Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

Serum total periostin is an independent marker of overall survival in bone metastases of lung adenocarcinoma.

More than 35% of lung adenocarcinoma patients have bone metastases at diagnosis and have a poor survival. Periostin, a carboxylated matrix protein, mediates lung cancer cell dissemination by promoting epithelial-mesenchymal transition, and is involved in bone response to mechanical stress and bone formation regulation. This suggests that periostin may be used as a biomarker to predict survival in lung cancer patients. Serum periostin was assessed at diagnosis in a prospective cohort of 133 patients with lung adenocarcinoma of all stages. Patients were divided into localized and bone metastatic groups. Both groups were matched to healthy controls. Survival analysis and Cox proportional hazards models were conducted in the total population and in bone metastatic group. The median serum periostin level was higher in bone metastatic (n = 67; median: 1752 pmol/L) than in the localized group (n = 66; 861 pmol/L; p < 0.0001). Patients with high periostin (>median) had a poorer overall survival in the whole population (33.3 weeks vs. NR; p < 0.0001) and the bone metastatic group (24.4 vs. 66.1 weeks; p < 0.001). In multivariate analysis, patients with high periostin had increased risk of death (HR = 2.09, 95%CI [1.06-4.13]; p = 0.03). This was also found in the bone metastatic group (HR = 3.62, 95%CI [1.74-7.52]; p = 0.0005). Immunohistochemistry on bone metastasis biopsies showed periostin expression in the bone matrix and nuclear and cytoplasmic staining in cancer cells. Serum periostin was an independent survival biomarker in all-stage and in bone metastatic lung adenocarcinoma patients. IHC data suggest that periostin might be induced in cancer cells in bone metastatic niche in addition to bone microenvironment expression.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors.

Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.

Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests.

BACKGROUND: Systematic screening for liver fibrosis in heavy-drinking patients is a challenge. Aims To assess Fibroscan for non-invasive diagnosis of asymptomatic liver fibrosis in alcohol abuse patients, to determine diagnostic liver stiffness cut-off values and to compare performance of Fibroscan with seven non-invasive laboratory tests. METHODS: One hundred and three alcoholic patients were studied. Liver fibrosis was staged by METAVIR system. Fibroscan, Fibrotest, Fibrometer, Hepascore, APRI, PGA, PGAA and hyaluronic acid tests were performed. Liver stiffness cut-offs were determined using receiver-operating characteristic (ROC) curves. RESULTS: Liver stiffness was correlated with fibrosis (r = 0.72, P < 0.014), with median at 5.7, 6.3, 8.4, 15 and 47.3 kPa for F0 (n = 8), F1 (n = 18), F2 (n = 24), F3 (n = 20) and F4 (n = 33) stage fibrosis respectively. For Fibroscan, areas under ROC curves (AUROCs) were 0.84 (95% CI: 0.73-0.95) (F > or = 1), 0.91 (0.85-0.98) (F > or = 2), 0.90 (0.82-0.97) (F > or = 3) and 0.92 (0.87-0.98) (F = 4), yielding diagnostic stiffness cut-offs of 5.9 (F > or = 1), 7.8 (F > or = 2), 11 (F > or = 3) and 19.5 (F4) kPa. Sensitivity, specificity, PPV and NPV were 80%, 90.5%, 93% and 70% for F > or = 2, and 85.7%, 84.2%, 68.6% and 87.9% for F = 4. Performance of Fibroscan was higher than seven laboratory tests, for which AUROCs ranged from 0.66 to 0.77 (F > or = 1), from 0.54 to 0.82 (F > or = 2), from 0.43 to 0.88 (F > or = 3) and from 0.56 to 0.89 (F = 4), with significant difference only vs. APRI (P < 0.001) and Hepascore (P = 0.04). Combining Fibroscan with each tests did not improve performance. CONCLUSIONS: Fibroscan is effective to assess liver fibrosis in alcoholic patients. Instant screening of liver fibrosis in heavy drinkers is feasible without liver biopsy.

[Inflammatory fibroid polyp, a rare tumor of the appendix]. / Le polype fibroïde inflammatoire, une tumeur rare de l'appendice.

We report the rare occurrence of an inflammatory fibroid polyp of the appendix. The lesion was diagnosed in a 33-year-old woman presenting with abdominal pain, fever and localized tenderness in right iliac fossa on abdominal palpation. CT-scan showed an 8 cm appendiceal mass and a laparoscopic appendectomy was consequently performed. On microscopic examination, the tumor consisted of spindle cells dispersed in a loose fibromyxoid stroma containing numerous blood cells and inflammatory cells with abundant eosinophils. On immunohistochemistry, the spindle tumor cells were positive for vimentin, fascin and focally for CD34 and CD35. They were negative for smooth muscle actin, desmin, CD21, CD23, CD117 and S100 protein. Inflammatory fibroid polyp is a rare benign mesenchymal tumor of the gastrointestinal tract rarely reported in the appendix. This tumor shares some common pathologic features with the myofibroblatic inflammatory tumor but they are two different entities. The pathogenesis of this tumor remains unclear but fascin and CD35 immunoreactivity of the tumor cells suggests a probable dendritic cell origin.

Myelofibrosis and cytopenia are not always malignant.

Myelofibrosis (MF) is characterized by reticulin fibrosis of the bone marrow. It may occur in neoplastic disorders such as myelofibrosis with myeloid metaplasia (MMM) or other neoplasms involving the bone marrow. However, autoimmune phenomena have been described in patients with MF defining a distinct clinicopathological entity called autoimmune myelofibrosis (AIMF). We report two cases of AIMF and review the literature.

[Primary hepatic lymphoma of MALT-type: a tumor that can simulate a liver metastasis]. / Le lymphome primitif hépatique de type MALT: une tumeur rare pouvant simuler une métastase hépatique.

Primary hepatic lymphomas are rare tumors. We report a case of a 72 year-old woman with a past history of colonic adenocarcinoma who presented primary hepatic lymphoma of MALT-type. The patient had been operated on 3 years before for colonic adenocarcinoma, pT3N0, revealed by a bowel obstructive syndrome. She had been treated by chemotherapy for 6 months. During the follow-up, the computed tomography-scan (CT-scan) revealed the presence of a not well-demarcated mass in segment III of the liver, measuring 4 cm in diameter. The tumor was hypodense and was not enhanced on dynamic study. The mass was already present on the initial CT-scan. Left lobectomy was performed with the diagnosis of liver metastasis of the colonic adenocarcinoma. Surgical specimen showed a tumor composed of a dense infiltrate of small lymphocytes positive for B-cell markers on immunohistochemistry. The tumor contained reactive lymphoid follicles and there were numerous lympho-epithelial biliary lesions. The patient is alive and free of disease 2 years after the diagnosis. Primary hepatic lymphoma of MALT-type is a low-grade B cell lymphoma. Twenty-five cases had been reported in the literature so far. The patients were 16 females and 9 males, mean age 63.5 years. The pathogenesis is still unclear but half of the patients had a past history of chronic inflammatory liver disease (hepatitis B or C virus infection, ascaris infection, primary biliary cirrhosis) or malignant neoplasm. This tumor has a good prognosis; it is usually limited to the liver and surgical resection cures the patient in most cases.

First-line autologous stem cell transplantation in primary CNS lymphoma.

The treatment of primary central nervous system lymphoma (PCNSL) has been considerably improved over recent years. In this article, we report six cases of PCNSL treated by first-line induction chemotherapy followed by intensive chemotherapy and autologous stem cell transplantation (ASCT). Six immunocompetent patients presenting with a PCNSL, confirmed by thoraco-abdomino-pelvic computer tomography scan and bone marrow biopsy, were treated with induction chemotherapy followed by BEAM intensive chemotherapy and ASCT and radiotherapy. At the end of the treatment, all the patients were in complete remission. After a median follow-up of 41.5 months (17-70 months), four patients were alive without signs of relapse (median survival: 35.5 months). Two patients died from relapse at 19 and 23 months. The neurotoxicity was low with epilepsy in one patient and persistent left side dysesthesia in another one. These results are fairly encouraging. Other studies with greater numbers of patients and longer follow-up are needed to confirm this study.

[Orbital non-Hodgkin's lymphoma: a retrospective study of 22 patients]. / Les lymphomes malins non hodgkiniens conjonctivo-orbitaires.

INTRODUCTION: Although the number of non-Hodgkin's lymphoma (NHL) cases continues to grow throughout the world, orbital NHL is still a rare tumor that is difficult to diagnose. The objective of our study was to analyze the different orbital NHLs diagnosed in our Ophthalmology Department during the last 20 years. MATERIAL AND METHODS: [corrected] We conducted a retrospective study of conjunctive-orbital lymphomas diagnosed in the Amiens Ophthalmology Department between 1982 and 2002. The pathological reports of 22 cases were investigated, notably the mode of onset, the clinical and radiological description, the diagnostic mode, pathological results, and the type of treatment provided for these tumors. RESULTS: Every NHL was type B. They were for the most part low grade in terms of malignancy, isolated, primitive, orbital and inactive. DISCUSSION: Insidious, slow-growing lesions are often found, and biopsy can be difficult. This may explain delayed diagnosis. The first differential diagnosis is inflammatory pseudotumor. Only a good biopsy can confirm the diagnosis of NHL. CONCLUSION: New immunohistochemistry and genetic diagnostic methods make it increasingly possible to screen for NHL, even if the clinical history can be misleading. Moreover, treatments that are more and more precisely targeted to the immunohistochemical type of NHL seem to be giving very promising results. Several studies are ongoing.

[Microscopic vascular study of the colon with the corrosion casting technique]. / Etude vasculaire microscopique du colon par la technique d'injection-corrosion.

The aim of this study is, firstly, to assess the accuracy of vascular casts obtained at various times after death and secondly to describe the mucosal microvascular architecture of the cat colon. Two injections were realized, the first one on a non-embalmed human corpse, 12 days after the death, and the other one on a cat, immediately following euthanasia. Results show that this second cast seems finer and more detailed than the cast stemming from the human corpse; indeed, the finest vessels obtained are about 6 microns while they are about 15 microns on the human corpse. This could be explained by a post-mortem obstruction of microvessels, that prevented the passage of the injected product or by an insufficient amount of product injected. Finally, the vascular cast of the cat colic mucosa presents a regular honeycomb-like network that bounds the colonic mucosal glands, a finding consistent with the results reported previously.