Case Report: Primary Spinal Lymphoma.

This is the report on the case of a 74 year old male patient who was admitted to hospital emergency because of a distended bladder, which was detected on an MRI. This MRI was performed because of an acute paralysis of the patient's left leg. After various examinations we could conclude that the patient's neurological symptoms were not due to metastases of a solid tumour as we expected, but to a primary spinal diffuse B-cell lymphoma. The central nervous system, and especially the spinal cord, are an extremely rare location for primary B-Cell lymphoma.

Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia.

Evading apoptosis is a hallmark of B-cell chronic lymphocytic leukemia (CLL) cells and an obstacle to current chemotherapeutic approaches. Inhibiting histone deacetylase (HDAC) has emerged as a promising strategy to induce cell death in malignant cells. We have previously reported that the HDAC inhibitor MGCD0103 induces CLL cell death by activating the intrinsic pathway of apoptosis. Here, we show that MGCD0103 decreases the autophagic flux in primary CLL cells. Activation of the PI3K/AKT/mTOR pathway, together with the activation of caspases, and to a minor extent CAPN1, resulting in cleavage of autophagy components, were involved in MGCD0103-mediated inhibition of autophagy. In addition, MGCD0103 directly modulated the expression of critical autophagy genes at the transcriptional level that may contribute to autophagy impairment. Besides, we demonstrate that autophagy is a pro-survival mechanism in CLL whose disruption potentiates cell death induced by anticancer molecules including HDAC and cyclin-dependent kinase inhibitors. In particular, our data highlight the therapeutic potential of MGCD0103 as not only an inducer of apoptosis but also an autophagy suppressor in both combination regimens with molecules like flavopiridol, known to induce protective autophagy in CLL cells, or as an alternative to circumvent undesired immunomodulatory effects seen in the clinic with conventional autophagy inhibitors.

[Giant melanoma of the scalp: Case report]. / Mélanome géant du scalp: case report.

We present a case of giant melanoma of the scalp observed in our department. It is a rare but very aggressive pathology which is generally treated by radical surgery. We emphasize early diagnosis because a large extension of the tumor can lead to the need of a very extensive surgical resection. Prognosis is very severe despite adjuvant medical treatments.

7-year results of cell therapy in patients with severe ischemic cardiomyopathy.

BACKGROUND: Intracoronary infusion of autologous bone marrow cells (CTX) has been shown to improve myocardial function in post infarct patients and in patients with chronic ischemic cardiomyopathy. Long term results of CTX are unknown. METHODS AND RESULTS: In this small pilot study, eleven patients with chronic ischemic cardiomyopathy and ejection fraction (EF) of 19 +/- 1% were treated with CTX and followed for 7 years. Four patients died during follow-up, all because of progressive heart failure. All patients received an implantable cardioverter defibrillator (ICD) during the course of the study but only 1 patients developed ventricular tachycardia after CTX. One patient received resynchronization therapy. The overall clinical benefit of CTX was modest (NYHA 3.0 +/- 0.1 pre and 2.5 +/- 0.2 post CTX, p= 0.06). CTX was not associated with reverse remodeling. However, left ventricular EF (19 +/- 1% pre and 18 +/- 6% post) and left ventricular end-diastolic volumes (289 +/- 71 ml pre and 294 +/- 123 ml post) remained remarkably stable over 7-year follow-up in the survivors of this very sick population. CONCLUSIONS: During 7-year follow-up, CTX was associated with stabilization of EF and ventricular volumes but without significant clinical benefit or evidence of reverse remodeling.

Lung cancer statistics in Luxembourg from 1981 to 2008.

Lung cancer is the leading cause of cancer-related death in the world and in Luxembourg. As a part of "The health science initiative focused on personalized medicine", Luxembourg aims to participate by developing diagnostics to improve the detection and treatment of lung cancer. In line with this objective, this study made a review of evolution of lung cancer in Luxembourg from 1981 to 2008 and compared this statistics to the situation in the Nordic countries, Europe in general and the World. Incidence data of the national morphological tumour registry and mortality data of the service of statistics of the national ministry of health is depicted in charts with trend lines, in the framework of a statistical evaluation of relevant parameters. The data indicate that while male lung cancer incidence decreased in Luxembourg, the incidence in women and its mortality have doubled over the 28-year span considered. Notwithstanding this increase, the female lung cancer incidence and mortality remain low compared to the Nordic countries and Europe. Interestingly, the study also potentially suggests that the lung cancer pattern follows the smoking pattern in incidence and mortality.

Immune surveillance of human cancer: if the cytotoxic T-lymphocytes play the music, does the tumoral system call the tune?

Accumulating evidence indicates that the innate and adaptive immune systems participate in the recognition and destruction of cancer cells by a process known as cancer immunosurveillance. Tumor antigen-specific cytotoxic T-lymphocytes (CTL) are the major effectors in the immune response against tumor cells. The identification of tumor-associated antigen (TAA) recognized primarily by CD 8(+) T-lymphocytes has led to the development of several vaccination strategies that induce or potentiate specific immune responses. However, large established tumors, which are associated with the acquisition of tumor resistance to specific lysis, are usually not fully controlled by the immune system. Recently, it has become clear that the immune system not only protects the host against tumor development but also sculpts the immunogenic phenotype of a developing tumor and can favor the emergence of resistant tumor cell variants. Moreover, it has become obvious that the evasion of immunosurveillance by tumor cells is under the control of the tumor microenvironment complexity and plasticity. In this review, we will focus on some new mechanisms associated with the acquisition of tumor resistance to specific lysis during tumor progression, involving genetic instability, structural changes in cytoskeleton, and hypoxic stress. We will also discuss the interaction between CTLs and tumor endothelial cells, a major component of tumor stroma.

Overexpression of both catalytically active and -inactive cathepsin D by cancer cells enhances apoptosis-dependent chemo-sensitivity.

The aspartic protease cathepsin D (cath-D) is a key mediator of induced-apoptosis and its proteolytic activity has been generally involved in this event. During apoptosis, cath-D is translocated to the cytosol. Because cath-D is one of the lysosomal enzymes that requires a more acidic pH to be proteolytically active relative to the cysteine lysosomal enzymes such as cath-B and -L, it is therefore open to question whether cytosolic cath-D might be able to cleave substrate(s) implicated in the apoptotic cascade. Here, we have investigated the role of wild-type cath-D and its proteolytically inactive counterpart overexpressed by 3Y1-Ad12 cancer cells during chemotherapeutic-induced cytotoxicity and apoptosis, as well as the relevance of cath-D catalytic function. We demonstrate that wild-type or mutated catalytically inactive cath-D strongly enhances chemo-sensitivity and apoptotic response to etoposide. Both wild-type and mutated inactive cath-D are translocated to the cytosol, increasing the release of cytochrome c, the activation of caspases-9 and -3 and the induction of a caspase-dependent apoptosis. In addition, pretreatment of cells with the aspartic protease inhibitor, pepstatin A, does not prevent apoptosis. Interestingly therefore, the stimulatory effect of cath-D on cell death is independent of its catalytic activity. Overall, our results imply that cytosolic cath-D stimulates apoptotic pathways by interacting with a member of the apoptotic machinery rather than by cleaving specific substrate(s).

[Early detection of synchronous thyroid carcinoma and malignant melanoma by fluorodeoxyglucose positron emission tomography]. / Detection précoce d'un carcinome thyroïdien et d'un mélanome malin synchrones par une tomographie par emission de positron a la fluorodeoxyglucose: cas clinique.

Functional tumor imaging using Fluorodeoxyglucose positron emission tomography (FDG-PET) is a new method in clinical oncology. The 18 FDG, is a glucose analog that accumulates in cells in proportion to the rate of glucose metabolism, and increased carbohydrate metabolism has been recognized as a feature of malignant cells versus normal cells. In addition, it permits the detection of metastases or synchronous tumours not discovered by anatomic imaging. Although detection of the primary site of disease is usually accomplished well with conventional techniques, the performance of FDG-PET may be useful to determine tumours that are not clinically evident. The authors describe a case of early detection of synchronous thyroid carcinoma by FDG-PET in a young patient opereted on for a malignant melanoma on his arm.

Clinical benefit from erythropoietin.

Advances continue in erythropoietin biology, and additional data reviewed here have recently become available on complex feedback mechanisms describing the interrelations of hypoxia and its effects on anemia and tumor behavior (eg, apoptosis, angiogenesis). In addition to biology, other clinically relevant data in oncology are included and an attempt is made to identify patients who are most likely to benefit from treatment. The latter aspects will better define the profile of the target patient, probably prevent overtreatment, and improve cost-benefit ratios. Interesting data on radiotherapy results improved by increasing tissue hemoglobin have been published but will need further confirmation.

Nanomolar range docetaxel treatment sensitizes MCF-7 cells to chemotherapy induced apoptosis, induces G2M arrest and phosphorylates bcl-2.

Docetaxel (Taxotere), a member of the taxoid family of chemotherapy drugs is currently being tested in clinical trials simultaneously with other apoptosis inducing drugs like doxorubicin. We show, in vitro, in MCF-7 breast cancer cells that when it is used at doses as low as 5nM, 24 hours before either doxorubicin or etoposide, docetaxel is capable of inducing a significant increase in cell death compared to the reverse sequence or simultaneous treatment. We further show that this increase in cell death is due to an increase in apoptosis, and that this sensitization coincides with a docetaxel induced G2-M arrest and phosphorylation of the bcl-2 oncoprotein. We speculate that this phosphorylation of the apoptosis blocker bcl-2 might be responsible for the sensitization, and we suggest a clinical study comparing a 24 hour docetaxel pretreatment to the current simultaneous schedules.

The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and -11.

Some epidemiological studies have suggested that aspirin could be a chemopreventive agent against breast cancer. We tested the effects of the aspirin metabolite salicylate (SA) on four (Hs578T, MCF-7, MDA-MB-231, and T-47D) breast cancer cell (BCC) lines in vitro. Two features were studied: the proliferation of BCC and their production of the osteolytic cytokines interleukins-6 (IL-6) and -11 (IL-11) since BCC frequently metastasize to bone and induce tumor-induced osteolysis. SA, from 0.5 to 5 mM, caused BCC growth inhibition by up to 70% (IC50 range 2.54 to 4.28 mM). At high concentrations, the drug induced apoptosis only (MDA-MB-231), or both apoptosis and primary necrosis (MCF-7). SA, as well as indomethacin (INDO), reduced the synthesis of IL-6 and -11, at both the protein and mRNA levels, in the two cell lines producing these cytokines (MDA-MB-231 and Hs578T). This latter effect seemed to be mediated by PGE2 since SA and INDO reduced PGE2 levels in MDA-MB-231 and Hs578T cells, PGE2 was not detected in MCF-7 and T-47D cells and exogenous PGE2 increased IL-6 and -11 expression by MDA-MB-231 cells. Collectively, our results suggest that SA could reduce the growth of breast tumors and inhibit to some extent the ability of BCC to induce osteoclast recruitment and osteolysis. These data indicate the need for further epidemiological and experimental studies.

[Diagnosis of lung cancer]. / Depistage de la neoplasie bronchique.

Due to the frequent diagnosis at a late inoperable stage and the bad prognosis of metastatic disease, lung cancer has become the first cause of cancer mortality. Early detection is thus the only way to influence mortality as there is no good treatment available for advanced disease. In the eighties, large screening studies using standard chest X Ray and sputum cytology have not been able to show a significant reduction in global lung cancer mortality. However these studies are now largely criticized for their methodological flaws. Recently, a new technique using auto-fluorescence fibroscopy has been developed, which is able to detect dysplastic and in situ neoplastic lesions which are invisible to standard fibroscopic techniques. This technique holds great promise in the detection of early lesions. In addition, molecular biology techniques are being developed which aim at detecting early invasive lesions at a stage where surgical treatment is still curative. The addition of these two techniques will probably in the future increase the efficiency of lung cancer screening. Therefore we think that new large scale screening studies are needed.

A secreted FGF-binding protein can serve as the angiogenic switch in human cancer.

The growth and metastatic spread of cancer is directly related to tumor angiogenesis, and the driving factors need to be understood to exploit this process therapeutically. However, tumor cells and their normal stroma express a multitude of candidate angiogenic factors, and very few specific inhibitors have been generated to assess which of these gene products are only innocent bystanders and which contribute significantly to tumor angiogenesis and metastasis. Here we investigated whether the expression in tumors of a secreted fibroblast growth factor (FGF)-binding protein (FGF-BP) that mobilizes and activates locally stored FGFs (ref. 11) can serve as an angiogenic switch molecule. Developmental expression of the retinoid-regulated FGF-BP gene is prominent in the skin and intestine during the perinatal phase and is down-modulated in the adult. The gene is, however, upregulated in carcinogen-induced skin tumors, in squamous cell carcinoma (SCC) and in some colon cancer cell lines and tumor samples. To assess the significance of FGF-BP expression in tumors, we depleted human SCC (ME-180) and colon carcinoma (LS174T) cell lines of their endogenous FGF-BP by targeting with specific ribozymes. We found that the reduction of FGF-BP reduced the release of biologically active basic FGF (bFGF) from cells in culture. Furthermore, the growth and angiogenesis of xenograft tumors in mice was decreased in parallel with the reduction of FGF-BP. This suggests that human tumors can utilize FGF-BP as an angiogenic switch molecule.

Resistance to apoptosis and up regulation of Bcl-2 in benign prostatic hyperplasia after androgen deprivation.

PURPOSE: Benign prostatic hyperplasia (BPH) is related to advancing age and the presence of androgens and occurs in virtually all older men. BPH causes morbidity, most often by urinary obstruction, in a substantial fraction of men over sixty. Both finasteride and androgen ablation induce partial diminution in BPH that occurs over weeks to months. This is in contrast to the often rapid involution seen in both normal prostatic epithelium and prostatic carcinoma in response to androgen withdrawal. This study was performed to analyze the response of prostatic cells, and in particular BPH, to acute androgen ablation. MATERIALS AND METHODS: We subjected a cohort of 26 men to androgen ablation with goserelin, a gonadotrophin releasing hormone agonist, for 3-4 weeks prior to radical prostatectomy for prostate cancer. Preablation biopsy specimens and prostatectomy specimens were immunohistochemically stained for apoptotic cells and for expression of apoptosis regulatory proteins Bcl-2, Bax, Bcl-x, and Bak. RESULTS: Normal prostatic epithelial cells and prostate cancer responded to hormone deprivation by undergoing apoptosis, but in 19/26 specimens prostatic hyperplasia had a total absence of apoptosis. In all 26 specimens, benign prostatic hyperplasia demonstrated increased expression of the Bcl-2 protein, but no change in the expression of Bax, Bcl-x, and Bak. In contrast, adjacent normal and malignant prostatic epithelium showed positive staining for apoptosis and did not alter Bcl-2 expression in response to androgen ablation. CONCLUSIONS: BPH demonstrated increased staining for Bcl-2 after androgen deprivation that may render hyperplastic epithelium relatively resistant to apoptosis induced acutely by androgen withdrawal.

In vivo inhibition of angiogenesis and induction of apoptosis by retinoic acid in squamous cell carcinoma.

Retinoids inhibit the growth and reverse aberrant differentiation of squamous cell carcinoma (SCC) cells in vitro. To investigate the potential mechanisms of antitumor activity of retinoids in vivo, we used the cervical SCC cell line ME-180 as a s.c. tumor xenograft in athymic nude mice. After s.c. injection, tumor cells were allowed to form visible tumors and antitumor activity of all-trans-retinoic acid (tRA) was studied. tRA was administered daily for a 1-week or a 2-week period at 60 mg/kg/day. Tumor specimens were then analyzed using immunohistochemical staining for the number of blood vessels and apoptotic cells and for proliferating cell nuclear antigen expression. Furthermore, we studied the effect of the tRA treatment on the expression of a binding protein for fibroblast growth factors (BP; Gen-Bank accession no. M60047) that is a candidate angiogenesis modulator in SCC (F. Czubayko et al., J. Biol. Chem., 269: 28243-28248, 1994). We found that in vivo tRA treatment reduces BP expression in SCC xenografts, inhibits their angiogenesis, induces apoptosis of the tumor cells, and leads to a decrease of the tumor growth rate. We speculate that the tRA down-regulation of BP is responsible for the reduction of angiogenesis.

Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin.

Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro. In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased. Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.

Cooperation of TGF alpha and c-Myc in mouse mammary tumorigenesis: coordinated stimulation of growth and suppression of apoptosis.

We have previously shown that TGF alpha and c-Myc interact in a strong, synergistic fashion to induce mammary gland tumors in double transgenic mice. Here we show this interaction can be explained, at least in part, by a cooperative growth stimulus by the two proteins, and by TGF alpha-mediated inhibition of c-Myc-induced apoptosis. We initially compared rapidly progressing mammary tumors from double transgenic mice to long latency tumors from single transgenic mice and observed a striking difference in the occurrence of apoptosis among the three groups. Tumors exhibiting apoptosis were derived exclusively from mice that expressed the c-myc transgene in the absence of the TGF alpha transgene, indicating that TGF alpha might protect c-Myc-overexpressing cells from programmed cell death. Cell lines were derived from single and double transgenic mammary tumors to examine further the mechanism underlying the cooperative interaction between the two gene products. In accordance with our in vivo data, apoptosis was only detected when the c-myc transgene was expressed without the TGF alpha transgene. Furthermore, exogenous addition of TGF alpha inhibited apoptosis in cells overexpressing c-Myc alone. In addition, tumor-derived cells that overexpressed both TGF alpha and c-Myc exhibited faster growth rates in vitro and in vivo and were less sensitive to the inhibitory effects of TGF beta in vitro compared to cell lines expressing only one of the transgenes. Based on our findings we propose that TGF alpha acts both as a proliferative and a survival factor for c-Myc-expressing tumor cells. Our results indicate that TGF alpha and c-Myc cooperate in tumorigenesis via a dual mechanism: TGF alpha can inhibit c-Myc-induced apoptosis and both proteins provide a growth stimulus.

Epirubicin cardiotoxicity: a study comparing low- with high-dose-intensity weekly schedules.

Epirubicin is one of the less cardiotoxic alternatives to doxorubicin. We were interested in studying the cardiotoxic effect of the total cumulative dose, and weekly schedules of low compared to high dose intensity. Fifty-seven patients were treated with different epirubicin-containing regimens. We confirm the classical notion that total cumulative doses of less than 600 mg/m2 do not induce significant cardiotoxicity, whereas doses above 600 mg/m2 are associated with a trend towards cardiotoxicity. Patients receiving a high weekly dose intensity (> 40 mg/m2), however, did have a significantly lower incidence of cardiotoxicity than those receiving a low dose intensity per week (< 40 mg/m2) (22.8% versus 50%; P < 0.05). We identified the association of a dose intensity of more than 40 mg m-2/ week-1 and a cumulative dose of 400-899 mg/m2 or a dose intensity of less that 40 mg m-2/week-1 and a cumulative dose of less than 400 mg/m2 to have the lowest incidence rate of cardiotoxicity. We conclude from this study that epirubicin in weekly schedules of high dose intensity is not more cardiotoxic than in weekly schedules of low dose intensity.