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Purpose of Review: To review the studies addressing mammalian target of rapamycin (mTOR) inhibitors in breast cancer and resistance to rapalogs. Preclinical and clinical studies have suggested mTOR inhibitors may help overcome the resistance to endocrine therapy and trastuzumab. Despite much interest, knowledge of the mechanism and molecular response to mTOR inhibitors is incomplete., Recent Findings: Resistance to mTOR inhibitors has been explored in preclinical studies and can be defined as primary, associated with amplifications or mutations of different kinases, or secondary, in which rapalog activates the feedback loops involving the insulin-like growth factor I receptor (IGF-IR), platelet-derived growth factor receptor and mitogen-activated protein kinase (MAPK) pathway. Current clinical trials are testing the combinations of rapamycin with other kinase inhibitors including IGF-IR, phosphoinositide 3-kinase and MAPK-extracellular signal-regulated kinase inhibitors., Summary: Recent findings on the resistance to rapalogs have stimulated the assessment of combinations of inhibitors in clinical trials. This review summarizes the current knowledge of primary and secondary rapalog resistance, and the current efforts to overcome this resistance.

Background: To evaluate a strategy whereby extensive surgery ± external radiotherapy (RT) could improve local control in pterygopalatine/infratemporal fossa (PIF) sarcoma., Procedure: Forty-one patients with a diagnosis of sarcoma involving the PIF and referred to our Institute from 1984 to 2009 were included in the analysis. Patients received multidrug chemotherapy and radiotherapy ± surgery, depending on the period of treatment., Results: The median age at diagnosis was 7.6 years (range: 0.1-22 years). There were 36 RMS, 3 undifferentiated sarcoma and 2 other soft-tissue sarcomas. Sixty-eight percent of patients had meningeal risk factors at diagnosis. Local treatment consisted of RT alone in 19 patients, surgery in combination to RT in 19 patients and surgery alone in 3 patients. The local progression rate (LPR) at 5 years was 45% for the entire population, 59% for the 19 patients treated with RT alone and 34% for the 22 patients who had surgery as part of their treatment. All locoregional failures after extensive surgery occurred at the skull base and/or in leptomeningeal spaces., Conclusions: Multidisciplinary approach including extensive surgery for PIF sarcoma is feasible and yields good local control with 15/22 patients in local complete remission. Future studies are warranted to confirm these promising results, to evaluate the possibility of avoiding RT or limiting the RT field, and to extend the indication for extensive surgery to other "worse" sites of PM sarcoma such as the paranasal sinuses., (Copyright © 2013 Wiley Periodicals, Inc.)

Non-small cell lung carcinoma (NSCLC) is the most common form of lung cancer and is associated with a high mortality rate worldwide. The majority of individuals bearing NSCLC are treated with surgery plus adjuvant cisplatin, an initially effective therapeutic regimen that, however, is unable to prevent relapse within 5 years after tumor resection in an elevated proportion of patients. The factors that predict the clinical course of NSCLC and its sensitivity to therapy remain largely obscure. One notable exception is provided by pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. PDXK has recently been shown to be required for optimal cisplatin responses in vitro and in vivo and to constitute a bona fide prognostic marker in the NSCLC setting. Together with PDXK, 84 additional factors were identified that influence the response of NSCLC cells to cisplatin, in vitro including the hepatic lipase LIPC. Here, we report that the intratumoral levels of LIPC, as assessed by immunohistochemistry in two independent cohorts of NSCLC patients, positively correlate with disease outcome. In one out of two cohorts studied, the overall survival of NSCLC patients bearing LIPChigh lesions was unaffected, if not slightly worsened, by cisplatin-based adjuvant therapy. Conversely, the overall survival of patients with LIPClow lesions was prolonged by post-operative cisplatin. Pending validation in appropriate clinical series, these results suggest that LIPClow NSCLC patients would be those who mainly benefit from adjuvant cisplatin therapy. Thus, the expression levels of LIPC appear to have an independent prognostic value (and perhaps a predictive potential) in the setting of NSCLC. If these findings were confirmed by additional studies, LIPC expression levels might allow not only for NSCLC patient stratification, but also for the implementation of personalized therapeutic approaches.

The destruction of tumor cells by the immune system is under the control of positive and negative receptors that tightly regulate T-cell effector functions. The T-cell receptor (TCR) inhibitory molecule CD5 critically contributes to the regulation of antitumor immune responses. Indeed, the modulation of CD5 within the tumor microenvironment corresponds to a strategy adopted by tumor-specific cytotoxic T lymphocytes (CTLs) to optimize their cytotoxic and cytokine secretion functions. In this review, we provide insights into the immunobiology of CD5 and its role in regulating antitumor CD8 T-cell responses, and suggest the possibility of targeting CD5 to improve the efficacy of current immunotherapeutic approaches against cancer.

Purpose: Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors., Experimental Design: We took advantage of a cohort of 91 patients with resected NSCLC, for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1-positive and ERCC1-negative tumors of NSCLC. We carried out a global molecular analysis including assessment of ERCC1 expression levels by using both immunohistochemistry (IHC) and quantitative reverse transcriptase PCR (qRT-PCR), genomic instability, global gene and miRNA expression, and sequencing of selected key genes involved in lung carcinogenesis., Results: ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1-negative tumors had a higher rate of genomic abnormalities versus ERCC1-positive tumors. ERCC1-positive tumors seemed to share a common DNA damage response (DDR) phenotype with the overexpression of seven genes linked to DDR. The miRNA expression analysis identified miR-375 as significantly underexpressed in ERCC1-positive tumors., Conclusions: Our data show inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Furthermore, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1-negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC., (©2011 AACR.)

The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.

Background: Tumor-related proteases such as urokinase-type plasminogen (uPA), plasminogen activator inhibitor (PAI-1), and cathepsin D (cath-D) are involved in the prognosis of breast cancer (BC) and promote the metastatic process. We investigated the relationship between these proteases and their prognostic significance according to the ER status., Methods: uPA, PAI-1, and cath-D levels were prospectively measured in tumor from 316 patients with primary BC. The distribution and relationship between these proteases and ER subsets were analyzed as well as the prognostic significance., Results: Quantitative levels of uPA, and PAI-1 were higher in ER-patients (p< 0.001) whereas no difference was observed for cath-D levels in ER subsets (p = 0.96). In patients with a positive and highly positive ER status, a high cath-D level was associated with a poorer prognosis. Patients in the highly positive ER group experienced poorer survival in the group with a high PAI-1 level compared to the group with a low PAI-1 level. In ER+ patients, cath-D (p= 0.02) and the tumor size (p= 0.03) were independent factors for OS., Conclusion: The prognostic significance of proteases is modulated by the ER status. Cath-D and PAI-1 could identify a high-risk group with an adverse outcome in ER+ patients.

Interaction of the integrin αE(CD103)β7 expressed on tumor-infiltrating lymphocytes (TIL) with E-cadherin on epithelial tumor cells is required to trigger polarized exocytosis of cytotoxic granules in TIL that elicit tumor cell lysis. In this study, we investigated the functional and signaling properties of CD103 and its individual contribution to T-cell-mediated cancer-cell killing. Our results indicated that the binding of CD103 on tumor-specific CTL to immobilized recombinant E-cadherin-Fc is sufficient to induce the polarization of cytolytic granules, whereas the degranulation of cytolytic granules also requires the coengagement of the T-cell receptor. Moreover, minimal CD103 triggering promotes the phosphorylation of the ERK1/2 kinases and phospholipase Cγ1 (PLCγ1). Inhibiting PLCγ blocks granule relocalization, decreasing T-cell receptor-mediated cytotoxicity. Thus, our results emphasize a unique costimulatory role of CD103 in tumor-specific CTL activation by providing signals that promote T-cell effector functions needed to specifically target and lyse cancer cells., (© 2011 AACR.)

Adhesion properties of hematopoietic stem cells (HSCs) in the bone marrow (BM) niches control their migration and affect their cell-cycle dynamics. The serum response factor (Srf) regulates growth factor-inducible genes and genes controlling cytoskeleton structures involved in cell spreading, adhesion, and migration. We identified a role for Srf in HSC adhesion and steady-state hematopoiesis. Conditional deletion of Srf in BM cells resulted in a 3-fold expansion of the long- and short-term HSCs and multipotent progenitors (MPPs), which occurs without long-term modification of cell-cycle dynamics. Early differentiation steps to myeloid and lymphoid lineages were normal, but Srf loss results in alterations in mature-cell production and severe thrombocytopenia. Srf-null BM cells also displayed compromised engraftment properties in transplantation assays. Gene expression analysis identified Srf target genes expressed in HSCs, including a network of genes associated with cell migration and adhesion. Srf-null stem cells and MPPs displayed impair expression of the integrin network and decreased adherence in vitro. In addition, Srf-null mice showed increase numbers of circulating stem and progenitor cells, which likely reflect their reduced retention in the BM. Altogether, our results demonstrate that Srf is an essential regulator of stem cells and MPP adhesion, and suggest that Srf acts mainly through cell-matrix interactions and integrin signaling.

Objective: Oestrogen receptor (ER) determination in breast cancer (BC) is a major yardstick for the prognosis and for response to hormonal therapy (HT). As several techniques have been proposed for ER quantification, the purpose of our study was to assess whether the qualitative or quantitative analysis of ER expression might influence the prognosis and response to treatment., Materials and Methods: We analysed overall survival (OS) and disease-free survival (DFS) in 797 primary BC cases with ER determination by enzyme immunoassay (EIA) and immunohistochemistry (IHC). The clinical impact according to qualitative or quantitative analysis of ER expression was assessed. Response to HT was evaluated according to quantitative EIA-determined ER expression levels., Results: According to the qualitative analysis of ER expression, patients with EIA-determined and IHC-determined ER-positive tumours had significantly longer OS and DFS (p<0.001). The analysis stratified on quartiles of ER levels showed significantly different outcomes according to EIA- and IHC-determined subgroups. In the group of patients who received adjuvant treatment, 5-year OS was significantly different between the groups, with a clear benefit for the highest EIA-determined ER quartiles (p<0.001). Comparatively, in terms of 5-year DFS, a clear separation was noted between groups for adjuvant treatment (p<0.001). The group with moderate ER+ values was clearly distinct from the ER-negative population. Quantitative ER expression helped to better distinguish the beneficial or detrimental effect of HT within quartiles of ER-expressing tumours. Based on the STEPP analysis which showed a trend towards an ER effect on DFS as a function of HT assignment, we confirm the benefit of HT in patients with a very high EIA-determined ER level and a detrimental impact on negative and weakly positive groups., Conclusion: Quantitative ER expression in BC helps to better discriminate heterogeneity in clinical outcome and response to HT., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Introduction: The use of biomarkers to evaluate the presence of a target or to select a specific therapy is increasingly advocated. The correlation of biomarker expression between the primary tumor and its corresponding metastasis has not yet been well documented and analyzed in patients with non-small cell lung cancer (NSCLC)., Methods: The expression of epidermal growth factor receptor (EGFR), excision repair cross-complementing (ERCC1), vascular-endothelial growth factor receptor, and Ki-67 was immunohistochemically analyzed in tumor samples of primary NSCLC and one corresponding metastasis in a population of 49 patients., Results: Sixteen cases (33%) displayed clear discordance in the EGFR status between the primary tumor and the metastasis, with a significant trend toward downregulation of EGFR in the metastasis (p = 0.01). The ERCC1 status was discordant in 20 cases (41%), with a trend toward overexpression in brain and adrenal metastases (p = 0.01 and p = 0.08, respectively). The vascular-endothelial growth factor receptor and Ki-67 statuses were discordant in 13 (27%) and 15 (31%) cases, respectively. No difference in expression was observed between synchronous and metachronous metastasis., Conclusion: Biomarker expression is discordant between the primary tumor and its corresponding metastasis in about one third of patients with NSCLC. These findings should be considered in the setting of clinical trials and further explored using frozen material and high-throughput techniques.

Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04-71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58-96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96-61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43-60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies.

On the basis of experimental models and some human data, we can assume that tumor outgrowth results from the balance between immunosurveillance (the extrinsic tumor suppressor mechanisms) and immunosubversion dictated by transformed cells and/or the corrupted surrounding microenvironment. Cancer immunosurveillance relies mainly upon conventional lymphocytes exerting either lytic or secretory functions, whereas immunosubversion results from the activity of regulatory T or suppressor myeloid cells and soluble mediators. Although specific tools to target or ablate dendritic cells (DCs) became only recently available, accumulating evidence points to the critical role of the specialized DC system in dictating most of the conventional and regulatory functions of tumor-specific T lymphocytes. Although DC can be harnessed to silence tumor development, tumors in turn can exploit DC to evade immunity. Indeed, DCs harbor defects in their differentiation and stimulatory functions in cancer-bearing hosts and can actively promote T-cell tolerance to self-tumor antigens. In this review, we will focus on the dual role of DC during tumor progression and discuss pharmacoimmunological strategies to harness DC against cancer.

Objectives: Menopause, the permanent cessation of ovarian activity, is part of normal aging, resulting in climacteric symptoms for most women, particularly in Western countries. The objective of the present study was to analyse risk factors for onset of menopausal symptoms., Methods: Analyses were based on the 28,118 women participating in the French E3N cohort study who reached menopause between 1990 and 2000. Questionnaires were sent every 2 years, and specifically enquired about use of hormonal treatments, reproductive factors, smoking status, anthropometric measurements, dietary habits and personal medical history, including onset of menopausal symptoms. Hazard ratios were computed from multivariable Cox proportional hazard models with age as the time-scale., Results: The risk of onset of menopausal symptoms was negatively associated with education level and with some hormonal and reproductive factors (usual duration of menstrual cycles, parity and current use of oral contraceptives). A decrease in risk was found in those with underweight, overweight and obesity, but only in post-menopause. The risk was positively associated with smoking and alcohol consumption; it was also positively related to certain frequent medical conditions (depression, migraine, benign thyroid disease, atopy), possibly due to underlying common mechanisms such as the influence of vaso-active substances. Among dietary factors, rapidly absorbed sugars and snacking were positively associated with the risk of onset of menopausal symptoms., Conclusions: Onset of menopausal symptoms seems to be affected by various reproductive, hormonal and environmental factors. Some of them are modifiable, which may allow suggesting recommendations.

For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens.

A JAK2(V617F) mutation is frequently found in several BCR/ABL-negative myeloproliferative disorders. To address the contribution of this mutant to the pathogenesis of these different myeloproliferative disorders, we used an adoptive transfer of marrow cells transduced with a retrovirus expressing JAK2(V617F) in recipient irradiated mice. Hosts were analyzed during the 6 months after transplantation. For a period of 3 months, mice developed polycythemia, macrocytosis and usually peripheral blood granulocytosis. Transient thrombocytosis was only observed in a low-expresser group. All mice displayed trilineage hyperplasia in marrow and spleen along with an amplification of myeloid and erythroid progenitor cells and a formation of endogenous erythroid colonies. After 3 to 4 months, polycythemia regressed, abnormally shaped red blood cells and platelets were seen in circulation, and a deposition of reticulin fibers was observed in marrow and spleen. Development of fibrosis was associated with anemia, thrombocytopenia, high neutrophilia, and massive splenomegaly. These features mimic human polycythemia vera and its evolution toward myelofibrosis. This work demonstrates that JAK2(V617F) is sufficient for polycythemia and fibrosis development and offers an in vivo model to assess novel therapeutic approaches for JAK2(V617F)-positive pathologies. Questions remain regarding the exact contribution of JAK2(V617F) in other myeloproliferative disorders.

Purpose: The aim of the study was to compare reproductive factors in patients with inflammatory breast cancer (IBC), and with non-inflammatory breast cancer (non-IBC). The study was performed in two centers: one French including 49 IBC patients and 140 non-IBC and another Tunisian including 97 IBC and 139 non-IBC. Unconditional logistic regression was used for the analyses., Patients and Methods: The French IBC patients had a lower educational level, a higher body mass index and a longer cumulative duration of breast-feeding, and they included a greater proportion of non-European women, than the non-IBC patients. In the multivariate analysis, only breast-feeding duration remained associated with the IBC status (P=10(-3)). These results could not be verified in the Tunisian series, because the duration of breast-feeding was unavailable in this center., Results: This study suggests that the etiology of IBC might be different of that of non-IBC.

The identification of the JAK2 V617F mutation in patients with myeloproliferative disorders (MPDs) represents a major breakthrough in our understanding of the pathogenesis of these diseases. One year after its discovery, an impressive number of publications appeared. These articles confirmed most of the initial results and tried to focus on the main issues arising from this discovery. JAK2 V617F came as recognition of the work of many investigators, starting with William Dameshek, who demonstrated that classical MPDs shared phenotypical mimicry and a general pattern of clinical evolution. We now know that this mutation is the common mark of a molecular clinical entity of MPD shared by 90% of polycythemia vera (PV) and approximately 50% of essential thrombocythemia and idiopathic myelofibrosis patients. However, many questions arise from this discovery. This review, in view of the recent literature, tries to address crucial questions regarding the mechanism of action and the clinical relevance of the JAK2 V617F mutation. The first question is how a unique mutation may explain the clinical diversity of JAK2 V617F-positive MPDs. We now know that acquisition of this mutation is only one step, and that gain of the JAK2 V617F locus, as gain in constitutive Janus kinase 2 (JAK2) activity, may represent another step in disease progression. It is still not known if and how this event or other unknown events may favor disease diversity and possibly disease onset. The second question is how the identification of the JAK2 V617F mutation will change our approach to patients. If detection of JAK2 V617F drastically simplifies the diagnosis of MPDs, and especially PV, prospective clinical trials will be necessary to determine if the therapeutic attitude and disease prognosis will depend on the presence of JAK2 V617F. The third question is how this discovery will benefit the patients. The immediate benefits are still difficult to evaluate, but this discovery, as a major advance in our understanding of the pathogenesis of MPDs, surely has opened perspectives for possible targeted therapies and raises new hopes for patients and clinicians.

Background: Analyses of predictive factors for local recurrences are important, as an increasing number of patients with early breast cancer opt for a breast-conserving procedure. This study investigates whether factors predictive of local recurrence differ between patients treated with conservative or radical surgery., Patients and Methods: Two thousands and six patients with invasive breast carcinoma (< or =25 mm) were included. Of these patients, 717 were treated conservatively (lumpectomy and breast irradiation) and 1289 were treated with total mastectomy. All patients had axillary dissection and received lymph node irradiation if axillary nodes were positive. Most patients did not receive adjuvant chemotherapy or additive hormonal treatments. The mean duration of follow-up was 20 years. The main end point was the total local recurrence rate. The risk factors of local recurrence were estimated by multivariate analyses and interaction tests were used for intergroup comparisons., Results: Statistically significant predictive factors for mastectomized patients were histological grade, extensive axillary node involvement (10 nodes or more), and inner quadrant tumors, which were of borderline significance. Young age, however, was not a prognostic indicator for local recurrence. The main statistically significant factor for patients treated with a conservative approach was young age (< or =40 years). These younger patients had a five-fold increased risk of developing a breast recurrence compared with patients older than 60 years., Conclusions: Younger patients with early breast cancer treated with breast-conserving surgery should in particular be followed up at regular intervals so that any sign of local failure can be diagnosed early.

The p210(bcr-abl) protein was shown to inhibit apoptosis induced by DNA damaging agents. Apoptotic DNA fragmentation is delayed in the bcr-abl+ K562 and KCL-22 compared with the bcr-abl- U937 and HL-60 cell lines when treated with etoposide concentrations that induce similar DNA damage in the four cell lines. By the use of a cell-free system, we show that nuclei from untreated cells that express p210(bcr-abl) remain sensitive to apoptotic DNA fragmentation induced by triton-soluble extracts from p210(bcr-abl-) cells treated with etoposide. In the four tested cell lines, apoptotic DNA fragmentation is associated with a decreased expression of procaspase-3 (CPP32/Yama/apopain) and its cleavage into a p17 active fragment, whereas the long isoform of procaspase-2 (ICH-1L) remains unchanged and the poly(adenosine diphosphate-ribose)polymerase protein is cleaved. These events are delayed in bcr-abl+ compared with bcr-abl- cell lines. The role of p210(bcr-abl) in this delay is confirmed by comparing the effect of etoposide on the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent UT7 cells and the bcr-abl-transfected GM-CSF-independent UT7/9 clone. We conclude that the cytosolic pathway that leads to apoptotic DNA fragmentation in etoposide-treated leukemic cells is delayed upstream of procaspase-3-mediated events in bcr-abl+ cell lines.

In the present work, to analyze the heterogeneity of the tumor-specific cytotoxic immune response, a large number of T cell clones were generated from the infiltrate of a tumor-proximal invaded lymph node, and two kinds of melanoma-specific CD8+ CTL clones were derived. The majority of T cell clones (about a hundred) are characterized by a specific lysis of the autologous tumor cell lines. Among 34 of the latter clones, HLA-A2 molecule and MART-1(27-35) peptide have been shown to play a predominant role in tumor recognition. However, no significant amplification at the tumor site was observed for 3 of these CTL. The other kind of tumor-specific CTL (1 oligoclonal and 2 clonal cell lines) did not lyse the autologous melanoma cell lines but lysed the "fresh" autologous tumor cells in a MHC class I-dependent manner. Functional analysis of the two different CTL clones have shown that they did not lyse NK targets, autologous peripheral monocytes, activated T cells, and transformed B cells or any of the few allogeneic cultured and uncultured melanoma cells we tested. TCR repertoire analysis has shown that one of these CTL clones was significantly detectable "in situ" among tumor-infiltrating lymphocytes, while not detectable among PBMC. Such melanoma-specific lymphocytes, which could not have been picked out through conventional screening procedures using tumor cell lines, could potentially play a role in tumor rejection. These results suggest that the immune response analyzed toward melanoma cell lines does not totally reflect the in situ immune status.

The authors discuss the immunological and oncological risk of prefilled silicone gel breast implants. A comparative study of 146 patients undergoing breast reconstruction by silicone implant at the Institut Gustave-Roussy and 146 matched controls demonstrated the absence of any difference between the two groups concerning survival, local recurrence rate and metastases.

Purpose: The analysis of complications in a prospective randomized trial comparing two preoperative brachytherapy low-dose rates in early stage cervical cancer is presented., Methods and Materials: Between 1985 and 1988, 204 patients with Stage I and limited Stage II cervical cancer were randomized to receive one of two preoperative brachytherapy low-dose rates (0.4 and 0.8 Gy/hr). The objective of this trial was to determine the benefits, if any, of the higher-dose rate within the therapeutic arsenal for this patient population, in terms of survival, local control, and complications. The type and severity of all complications were evaluated according to a common glossary and a strict follow-up schedule was established given that the treatment of cervical cancer is multidisciplinary, involving gynecologists, surgeons, and radiotherapists., Results: Overall survival: 85% at 2 years and local control: 93% at 2 years, were similarly distributed between the two groups. Regardless of their nature and severity, 139 and 175 complications were observed among 63% and 75% of patients, in the 0.4 and 0.8 Gy/h dose rate groups respectively. Gynecologic and urinary complications were the most frequent (38% and 28% of all complications), followed by vascular (15%), digestive (10%), nervous (5%) and cutaneous (5%). A total of 14 and 17 severe complications (Grade 3) were observed in 7% and 13% of patients, respectively in the 0.4 and 0.8 Gy/h dose rate groups (p = 0.12). Nonparametric survival methods used to compare the time to the first complication did not show a significant difference between the two groups: 62% and 72% at 2 years (p = 0.27). When the first complication and its evolution were considered (early complications), the prevalence of complications was not significantly different between the two groups: 28% vs. 34% at 2 years (p = 0.31). In this prospective trial, patients were regularly followed-up and complications of varying nature and severity were observed in succession during follow-up. When successive complications and their evolution were taken into account, the prevalence of complications was significantly greater in the higher-dose rate group: 30% vs. 45% at 2 years (p = 0.03)., Conclusion: The results of this trial showed that long-term effects of treatment, when represented by prevalence of complications over time, were more frequent in the higher dose rate group. This underlines the importance of the regular follow-up of patients and of coding, not only the occurrence of all complications, but also their evolution over time.

Two-hundred two patients with limited small cell lung cancer were tested by four consecutive alternating radiotherapy and chemotherapy protocols. The alternating schedule consisted of six cycles of chemotherapy (doxorubicin, etoposide, and cyclophosphamide, plus methotrexate in the first protocol; cisplatin replaced methotrexate in the other three protocols) and three courses of thoracic radiotherapy at a total dose of 45, 55, 65 and 61 Gy in the four consecutive protocols, respectively. A 1-week rest followed each chemotherapy cycle and each course of radiotherapy. Seventy-six percent of patients were in complete remission at the end of the induction treatment. Overall results showed a 2-year cumulative incidence rate of failure of 75%. The first cause of failure was local recurrence only, 33%; distant only, 25%; distant and local simultaneously, 9%; and intercurrent death, 8%. Overall survival rate at 5 years was 16%. No significant differences were observed between the four treatment groups. Alternating radio-chemotherapy approaches are feasible and currently included in Phase III trials.

Fotemustine has been administered to 10 patients with metastatic or redux soft sarcoma in a phase II pilot study. The main inclusion criteria were: at least one measurable site, Karnofsky index (KI) higher than 60%, no specific treatment within the last 4 weeks, correct haematological status. Induction treatment comprised fotemustine 100 mg/m2 D1-D8-D15 in a 1 h intravenous infusion protected from light, followed by a 5-week rest period. In patients with no progressive disease, maintenance treatment comprised fotemustine 100 mg/m2 D1 q 3 weeks, until progression or toxicity. Patients characteristics were: 9 M/1 F; median age: 51 years [26-66]; median KI 90% [60-100]; median number of previous drugs: 5 [2-8]; 6 patients had two or more metastatic sites and one patient had developed a sarcoma following chest radiotherapy. Evaluation was carried out in weeks 4 and 8, following the first fotemustine injection. One case of minor response and one case of stabilisation were observed, but they were of short duration. The main toxicity was haematological with delayed leucopenia and thrombopenia (nadir: week 6). In patients who have undergone previous chemotherapy, fotemustine is not efficient according to the first step of the Gehan statistical guidelines.

Human papilloma virus (HPV) DNA sequences (HPV types 16, 18, 33, 35 or uncharacterized) were detected by Southern blot hybridisation and polymerase chain reaction in 84% of 106 early-stage invasive carcinomas of the uterine cervix. Among HPV-positive patients, the risk of overall relapse did not differ with individual HPV types. Compared with HPV-positive patients, those with no detectable HPV DNA had a 2.6 times higher risk of overall relapse (p less than 0.05) and 4.5 times higher risk of distant metastases (p less than 0.01). The 24-month relapse-free survival rate in HPV-positive patients was significantly higher than that in HPV-negative patients (77% vs 40%), and the difference was similar (91% vs 56%) among those who were node-negative. These data indicate that HPV-negative cervical carcinomas may represent a biologically distinct subset of tumours that carry a poorer prognosis than do HPV-positive cancers.