RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma.

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.

Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations.

Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer.

Several known breast cancer susceptibility genes with moderate-to-high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein-truncating variants, and the role of rare missense mutations has remained poorly addressed. To identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious. Thirty-five variants were studied here for the disease association using Finnish breast cancer case (n = 492-2,035) and control (n = 277-1,539) cohorts. As a result, two missense variants in genes involved in DNA replication, RECQL p.I156M and POLG p.L392V, the former involving genomic and the latter mitochondrial DNA replication, showed significant association with risk of breast cancer. Rare RECQL p.I156M allele was observed in breast cancer cases only (6/1,946, 0.3%, p = 0.043), whereas POLG p.L392V was two times more frequent in breast cancer cases (53/2,238, 2.4%) compared to controls (18/1,539, 1.2%, OR = 2.1, 95% CI 1.2-3.5, p = 0.010). Based on the current genetic data, both RECQL p.I156M and POLG p.L392V represent novel breast cancer predisposing alleles.

Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype.

In epithelial-to-mesenchymal transition (EMT) epithelial cancer cells achieve mesenchymal features, essentially helping them to metastasize. There is some evidence that EMT could be increased in triple-negative (TNBC) or basal-like breast cancers, although more precise mechanisms considering e.g. EMT-regulating transcription factors are largely unknown. We assessed immunohistochemically vimentin (separately in in situ areas and in invasive cells) as an indicator of EMT, and also EMT-regulating transcription factors zeb1 (separately in stroma and tumour) and Sip1 (in nuclei and cytoplasm) in histological samples of 231 women with local or locally advanced invasive breast cancer. 51.1 % of patients had TNBC and 48.9 % oestrogen and progesterone receptor-positive and HER2 negative breast cancer. Basal-like breast cancers were defined as TNBC that also expressed epidermal growth factor receptor EGFR and/or cytokeratin 5/6. Vimentin expression in invasive cells was higher in TNBCs (p = 9 × 10(-12)) compared to non-TNBC tumours. Vimentin (p = 2 × 10(-6)), nuclear Sip1 (p = 0.035) and zeb1 in stroma (p = 0.013) were overexpressed in basal-like cancers compared to non-basal-like TNBCs. In non-TNBC group findings between studied markers and clinicopathological factors were rare. However, in TNBC cases, vimentin expression in invasive cells associated with poor differentiation (p = 0.00007), zeb1 expression in cancer cells with higher grade (p = 0.002), vascular invasion (p = 0.036) and larger T-class (p = 0.027), whereas stromal zeb1 associated with lymphatic vessel invasion (p = 0.036) and vascular invasion (p = 0.039). High nuclear Sip1 expression was prognostic for poor disease-free survival (p = 0.002) in the whole cohort. The current results emphasize the increased role of EMT in TNBC and especially in basal-like breast cancers. These observations also support the role of studied parameters in tumour progression.

Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models.

The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.

Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer.

Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.

Divergent behaviour of oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) in breast carcinogenesis.

AIMS: To clarify the role of oxidative stress during breast carcinogenesis by studying the expression of 8-hydroxydeoxyguanosine (8-OHdG) (a marker of oxidative DNA damage) and 4-hydroxy-2-nonenal (HNE) (a marker of lipid peroxidation) during the different phases of breast carcinogenesis. METHODS AND RESULTS: The study material consisted of a total of 219 patients: 31 with usual ductal hyperplasia (UDH), 25 with atypical ductal hyperplasia (ADH), 30 with ductal carcinoma in situ (DCIS) and 133 with invasive carcinoma. The expression of 8-OHdG and HNE were evaluated immunohistochemically. Both 8-OHdG (77.4%) and HNE (45.8%) expression was already seen in UDH lesions. Interestingly, the trend of these two immunostainings during breast carcinogenesis was diverse. 8-OHdG expression diminished significantly in invasive breast carcinomas compared to non-invasive lesions (P < 0.005 when set against non-invasive cohorts). Also within the same lesions, 8-OHdG expression was the most intensive in benign cells. Conversely, HNE immunostaining was strongest in invasive breast carcinomas (UDH versus invasive cohort, P = 0.015). CONCLUSIONS: 4-hydroxy-2-nonenal as a marker of lipid peroxidation increases during breast carcinogenesis, reflecting the role of oxidative stress in the pathogenesis of breast cancer. However, 8-OHdG shows diminished levels in carcinomas, possibly resulting from the induction of DNA repair in these invasive lesions.

Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas.

BACKGROUND: Triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC) are breast cancer subtypes with an especially poor prognosis. 8-Hydroxydeoxyguanosine (8-OHdG) is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs) are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC. METHODS: We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression). Control cases (n = 42) were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1). RESULTS: Patients with TNBC had worse breast cancer-specific survival (BCSS) than the control group (p = 0.015). Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p < 0.005). 8-OHdG immunostaining was associated with better BCSS (p = 0.01), small tumor size (p < 0.0001) and low grade (p < 0.0005). Keap1 overexpression was observed in the TNBC cohort (p = 0.001) and Keap1-positive patients had worse BCSS than Keap1-negative women (p = 0.014). PRDX IV was overexpressed in the TNBC vs. the non-TNBC group (p = 0.022). CONCLUSIONS: Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC.

Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer.

BACKGROUND: Breast cancer is strongly influenced by hereditary risk factors. Yet, the known susceptibility genes and genomic loci explain only about half of the familial component of the disease. To identify novel breast cancer predisposing gene defects, here we have performed massive parallel sequencing for Northern Finnish breast cancer cases. METHODS: Ninety-eight breast cancer cases with indication of hereditary disease susceptibility were exome sequenced. Data filtering strategy focused on predictably deleterious rare variants that were still enriched in the sequenced cohort. Findings were confirmed with additional, geographically matched breast cancer cohorts. RESULTS: A recurrent heterozygous splice acceptor variant, c.918-1G>C, in SERPINA3, was identified, and it was significantly enriched both in the hereditary (6/201, 3.0%, p = 0.006, OR 5.1, 95% CI 1.7-14.8) and unselected breast cancer cohort (26/1569, 1.7%, p = 0.009, OR 2.8, 95% CI 1.3-6.2). SERPINA3 c.918-1G>C carriers were also significantly more likely to have a rare tumor subtype, medullary breast cancer, than the non-carriers (4/26, 15.4%, p = 0.000014, OR 42.9, 95% CI 11.7-157.1). CONCLUSION: These findings demonstrate that c.918-1G>C germline variant in SERPINA3 gene, encoding a member of the serine protease inhibitor class, is a novel breast cancer predisposing allele.

Incidence and clinicopathological features of Follicular T-cell lymphoma in Finland: a population-based immunohistochemical study.

Follicular T-cell lymphoma (FTCL) is a rare subtype of mature T-cell lymphoma. It was recently recognized as a separate lymphoma entity in the 2017 revised fourth edition of the World Health Organization classification. The main goals of the present study were to gain better knowledge of the incidence and histopathological and clinical features of FTCL in Finland. In this study, we reviewed all angioimmunoblastic T-cell (AITL) and peripheral T-cell lymphomas, not otherwise specified, from the patient records in three hospital districts in Finland over a 10-year period, to identify FTCL cases and estimate its incidence. Five patients rediagnosed with FTCL and 34 with AITL were analyzed. Hodgkin/Reed-Sternberg (HRS)-like cells were observed in 24 of the 34 AITL cases and four of the five FTCL cases. We found that the main features that differentiated FTCL from AITL were rosetting of T-cells around HRS-like cells, the absence of clear cells, follicular dendritic cell meshwork and T-cell monoclonality. Our estimated incidence of FTCL is 0.20 per 100,000 people in Finland.

The effect of topical pimecrolimus on inflammatory infiltrate in vulvar lichen sclerosus.

OBJECTIVE: Lichen sclerosus (LS) is a relatively common chronic inflammatory disorder of the skin and mucosal surfaces. STUDY DESIGN: A total of 29 women with histologically confirmed, active LS were recruited to this study with 2 aims. First, we evaluated the effectiveness of pimecrolimus treatment to LS not responding to conventional corticosteroid treatment. The second aim in this study was to provide information of in vivo effects of topical pimecrolimus in acute LS lesions, especially the inflammatory cell infiltration. RESULTS: In all, 25 of 29 women applied cream as recommended. After 2 months of treatment, 20 patients had reached partial or complete clinical remission. Histology showed decreased inflammatory lymphoid infiltrate with down-regulation of CD3(+) T cells, CD8(+) T cells, and CD57(+) natural killer cells. Also macrophage marker CD68 staining showed down-regulation. There was no change in CD20(+) B lymphocytes. CONCLUSION: We conclude that calcineurin inhibitors are an effective treatment for patients not responding to corticosteroid treatment.

Tonsillar granuloma associated with hypogammaglobulinemia.

BACKGROUND: Rare tonsillar granulomas may be caused for example by infections, malignancies or sarcoidosis. Granulomas also occur in inborn errors of immunity (IEI) such as common variable immunodeficiency (CVID) with B cell maturation defects and hypogammaglobulinemia. CVID shares various features with sarcoidosis and drug-induced secondary hypogammaglobulinemia; careful consideration of differential diagnosis between these conditions is warranted. CASE PRESENTATION: A 29-year-old female with epilepsy developed dysphagia, dyspnea and impaired exercise tolerance. Obstruction caused by swollen lingual tonsil and edema in the epiglottis and arytenoid mucosa were found. Lingual tonsil and epiglottis biopsies displayed non-necrotizing granulomas. There was no evidence of viral, bacterial, mycobacterial or fungal infections. Chest X-ray, computerized tomography of chest and ultrasound of neck and abdomen remained unremarkable. Positron emission tomography/computed tomography (PET/CT) showed laryngeal enhancement. Empiric antimicrobials combined with prednisolone were insufficient to control her disease. In immunological evaluation, the patient had normal counts of B and T cells. Proportions of CD27+ memory B cells (30.3%) and IgD-IgM-CD27+ switched memory B cells (7.2%; normal range 6.5-29.2%) were normal. Percentage of activated CD21low B cells was high (6.6%; normal range 0.6-3.5%). IgG (3.5 g/L; normal range 6.77-15.0 g/l) and all IgG subclass concentrations were low. Anti-polysaccharide responses were impaired, with 3/10 serotypes reaching a level of 0.35 µg/ml after immunization with Pneumovax®. The findings were consistent with hypogammaglobulinemia resembling CVID, possibly secondary to antiepileptic medication. Her dyspnea and dysphagia responded favorably to subcutaneous IgG and rituximab. CONCLUSIONS: Tonsillar granulomas can be the presenting and only clinical feature of B cell deficiency, highlighting the diversity of symptoms and findings in primary or secondary immunodeficiencies.

Increased BTB-Kelch type substrate adaptor protein immunoreactivity associates with advanced stage and poor differentiation in renal cell carcinoma.

Renal cell carcinoma (RCC) is a malignancy with increasing incidence. Despite the well-known prognostic factors - the stage, grade and histological subtype - the clinical course of RCC can seem quite random. The aim of this study was to evaluate markers of the oxidative system as candidate prognostic factors for RCC. Our study population consisted of 152 patients who underwent operation for RCC between 1990 and 1999. The tumours were examined with three immunohistochemical markers of the oxidative system, thioredoxin (Trx), NF-E2-related factor (Nfr2) and BTB-Kelch type substrate adaptor protein (Keap1). Cytoplasmic Keap1 staining was related to poorer prognosis in renal cancer-specific survival. The difference was statistically significant (P=0.02). Keap1 staining was associated with a more advanced stage and a higher nuclear grade. Cytoplasmic Trx staining was associated with a trend of better prognosis in renal cancer-specific survival. Nfr2 staining was not a prognostic factor in renal cancer-specific survival. In RCC, Keap1 is associated with a more advanced disease, a higher grade and a poorer prognosis.

Primary sex cord-like variant of endometrioid adenocarcinoma arising from endometriosis.

Endometriosis, a relatively common disease generally affecting women in the reproductive age group, is mostly found in the pelvic organs. Although endometriosis is a benign disease, some malignant tumors have been reported to develop in endometriotic lesions, most commonly in the ovary. The relationship between endometriosis and malignancy is not well known, but the majority of endometriosis-associated ovarian malignancies are usually endometrioid adenocarcinomas and clear cell carcinomas. The sex cord-like variant of endometrioid adenocarcinoma is a rare tumor that histologically closely resembles the sex cord-stromal tumor. Despite its rarity, the correct histological diagnosis of the sex cord-like variant of endometrioid adenocarcinoma is crucial to avoid misdiagnosis of a less aggressive tumor. We here report a 53-year-old woman who was diagnosed as having this very rare subtype of endometroid adenocarcinoma curiously arising from an endometriotic lesion at the site of previous salpingo-oophorectomy. The tumor was diagnosed based on light microscopy and immunohistochemistry.

The damage-responsive Drosophila gene sickle encodes a novel IAP binding protein similar to but distinct from reaper, grim, and hid.

In flies and mammals, critical regulators of cell death function by antagonizing Inhibitor of Apoptosis Proteins (IAPs), which themselves directly block caspase action. The three currently known IAP antagonists in Drosophila map to the H99 genomic interval required for all programmed cell death. Here we describe a fourth member of this genetic group, sickle (skl), which maps just outside of the H99 deletion. At its N terminus, Skl shares residues in common with other IAP antagonists in flies (Rpr, Grim, and Hid) and in mammals (Smac/DIABLO and Omi/Htra2). Like other activators of apoptosis mapping in the Reaper region, full-length skl induced apoptosis when overexpressed, and the N terminus of this protein specifically bound to the BIR2 domain of DIAP1. However, unlike the N termini of Grim, Hid, and Rpr, the N terminus of Skl did not induce apoptosis. skl transcripts accumulate in cells that are fated to die in some but not all regions of the embryo. Genotoxic stimuli induced skl expression, but skl was not responsive to all signals that trigger premature apoptosis. skl is potentially a fourth IAP antagonist in the "Reaper region" and a new candidate transducer of apoptotic damage signaling in Drosophila.

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.

Prebiopsy Multiparametric Magnetic Resonance Imaging for Prostate Cancer Diagnosis in Biopsy-naive Men with Suspected Prostate Cancer Based on Elevated Prostate-specific Antigen Values: Results from a Randomized Prospective Blinded Controlled Trial.

BACKGROUND: Multiparametric magnetic resonance imaging (MP-MRI) may improve the detection of clinically significant prostate cancer (PCa). OBJECTIVE: To compare MP-MRI transrectal ultrasound (TRUS)-fusion targeted biopsy with routine TRUS-guided random biopsy for overall and clinically significant PCa detection among patients with suspected PCa based on prostate-specific antigen (PSA) values. DESIGN, SETTING, AND PARTICIPANTS: This institutional review board-approved, single-center, prospective, randomized controlled trial (April 2011 to December 2014) included 130 biopsy-naive patients referred for prostate biopsy based on PSA values (PSA <20 ng/ml or free-to-total PSA ratio ≤0.15 and PSA <10 ng/ml). Patients were randomized 1:1 to the MP-MRI or control group. Patients in the MP-MRI group underwent prebiopsy MP-MRI followed by 10- to 12-core TRUS-guided random biopsy and cognitive MRI/TRUS fusion targeted biopsy. The control group underwent TRUS-guided random biopsy alone. INTERVENTION: MP-MRI 3-T phased-array surface coil. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the number of patients with biopsy-proven PCa in the MP-MRI and control groups. Secondary outcome measures included the number of positive prostate biopsies and the proportion of clinically significant PCa in the MP-MRI and control groups. Between-group analyses were performed. RESULTS AND LIMITATIONS: Overall, 53 and 60 patients were evaluable in the MP-MRI and control groups, respectively. The overall PCa detection rate and the clinically significant cancer detection rate were similar between the MP-MRI and control groups, respectively (64% [34 of 53] vs 57% [34 of 60]; 7.5% difference [95% confidence interval (CI), -10 to 25], p=0.5, and 55% [29 of 53] vs 45% [27 of 60]; 9.7% difference [95% CI, -8.5 to 27], p=0.8). The PCa detection rate was higher than assumed during the planning of this single-center trial. CONCLUSIONS: MP-MRI/TRUS-fusion targeted biopsy did not improve PCa detection rate compared with TRUS-guided biopsy alone in patients with suspected PCa based on PSA values. PATIENT SUMMARY: In this randomized clinical trial, additional prostate magnetic resonance imaging (MRI) before prostate biopsy appeared to offer similar diagnostic accuracy compared with routine transrectal ultrasound-guided random biopsy in the diagnosis of prostate cancer. Similar numbers of cancers were detected with and without MRI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01357512.

Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila.

In mammals, members of the tumor necrosis factor (TNF) family play an important role in the regulation of cellular proliferation, differentiation and programmed cell death. We describe isolation and characterization of an orthologous ligand/receptor axis in Drosophila. The ligand, designated Eiger, is a type II membrane glycosylated protein, which can be cleaved at residue 145 and released from the cell surface as a soluble factor, thereby representing the first potential cytokine to be described in Drosophila. Eiger exists in two alternatively spliced isoforms, Eiger long (Eiger-L) and Eiger short (Eiger-s), both of which are expressed throughout development and in the adult. We also describe the isolation and characterization of a novel Drosophila member of the TNF receptor family, designated Wengen, which is a type I membrane protein that can physically interact with the recently described TRAF2 homolog dTRAF2. Both Eiger and Wengen are expressed in distinctive patterns during embryogenesis and Eiger is responsive to genotoxic stress. Forced expression of Eiger-L, Eiger-s or Wengen, caused apoptotic cell death which could be rescued by caspase inhibitors or the JNK phosphatase Puckered. In addition, Eiger-induced cell killing was attenuated by RNAi-mediated suppression of Wengen. Our results illustrate that Eiger and Wengen represent proximal components of an evolutionarily conserved TNF-like signaling pathway in Drosophila.

Inflammation and prognosis in colorectal cancer.

AIM OF THE STUDY: Previous work has indicated that quantification of inflammatory cell reaction is of prognostic value in colorectal cancer. We evaluated the prognostic significance of inflammatory cell reaction patterns in colorectal cancer and developed a grading method which could be used in the routine assessment of tumours. METHODS: The intensity of overall inflammatory cell reaction, numbers of neutrophilic and eosinophilic granulocytes, lymphoid cells and macrophages in both the central region and the invasive margin were estimated in 386 colorectal cancer patients. Prognostic significance was analysed by uni- and multivariate analysis. RESULTS: Our method for classification of inflammatory reaction was reliable. High-grade inflammation at the invasive margin in Dukes' stage A and B cancers (pT1-2N0 and pT3N0, respectively) was associated with better 5-year-survival (87.6%) than low-grade inflammation (47.0%). CONCLUSIONS: Inflammatory cell response at the invasive border is a relevant prognostic indicator and could be easily incorporated into the routine evaluation of histopathological specimens.