higher for AI than for mpMRI but did not reach statistical significance (57.4% vs 53.6%, p = 0.073). However, for transition zone lesions, sensitivity was higher for AI than for MRI (61.8% vs 50.8%, p = 0.001). Reading time was longer for AI than for MRI (4.66 vs 4.03 minutes, p < 0.001). There was moderate interreader agreement for AI and MRI with no significant difference (58.7% vs 58.5%, p = 0.966). CONCLUSION. Overall sensitivity was only minimally improved by use of the AI system. Significant improvement was achieved, however, in the detection of transition zone lesions with use of the AI system at the cost of a mean of 40 seconds of additional reading time.

Interreader agreement of PI-RADS v. 2 in assessing prostate cancer with multiparametric MRI: A study using whole-mount histology as the standard of reference.

BACKGROUND: Most studies assessing interreader agreement of Prostate Imaging Reporting and Data System v. 2 (PI-RADS v2) have used biopsy as the standard of reference, thus carrying the risk of not definitively noting all existent cancers. PURPOSE: To evaluate the interreader agreement in assessing prostate cancer (PCa) of PI-RADS v2, using whole-mount histology as the standard of reference. STUDY TYPE: Monocentric prospective cohort study. POPULATION: In all, 48 patients with biopsy-proven PCa referred for radical prostatectomy, undergoing staging multiparametric magnetic resonance imaging (mpMRI) between May 2016 to February 2017. FIELD STRENGTH/SEQUENCE: 3.0T system using high-resolution T2 -weighted imaging, diffusion-weighted imaging (echo-planar imaging with maximum b-value 2000 sec/mm2 ), and dynamic contrast-enhanced imaging (T1 -weighted high resolution isotropic volume examination; THRIVE) ASSESSMENT: Three radiologists blinded to final histology (2-8 years of experience) analyzed mpMRI images independently, scoring imaging findings in accordance with PI-RADS v2. On a per-lesion basis, we calculated overall and pairwise interreader agreement in assigning PI-RADS categories, as well as assessing malignancy with categories ≥3 or ≥4, and stage ≥pT3. STATISTICAL TESTS: Cohen's kappa analysis of agreement. RESULTS: On 71 lesions found on histology, there was moderate agreement in assigning PI-RADS categories to all cancers (k = 0.53) and clinically significant cancers (csPCa) (k = 0.47). Assessing csPCa with PI-RADS ≥4 cutoff provided higher agreement than PI-RADS ≥3 cutoff (k = 0.63 vs. 0.57). Interreader agreement was higher between more experienced readers, with the most experienced one achieving the highest cancer detection rate (0.73 for csPCa using category ≥4). There was substantial agreement in assessing stage ≥pT3 (k = 0.72). DATA CONCLUSION: We found moderate to substantial agreement in assigning the PI-RADS v2 categories and assessing the spectrum of cancers found on whole-mount histology, with category 4 as the most reproducible cutoff for csPCa. Readers' experience influenced interreader agreement and cancer detection rate. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:546-555.

Surgical Treatment of Eosinophilic Cystitis in Adults: A Report of Two Cases and a Literature Review.

Eosinophilic cystitis is a rare disease that presents with either urinary frequency, hematuria, suprapubic pain or urinary retention. Although benign, this entity may progress to diffuse bladder involvement with the need for surgical treatment. We report on 2 cases of advanced disease that required cystectomy with very complex lower urinary tract reconstruction, and review the literature of surgically treated cases.

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma.

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.

Lipophyllodes of the breast. A reappraisal of fat-rich tumors of the breast based on 22 cases integrated by immunohistochemical study, molecular pathology insights, and clinical follow-up.

We have studied 22 cases of mammary lipophyllodes tumors (LPT), analyzing their clinicopathologic features along with available follow-up. All cases were tested for cytokeratins, S100 protein, and MDM2, and in selected cases for estrogen receptor, smooth muscle actin, bcl2, desmin, and myogenin. Patients were women aged 21 to 69 years (average, 45 years), and LPT size ranged from 1.6 to 30 cm (average, 9.7 cm). Microscopically, LPT segregated as follows: atypical lipoma-like tumor/well-differentiated liposarcoma (ALT/WDL), 8 cases; myxoid, 6; and pleomorphic/poorly differentiated/round cell, 8, including a case of dedifferentiated liposarcoma. Immunohistochemistry studies showed focal positive staining for S100 and CD34 in most ALT/WDL, and desmin and myogenin in 2 cases with evidence of rhabdomyoblastic differentiation. MDM2 positivity was focally seen in 1 case. Follow-up was available in 8 cases. Multiple recurrent tumors were seen in 2 patients, and metastatic disease to the lung was seen in 2 patients. In 4 patients with a follow-up between 2 and 15 years there was no evidence of recurrent or metastatic disease. Patients with ALT/WDL (2/2) were alive with no evidence of disease; 2 of 4 patients with myxoid liposarcoma component experienced tumor recurrence, whereas pleomorphic liposarcoma LPT pursued a less favorable course although only 1 patient died of the condition. Absence of MDM2 reactivity in most cases seems not as meaningful as in fatty tumors of somatic soft parts.

c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas.

Genomic amplification of the c-Jun proto-oncogene has been identified in ∼30% of dedifferentiated liposarcomas (DDLPS), but the functional contribution of c-Jun to the progression of DDLPS remains poorly understood. In previous work we showed that knock-down of c-Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line (LP6) with genomic amplification of the c-Jun locus. Here, we used gene expression analysis and functional studies in a broad panel of cell lines to further define the role of c-Jun in DDLPS and other soft tissue sarcomas. We show that c-Jun knock-down impairs transition through the G1 phase of the cell cycle in multiple DDLPS cell lines. We also found that high levels of c-Jun expression are both necessary and sufficient to promote DDLPS cell migration and invasion in vitro. Our data suggest that high levels of c-Jun enhance motility in part by driving the expression of ENPP2/Autotaxin. c-Jun over-expression has minimal effects on in vitro proliferation but substantially enhances the in vivo growth of weakly tumourigenic DDLPS cell lines. Finally, we provide evidence that c-Jun genomic amplification and over-expression may have similar functional consequences in other types of soft tissue sarcoma. Our data suggest a model in which relatively low levels of c-Jun are sufficient for in vitro proliferation, but high levels of c-Jun enhance invasiveness and capacity for in vivo tumour growth. These observations provide an explanation for the selective advantage provided by c-Jun genomic amplification in vivo and suggest that sarcomas with elevated c-Jun levels are likely to have a particularly high malignant potential. Data from exon array and RNA-Seq experiments have been deposited in the GEO database (Accession No. GSE57531).

Susceptibility to Helicobacter pylori infection: results of an epidemiological investigation among gastric cancer patients.

The aim of this study was to identify the clinical, demographic, lifestyle factors and selected genetic polymorphisms that affect the susceptibility towards Helicobacter pylori (H. pylori) infection in gastric cancer patients. Histological confirmed gastric adenocarcinoma cases that underwent curative gastrectomy between 2002 and 2012 were included. Gastric biopsy samples were obtained to determine the H. pylori status, and further cagA status and vacA m and s genotypes by polymerase chain reaction. Patients were interviewed with structured questionnaires, and blood samples were collected for EPHX1, GSTM1, GSTT1, IL1B, IL1-RN, MTHFR and p53 genotyping. Proportions were compared in univariate analysis, while the relation between putative risk factors and H. pylori status and genotype were measured using logistic regression analysis. One hundred forty-nine gastric cancer patients were included, of which 78.5% were H. pylori positive. Among positive patients 50% were cagA+, 72.5% vacA m1 and 80.7% vacA s1. The presence of cagA was less frequent among vacA m1 (p = 0.031) and vacA s1 (p = 0.052) subtypes. The presence of father history for any cancer was a significant risk factor for H. pylori infection [adjusted odds ratio (OR) = 8.18, 95% confidence interval (CI) 1.04-64.55]. EPHX1 exon 3 T > C (OR = 0.35, CI 95% 0.13-0.94), IL1B-511 T > C (OR = 0.38, CI 95% 0.15-0.97) and IL1-RN VNTR (OR = 0.19, CI 95% 0.06-0.58) polymorphisms were protective towards H. pylori infection in the univariate analysis. Wine consumption was associated with higher risk of carrying the H. pylori vacA m1 virulent subtype (p = 0.034). Lastly, cardiovascular diseases were less common among cagA positive subjects (p = 0.023). Father history of any cancer is a risk factor for H. pylori infection. Polymorphisms in IL1B-511, IL1-RN and EPHX1 exon 3 genes might be protective towards H. pylori infection.

Aberrant AKT activation drives well-differentiated liposarcoma.

Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.

Well-differentiated and dedifferentiated liposarcomas with prominent myxoid stroma: analysis of 56 cases.

AIMS: Occasional cases of well-differentiated and dedifferentiated liposarcoma (LPS) contain myxoid stroma, leading to confusion with other sarcomas. The aim of this study was to analyse the clinicopathological and genetic features of well-differentiated/dedifferentiated LPS with prominent myxoid stroma. METHODS AND RESULTS: Fifty-six cases of LPS (22 well-differentiated; 34 dedifferentiated) with prominent myxoid stroma were evaluated. Most arose in the retroperitoneum, abdominal cavity, or spermatic cord. The mean size was 170 mm. Myxoid LPS-like plexiform vessels were conspicuous in 11 cases of well-differentiated LPS. In 22 cases of dedifferentiated LPS, myxofibrosarcoma-like curvilinear vessels were prominent. In other cases, the myxoid component had variably bland or pleomorphic morphology. By immunohistochemistry, staining for MDM2 was positive in 95% of cases, and CDK4 in 78%. Cytogenetics in 13 cases showed ring and giant marker chromosomes. Fluorescence in-situ hybridization showed amplification of 12q13-15 in six cases evaluated. Of 30 patients with follow-up, all but one had local recurrences (up to four), but only one has so far had distant metastases. CONCLUSIONS: Well-differentiated/dedifferentiated LPS with prominent myxoid stroma can closely resemble other sarcoma types, especially myxoid LPS and myxofibrosarcoma. The clinical presentation (large retroperitoneal or abdominal tumour) is a clue to the correct diagnosis; the degree of nuclear atypia helps to exclude myxoid LPS. Immunohistochemistry for MDM2 and CDK4 and genetic analysis can be useful to confirm the diagnosis.

CD133 antigen expression in ovarian cancer.

BACKGROUND: Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs are able to proliferate and self-renew extensively, thus sustaining tumor growth, the identification of CSCs through their antigenic profile might have relevant clinical implications. In this context, CD133 antigen has proved to be a marker of tumor cells with stemness features in several human malignancies.The aim of the study was to investigate the clinical role of the immunohistochemically assessed expression of CD133 in a large single Institution series of ovarian cancer patients. METHODS: The study included 160 cases admitted to the Gynecologic Oncology Unit, Catholic University of Campobasso and Rome. CD133 antigen was identified by the monoclonal mouse anti-CD133-1 antibody (clone CD133 Miltenyi biotec). RESULTS: In the overall series CD133 positive tumor cells were observed in 50/160 (31.2%) cases. A diffuse cytoplasmic pattern was identified in 30/50 (60.0%), while an apical cytoplasmic pattern was found in 20/50 (40.0%) of CD133 positive tumors.As of September 2008, the median follow up was 37 months (range: 2-112). During the follow up period, progression and death of disease were observed in 123 (76.9%), and 88 (55.0%) cases, respectively. There was no difference in TTP between cases with negative (median TTP = 23 months) versus positive CD133 expression (median TTP = 24 months) (p value = 0.3). Similar results were obtained for OS. When considering the TTP and OS curves according to the pattern of CD133 expression, a trend to a worse prognosis for cases with diffuse cytoplasmic versus the apical cytoplasmic pattern was documented, although the statistical significance was not reached. CONCLUSION: The immunohistochemical assessment of CD133 expression seems not to provide additional prognostic information in ovarian cancer patients. The role of the different pattern of CD133 immunoreaction deserves further investigation in a larger series.

Stage II endometrioid adenocarcinoma of the endometrium: clinical implications of cervical stromal invasion.

OBJECTIVES: Endometrioid adenocarcinoma of the endometrium (EEC) is the most common histologic type of endometrial cancer, with stage being the most critical prognostic factor. Cervical involvement (CI), divided into IIA (epithelial involvement) and IIB (stromal invasion), is overall associated with decreased survival (70 vs 90%). However, the impact on prognosis of sub-stages IIA vs IIB is unclear. The purpose of this study was to investigate the prognostic significance of cervical involvement as well as its substaging in patients diagnosed with EEC. METHODS: Eighty-one patients treated for stage II EEC were identified (1993-2003) in our institution. They were stratified into Group 1 (46) with available slides for review and Group 2 (35) with information obtained from the pathology report. All pathology reports, for all 81 patients, contained information on cervical glandular and stromal involvement. In Group 1, 1 to 6 slides of cervix (mean 3) were reviewed. Tumors were classified as Stage IIA or IIB according to the most recent FIGO criteria. Stromal invasion (SI) in Group 1 tumors was sub-classified in 4 subgroups based on depth of invasion; A) < or =1 mm; B) >1 mm and < or =3 mm; C) >3 mm and < or =5 mm and D) >5 mm. Other histopathologic parameters evaluated include grade, depth of myometrial invasion (MI), and lymphovascular invasion (LI). Clinical data included age, type of surgery, type of radiation, and survival. Statistical analysis was performed. RESULTS: Patients ranged in age from 33-91 (median 64) years. In Group 1, 11 patients had stage IIA and 35 stage IIB tumors. Depth of SI ranged from 1-12 mm (mean 3.4 mm). The pathologists reviewing the slides in Group 1 agreed with the initial reported description of cervical glandular and stromal involvement. In Group 2, 15 patients had stage IIA and 20 stage IIB tumors with no further information regarding depth of SI. In Group 1, 12 EECs were Grade 1, 29 Grade 2, and 5 Grade 3. Thirty tumors had <50% MI, 15 showed >50% MI and LVI was present in 11. In Group 2, 13 tumors were Grade 1, 13 Grade 2, and 9 Grade 3. Twenty-one had <50% or no MI and 9 showed LVI. Median follow-up was 73 (range 5-210) months. Five- and 10-year survival rates were 83% and 78% for patients with stage IIA and 71% and 65% for stage IIB EECs respectively. By univariate analysis, age, MI, LVI and type of treatment affected survival but not substaging into IIA vs IIB or depth of SI. By multivariate analysis, only age (p=0.001), LVI (p=0.017), and type of treatment (p=0.022) were predictors of survival in stage II EECs. CONCLUSIONS: This study showed that the distinction between stage IIA and IIB or depth of SI does not affect survival in patients with EEC. LVI and type of hysterectomy performed were predictors of survival in stage II EECs. Our results suggest that substaging should be eliminated, women with suspect cervical SI should be offered a radical hysterectomy, and that the presence of LVI may be a useful tool in guiding recommendations about the need for adjuvant radiation therapy.

Occipital ganglio-neuroblastoma in an adult.

INTRODUCTION: Ganglioneuroblastomas (GNBs) are embryonic neoplasms, whose behaviour are not well established; 80% of cases occur in the first decade, while only two cases in the adulthood had been reported. CLINICAL REPORT: This 60-year-old female presented with a 2-month history of headache, vertigo, amnesia. A right brachio-crural hemiparesis, right homonymous hemianopsia and sensorial dysphasia was evident. A CT scan revealed a left occipital lesion. MRI scan was not performed because the patient had an anal sphincter stimulator. Three years before thyroidectomy for a follicular carcinoma was performed. A total body CT scan was negative. A left occipital craniotomy was carried out and a solid mass was totally excised. A diagnosis of GNB was made from histopathological examination and immunohistochemistry. Post-operatively the patient recovered from the hemiparesis while the visual disturbances persisted. She underwent fractioned radiotherapy (60 Gy) and chemotherapy with Temozolomide. She remained disease free 18 months after diagnosis. A CT scan showed no evidence of recurrence. DISCUSSION: Recent observations suggest that in spite of an embryonal appearance, these tumours are circumscribed and have a better prognosis than malignant gliomas.

A Prospective Accuracy Study of Prostate Imaging Reporting and Data System Version 2 on Multiparametric Magnetic Resonance Imaging in Detecting Clinically Significant Prostate Cancer With Whole-mount Pathology.

OBJECTIVE: To assess the accuracy of Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) in detecting clinically significant prostate cancer (csPCa) on multiparametric magnetic resonance imaging (mpMRI) using whole-mount sections after radical prostatectomy (RP) as reference standard. METHODS: Forty-eight patients undergoing mpMRI before RP were prospectively enrolled. Two experienced radiologists independently scored and mapped imaging findings according to PI-RADS v2. One experienced uropathologist mapped cancers detected on whole-mount sections using the PI-RADS v2 sector scheme. Per-lesion and per-patient analyses were run. Primary outcomes were sensitivity and false discovery rate (FDR) in detecting csPCa using PI-RADS v2 score ≥3 and ≥4 as thresholds. Secondary outcome was inter-reader agreement. RESULTS: On the per-lesion analysis, sensitivity and FDR at the PI-RADS v2 threshold score ≥3 were 0.75 and 0.17 for Reader 1, and 0.67 and 0.13 for Reader 2, respectively. At the PI-RADS v2 threshold score ≥4, sensitivity was slightly lower, and FDR nearly halved for both readers. On the per-patient analysis, sensitivity for csPCa at the PI-RADS v2 threshold score ≥3 was 0.85 for Reader 1, and 0.78 for Reader 2. At the PI-RADS v2 threshold score ≥4, sensitivity was slightly lower for both readers. Inter-reader agreement was substantial (k 0.72 and 0.65 for PI-RADS v2 threshold score ≥3 and ≥4, respectively). CONCLUSION: In our prospective study with pathology after RP as standard of reference, PI-RADS v2 showed good sensitivity in detecting csPCa on mpMRI with substantial agreement between 2 experienced readers. Threshold score ≥4 had lower FDR.

Genomic Evolutionary Patterns of Leiomyosarcoma and Liposarcoma.

PURPOSE: Leiomyosarcoma and liposarcoma are common subtypes of soft tissue sarcoma (STS). Patients with metastatic leiomyosarcoma or dedifferentiated liposarcoma (DDLPS) typically have worse outcomes compared with localized leiomyosarcoma or well-differentiated liposarcoma (WDLPS). A better understanding of genetic changes between primary/metastatic leiomyosarcoma and between WDLPS/DDLPS may provide insight into their genetic evolution. EXPERIMENTAL DESIGN: We interrogated whole-exome sequencing (WES) from "trios" of normal tissue, primary tumor, and metastatic tumor from individual patients with leiomyosarcoma (n = 9), and trios of normal tissue, well-differentiated tumor, and dedifferentiated tumor from individual patients with liposarcoma (n = 19). Specifically, we performed mutational, copy number, and tumor evolution analyses on these cohorts and compared patterns among leiomyosarcoma and liposarcoma trios. RESULTS: Leiomyosarcoma cases harbored shared drivers through a typical parent/child relationship where the metastatic tumor was derived from the primary tumor. In contrast, while all liposarcoma cases shared the characteristic focal chromosome 12 amplicon, most paired liposarcoma cases did not share additional mutations, suggesting a divergent evolutionary pattern from a common precursor. No highly recurrent genomic alterations from WES were identified that could be implicated as driving the progression of disease in either sarcoma subtype. CONCLUSIONS: From a genomic perspective, leiomyosarcoma metastases contain genetic alterations that are also found in primary tumors. WDLPS and DDLPS, however, appear to divergently evolve from a common precursor harboring 12q amplification, rather than as a transformation to a higher-grade tumor. Further efforts to identify specific drivers of these distinct evolutionary patterns may inform future translational and clinical research in STS.

Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC.

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

Can computer-aided diagnosis assist in the identification of prostate cancer on prostate MRI? a multi-center, multi-reader investigation.

For prostate cancer detection on prostate multiparametric MRI (mpMRI), the Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) and computer-aided diagnosis (CAD) systems aim to widely improve standardization across radiologists and centers. Our goal was to evaluate CAD assistance in prostate cancer detection compared with conventional mpMRI interpretation in a diverse dataset acquired from five institutions tested by nine readers of varying experience levels, in total representing 14 globally spread institutions. Index lesion sensitivities of mpMRI-alone were 79% (whole prostate (WP)), 84% (peripheral zone (PZ)), 71% (transition zone (TZ)), similar to CAD at 76% (WP, p=0.39), 77% (PZ, p=0.07), 79% (TZ, p=0.15). Greatest CAD benefit was in TZ for moderately-experienced readers at PI-RADSv2 <3 (84% vs mpMRI-alone 67%, p=0.055). Detection agreement was unchanged but CAD-assisted read times improved (4.6 vs 3.4 minutes, p<0.001). At PI-RADSv2 ≥ 3, CAD improved patient-level specificity (72%) compared to mpMRI-alone (45%, p<0.001). PI-RADSv2 and CAD-assisted mpMRI interpretations have similar sensitivities across multiple sites and readers while CAD has potential to improve specificity and moderately-experienced radiologists' detection of more difficult tumors in the center of the gland. The multi-institutional evidence provided is essential to future prostate MRI and CAD development.

Rhabdoid and Undifferentiated Phenotype in Renal Cell Carcinoma: Analysis of 32 Cases Indicating a Distinctive Common Pathway of Dedifferentiation Frequently Associated With SWI/SNF Complex Deficiency.

Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.

Introduction to small renal tumours and prognostic indicators.

Over the past years, the widespread use of radiological imaging for evaluating abdominal symptoms unrelated to kidney cancer has been linked to a significant increase in the percentage of renal tumours incidentally detected at an asymptomatic stage. The definition of 'small' renal tumours has changed over the years. Presently, according to dimensional criteria, surgical indications and prognostic impact, small renal tumours are defined as masses ≤4 cm in size. Classical preoperative variables that influence the decision-making process in the management of T1a renal tumours can be classified as patient-related and tumour-related factors. Age is an independent predictor of cancer-specific survival (CSS), with older patients exhibiting significantly worse survival. An accurate classification of the anatomical and topographical characteristics of small renal masses based on available nephrometry systems is necessary for standard preoperative evaluation of patients eligible for partial nephrectomy (PN). Renal tumour biopsies (RTBs) can be indicated in patients eligible for active surveillance or ablative treatments, those with other primary tumours, those with prior renal lesions and/or those with multiple synchronous tumours, showing a median diagnostic rate of 92%. Small renal tumours typically have a good prognosis. Patient age, mode of presentation, nuclear grading, coagulative necrosis and histologic subtype can influence the prognosis of this subgroup of RCC.