Search

IntroductionBreast cancer risk of recurrence is known to span 20 years, yet existing prognostic signatures are best at predicting early recurrences (≤ 5 years). There is a critical need to identify those patients at risk of late-relapse (>5 years), in order to select potential candidates for further treatment and to identify molecular targets for such treatment.MethodsA total of 252 breast primary tumors were selected at the Netherlands Cancer Institute from a retrospective series of ER+, HER2- breast cancer patients with a follow-up of at least 10 years. Gene expression analysis was performed using Agilent 4x44K microarrays. Patients were classified in 3 groups: no relapse (M0); relapse before 5 years (M0-5) or after 5 years (M5-15). We assessed the correlation of clinico-pathological variables with late Distant Metastases (DM). We divided the patient series into a training set of untreated patients (n = 140) and a test set of treated patients (n = 112), to investigate whether a gene-signature or single genes could be identified for predicting late DM. Pathway level late DM correlates were identified using PARADIGM and DAVID.ResultsOf the clinico-pathologic variables tested, only lymph node status associated with late DM. A 241-gene signature developed on the NKI training set was able to classify M5-15 patients in the test set with a sensitivity of 77% and a specificity of 33% (AUC 0.654). This signature showed enrichment in genes involved in immune response and extracellular matrix. An alternative analysis of individual genes identified CH25H as an independent predictor of distant metastasis in our patient series.ConclusionsWe identified a gene signature for late metastasis in breast cancer. Our data are consistent with a model in which suppressed anti-tumoral immunity enables dormant tumor cells to re-enter the cell cycle to form metastases in response to extrinsic events in the microenvironment.

Objectives: Using judicial files on neonaticides, (1) to examine the frequency of the association between neonaticide and denial of pregnancy; (2) to assess the accuracy of the concept of denial of pregnancy; (3) to examine its usefulness in programs to prevent neonaticides. Methods: Quantitative and qualitative analyses of data collected from judicial files during a population-based study carried out in 26 courts in 3 regions of France over a 5-year period. Results: There were 32 cases of neonaticides identified; 24, perpetrated by 22 mothers, were solved by police investigation. Aged 26 years on average, the mothers had occupations that resembled those of the general population and 17 had jobs, 13 were multiparous and 11 lived in a couple relationship. No effective contraception was used by women in 20 cases. Psychopathology was rare but mothers shared a personality profile marked by immaturity, dependency, weak self esteem, absence of affective support, psychological isolation and poor communication with partners. No pregnancy was registered nor prenatal care followed. Two (perhaps 3) pregnancies were undiscovered until delivery. No typical denial of pregnancy was observed in the other cases. Pregnancies were experienced in secrecy, with conflicting feelings of desire and rejection of the infant and an inability to ask for help. Those around the mothers, often aware of the pregnancy, offered none. In the absence of parallel clinical data, it is not possible to calculate the frequency of the association between neonaticide and denial of pregnancy. Conclusions: The term "denial of pregnancy" cannot fully reflect the complexity of emotions and feelings felt by all perpetrators of neonaticide and is used differently by different professionals. The term itself and its excessive generalization contribute to pathologizing women while absolving those around them and has little operational value in preventing neonaticides. The authors suggest rethinking the terms presently used to describe the phenomenon of pregnancy denial. (Contains 1 table.)

Objectives: Test the hypothesis of an underestimation of infant homicides in mortality statistics in France; identify its causes; examine data from the judicial system and their contribution in correcting this underestimation. Methods: A retrospective, cross-sectional study was carried out in 26 courts in three regions of France of cases of infant deaths submitted to the courts, 1996-2000, with follow-up of their files until case closing (1996-2008). For each case, cause of death established by the courts was compared with ICD cause of death as coded in official mortality statistics. Results: We examined 247 cases. Shortcomings in investigations were noted (autopsies: 75% of cases; fundus examination: 11%; diagnosis of sudden infant death syndrome [SIDS] without autopsy: 41%). Eighty deaths were considered homicides by the courts. Homicide rates in the court study are 2-3.6 times higher than those in mortality statistics. Nearly 1/3 of "accidental" deaths and 1/4 of deaths from unknown cause in mortality statistics are homicides. Mechanisms of underascertainment are: physicians' inappropriate death certification and underreporting of suspicious cases; inadequate investigation of cases; incomplete communication of final medical and forensic results to the mortality statistics department. Conclusions: In a country where neither transportation of the body to a hospital nor autopsy is obligatory, judicial data can make an important contribution to correcting mortality statistics. Practice implications: This study led to the first French protocol for investigating sudden unexpected deaths in infancy (SUDI). The protocol includes a physician "training" section focused on understanding the symptomatology and risk factors of violence, as well as the quality of death certification. (Contains 6 tables.)

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death., Author(s): Lionel Apetoh [1, 2, 3, 20]; Francois Ghiringhelli [1, 2, 3, 4, 20]; Antoine Tesniere [1, 2, 5, 20]; Michel Obeid [1, 2, 5]; Carla Ortiz [1, 2, 3]; [...]

Immunohistochemical analysis is used to determine the expression of the excision repair cross-complementation group 1 (ERCC1) protein in operative specimens of non-small-cell lung cancer through comparison of the effect of adjuvant cisplatin-based chemotherapy on survival. Patients with completely resected non-small-cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not.

Author(s): Julien Taieb [1, 11]; Nathalie Chaput [1, 11]; Cedric Menard [1, 11]; Lionel Apetoh [1]; Evelyn Ullrich [1]; Mathieu Bonmort [1]; Marie Pequignot [2]; Noelia Casares [2]; Magali Terme [...]

Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.

The initiation of T-cell-mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8[sup.+] T-cell-dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions., Author(s): Joseph Wolfers [1, 5]; Anne Lozier [1, 5]; Graca Raposo [3]; Armelle Regnault [2]; Clotilde Thery [2]; Carole Masurier [1]; Caroline Flament [1]; Stephanie Pouzieux [4]; Florence Faure [2]; [...]

Purpose. This study investigates the efficacy and toxicity of daily oral etoposide in chemotherapy for non-heavily pretreated advanced and metastatic soft tissue sarcoma (STS).

Interleukin-2 and interferon alfa-2a combined may be more effective than either alone in patients with a type of kidney cancer called renal-cell carcinoma. Researchers randomly assigned 425 patients with renal-cell carcinoma to receive either interleukin-2, interferon alfa-2a or both drugs. At 10 weeks, 18.6% of the patients receiving both drugs had responded, compared to 6.5% to 7.5% of those receiving either drug alone. There was no difference in survival rates, but those receiving both drugs were more likely to survive without relapse. Side effects were more common in those receiving interleukin-2.