Family physician involvement in cancer care and lung cancer patient emotional distress and quality of life.

PURPOSE: This study aims to describe emotional distress and quality of life (QoL) of patients at different phases of their lung cancer and the association with their family physician (FP) involvement. METHODS: A prospective study on patients with lung cancer was conducted in three regions of Quebec, Canada. Patients completed, at baseline, several validated questionnaires regarding their psychosocial characteristics and their perceived level of FP involvement. Emotional distress [profile of mood states (POMS)] and QoL [European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30)] were reassessed every 3-6 months, whether patients had metastasis or not, up to 18 months. Results were regrouped according to cancer phase. Mixed models with repeated measurements were performed to identify variation in distress and QoL. RESULTS: In this cohort of 395 patients, distress was low at diagnosis (0.79 ± 0.7 on a 0-4 scale), raising to 1.36 ± 0.8 at the advance phase (p < 0.0001). Patient's global QoL scores significantly decreased from the diagnosis to the advance phase (from 66 to 45 on a 0-100 scale; p < 0.0001). At all phases of cancer, FP involvement was significantly associated with patients' distress (p = 0.0004) and their global perception of QoL (p = 0.0080). These associations remained statistically significant even after controlling for age, gender, and presence of metastases. CONCLUSIONS: This study provides new knowledge on patients' emotional distress and QoL with cancer evolution and, particularly, their association with FP involvement. Other studies should be conducted to further explore FP role in cancer supportive care.

Enhancement of Leishmania amazonensis infection in BCG non-responder mice by BCG-antigen specific vaccine

Different patterns of cutaneous leishmaniasis can be induced when a challenge of alike dose of Leishmania amazonensis amastigotes in various inbred strains was applied. Two strains of mice, the Balb/c and C57 BL/10J, showed exceptional suscepbility, and 10(elevado a sexta potência) amastigotes infective dose lead, to ulcerative progressive lesions with cutaneous metastasis and loss by necrosis of leg on wich the footpad primary lesion occured. Lesions were also progressive but in a lower degree when C3H/HeN and C57BL/6 were infected. Lesions progress slowly in DBA/2 mice presenting lesions wich reach a discreet peack after 12 weeks, do not heal but do not uncerate. DBA/2 mice is, therefore, a good model for immunomodualtion. In attempt to determine the influence of BCG in vaccination schedule using microsomal fraction, DBA/2 became an excellent model, since it is also a non-responder to BCG. Vaccination of DBA/2 mice, receiving the same 10(elevado a sexta potência) BCG viable dose and 10 *g or 50 *g of protein content of microsomal fraction, lead to a progressive disease with time course similar to those observed in susceptible non-vaccinated C57BL/10J mice after 6 months of observation. An enhancement of infection in BCG non-responder mice suggests that use of BCG as immunostimulant in humans could be critical for both vaccination and immunoprophylactic strategies.

Current Molecular Imaging of Spinal Tumors in Clinical Practice.

Energy metabolism measurements in spinal cord tumors, as well as in osseous spinal tumors/metastasis in vivo, are rarely performed only with molecular imaging (MI) by positron emission tomography (PET). This imaging modality developed from a small number of basic clinical science investigations followed by subsequent work that influenced and enhanced the research of others. Apart from precise anatomical localization by coregistration of morphological imaging and quantification, the most intriguing advantage of this imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, MI represents one of the key technologies in translational molecular neuroscience research, helping to develop experimental protocols that may later be applied to human patients. PET may help monitor a patient at the vertebral level after surgery and during adjuvant treatment for recurrent or progressive disease. Common clinical indications for MI of primary or secondary CNS spinal tumors are: (i) tumor diagnosis, (ii) identification of the metabolically active tumor compartments (differentiation of viable tumor tissue from necrosis) and (iii) prediction of treatment response by measurement of tumor perfusion or ischemia. While spinal PET has been used under specific circumstances, a question remains as to whether the magnitude of biochemical alterations observed by MI in CNS tumors in general (specifically spinal tumors) can reveal any prognostic value with respect to survival. MI may be able to better identify early disease and to differentiate benign from malignant lesions than more traditional methods. Moreover, an adequate identification of treatment effectiveness may influence patient management. MI probes could be developed to image the function of targets without disturbing them or as treatment to modify the target's function. MI therefore closes the gap between in vitro and in vivo integrative biology of disease. At the spinal level, MI may help to detect progression or recurrence of metastatic disease after surgical treatment. In cases of nonsurgical treatments such as chemo-, hormone- or radiotherapy, it may better assess biological efficiency than conventional imaging modalities coupled with blood tumor markers. In fact, PET provides a unique possibility to correlate topography and specific metabolic activity, but it requires additional clinical and experimental experience and research to find new indications for primary or secondary spinal tumors.

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells.

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E-cadherin and β-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and β-catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/β-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer.

DIFFERENTIAL EXPRESSION OF GLUTARYL-CoA DEHYDROGENASE IN ADULT RAT CNS, PERIPHERAL TISSUES AND DURING EMBRYONIC DEVELOPMENT

Glutaryl-CoA dehydrogenase (GCDH, EC 1.3.99.7) deficiency, known as glutaric acidemia type I, is one of the more common organic acidurias. To investigate the role of this pathway in different organs we studied the tissue-specific expression pattern of rat Gcdh. The open reading frame cDNA of the rat Gcdh gene was cloned from rat brain mRNA by RT-PCR, allowing the synthesis of digoxigenin-labeled in situ hybridization (ISH) riboprobes. Gcdh mRNA expression was analyzed by ISH on cryosections of adult rat brain, kidney, liver, spleen and heart muscle, as well as on E15 and E18 rat embryos. Gcdh was found expressed in the whole rat brain, almost exclusively in neurons. Gcdh was absent from astrocytes but expressed in rare oligodendrocytes. Strong Gcdh expression was found in liver and spleen, where expression appears predominant to lymphatic nodules. In kidney, the highest Gcdh expression is found in the juxtamedullar cortex (but not in glomerula), and at lower levels in medulla. Heart muscle was negative. During embryonic development, Gcdh was found well expressed in liver, intestinal mucosa and skin, as well as at lower levels in CNS. Further studies are ongoing to provide evidence on the presence of the entire pathway in CNS in order to understand the mechanisms leading to neurotoxicity in glutaric aciduria. The high expression of Gcdh in kidney may explain why certain patients with residual enzyme activity are low excretors at the urine metabolite level.

The role of chemokines in cancer immune surveillance by the adaptive immune system.

Chemokines are key molecules involved in the migration and homeostasis of immune cells. However, also tumor cells use chemokine signals for different processes such as tumor progression and metastasis. It is thus unclear whether chemokines, through their immunostimulatory roles, contribute to the repression of tumor cells by tumor immunosurveillance or whether chemokines act primarily as growth factors and chemoattractants for primary and metastatizing tumors, respectively. Research of recent years, using gene knockout mice, recombinant chemokines, and agents able to block chemokine actions, has provided further insight into the diverse functions of chemokines. Here, we review the current knowledge on the complex actions of chemokines at the interface of the immune system and the tumor.

Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis.

New blood vessel formation, a process referred to as angiogenesis, is essential for embryonic development and for many physiological and pathological processes during postnatal life, including cancer progression. Endothelial cell adhesion molecules of the integrin family have emerged as critical mediators and regulators of angiogenesis and vascular homeostasis. Integrins provide the physical interaction with the extracellular matrix necessary for cell adhesion, migration and positioning, and induction of signaling events essential for cell survival, proliferation and differentiation. Antagonists of integrin alpha V beta 3 suppress angiogenesis in many experimental models and are currently tested in clinical trials for their therapeutic efficacy against angiogenesis-dependent diseases, including cancer. Furthermore, interfering with signaling pathways downstream of integrins results in suppression of angiogenesis and may have relevant therapeutic implications. In this article we review the role of integrins in endothelial cell function and angiogenesis. In the light of recent advances in the field, we will discuss their relevance as a therapeutic target to suppress tumor angiogenesis.

Adénopathies et fièvre chez une patiente VIH positive [Immunocompromised HIV patient with lymphadenopathy and fever].

The case of a immunocompromised HIV patient with fever and lymphadenopathy discussed in an anatomo-pathological round. This complex clinical case was used as an opportunity to discuss the broad differential diagnosis of fever in an immunocompromized individual with multiples lymphadenopathies. Clinical reasoning leading to the probable diagnosis based on clinical, biological and radiological informations is not only a difficult task for the speaker but also a rich source of learning opportunities for our medical community.

Accuracy of sentinel lymph node dissection for melanoma staging in the presence of a collision tumour with a lymphoproliferative disease.

Sentinel lymph node dissection (SLND) identifies melanoma patients with metastatic disease who would benefit from radical lymph node dissection (RLND). Rarely, patients with melanoma have an underlying lymphoproliferative disease, and melanoma metastases might develop as collision tumours in the sentinel lymph node (SLN). The aim of this study was to measure the incidence and examine the effect of collision tumours on the accuracy of SLND and on the validity of staging in this setting. Between 1998 and 2012, 750 consecutive SLNDs were performed in melanoma patients using the triple technique (lymphoscintigraphy, gamma probe and blue dye). The validity of SLND in collision tumours was analysed. False negativity was reflected by the disease-free survival. The literature was reviewed on collision tumours in melanoma. Collision tumours of melanoma and chronic lymphocytic leukaemia (CLL) were found in two SLN and in one RLND (0.4%). Subsequent RLNDs of SLND-positive cases were negative for melanoma. The patient with negative SLND developed relapse after 28 months with an inguinal lymph node metastasis of melanoma; RLND showed collision tumours. The literature review identified 12 cases of collision tumours. CLL was associated with increased melanoma incidence and reduced overall survival. This is, to our knowledge, the first assessment of the clinical value of SLND when collision tumours of melanoma and CLL are found. In this small series of three patients with both malignancies present in the same lymph node basin, lymphocytic infiltration of the CLL did not alter radioisotope uptake into the SLN. No false-negative result was observed. Our data suggest the validity of SLND in collision tumours, but given the rarity of the problem, further studies are necessary to confirm this reliability.

Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules.

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

Selectin ligands on leukemic cells

RESUME L'infiltration tissulaire par les cellules leucémiques, responsable de leucostase, est une complication grave de la leucémie aiguë hyperleucocytaire. Elle peut entraîner une détresse respiratoire et des troubles neurologiques de mauvais pronostic. Pendant longtemps, la prolifération intravasculaire des cellules leucémiques et l'augmentation de la viscosité étaient considérées comme en étant responsables, et le traitement reposait sur une cytoréduction rapide par leucaphérèse. Actuellement, l'interaction entre les cellules leucémiques et l'endothélium vasculaire est plutôt considérée comme la cause de ce phénomène. En effet, les cellules leucémiques peuvent induire l'expression des sélectives endothéliales. Les sélectives initient le roulement des leucocytes avant leur adhésion ferme et leur migration dans les tissus. Elles reconnaissent des ligands spécifiques exprimés à la surface des leucocytes, comme PSGL-1 qui est un ligand commun des sélectives. Cependant, plusieurs études suggèrent que d'autres ligands de la E-sélective soient exprimés par les leucocytes. L'interaction des cellules leucémiques avec la E- et la P- sélective est corrélée avec l'expression de la molécule CLA, reconnue par l'anticorps HECA-452. L'immunopurification des ligands de la E-sélective avec cet anticorps a permis d'isoler, des cellules THP1 et U937, une protéine de 170 kDa, ainsi qu'une autre protéine de 250 kDa des cellules U937, en plus de PSGL-1. Ces protéines ont également été purifiées avec la protéine de fusion Esélective/IgM. CD43 et CD44 semblent être des ligands de la E-sélective sur certaines lignées, mais leur interaction avec la E-sélective n'est pas toujours retrouvée. De plus, cette étude a permis de montrer que ces ligands de la E-sélectiné sont exprimés dans les rafts lipidiques, comme PSGL-1 et la L-sélective des neutrophiles. Ces deux nouveaux ligands sont en cours d'identification. Ils pourraient représenter une nouvelle cible dans le traitement de la leucostase, mais aussi lors d'inflammation chronique ou de métastases. ABSTRACT Leukostasis is alife-threatening complication of acute leukemia, that results from tissue infiltration of leukemic blasts that migrate out of blood flow and interfere with normal tissue functions. The process leading to these complications has been attributed to the overcrowding of leukemic cells in the microcirculation. However, leukostasis more likely results from the adhesive interactions between leukemic blasts and the endothelium. Activated endothelium express adhesion molecules like P- and E-selectin, and leukemic cells themselves can induce the expression of E-selectin on endothelial cells. Selectins are essential in initiating the rolling of intravascular cells on endothelium before firm adhesion and transmigration outside of blood vessels. They interact with specific ligands on leukocyte cell surface. P-selectin glycoprotein ligand-1 (PSGL-1) is common ligand for E-, P- and L-selectin. Recently, CD44, ESL-1 and CD44 were shown to cooperate. ìn supporting mouse neutrophil adhesion to E-selectin. Other E-selectin ligands remain to be identified in humans. Leukemic cells were screened in order to characterize human E-selectin ligands. The interactions of E- and P-selectin correlate with the expression of CLA epitope. Therefore, HECA-452 mAb that recognizes CLA was used for immunopurification. Aglycoprotein of 170 kDa was purified from THP1 and U937 cells, and a protein of 250 kDa from U937 cells. These proteins were also purified by affinity binding to E-selectin/IgM chimera. PSGL-1 bound to E-selectin as expected, but CD43 and CD44 were not always adsorbed on E-selectin chimera, depending on cell types. E-selectin ligands were also shown to be in lipid rafts in leukemic cells, like PSGL-1 and L-selectin in human neutrophils. The 170 kDa protein has been sequenced, and three interesting ligands were among the candidates: ESL-1, CD44 and podocalyxin. These ligands are under investigation, and may represent a new therapeutic target in leukostasis, inflammation or cancer metastasis.

La régression tumorale n'est pas un facteur de risque d'atteinte du ganglion sentinelle dans les mélanomes fins (indice de Breslow < or = 1 mm) [Tumour regression is not predictive for higher risk of sentinel node involvement in thin melanomas (Breslow thickness < or = 1 mm)]

Background: Thin melanomas (Breslow thickness <= 1 mm) are considered highly curable. The aim of this study was to evaluate the correlation between histological tumour regression and sentinel lymph node (SLN) involvement in thin melanomas. Patients and methods: This was a retrospective single-centre study of 34 patients with thin melanomas undergoing SLN biopsy between April 1998 and January 2005. Results: The study included 14 women and 20 men of mean age 56.3 years. Melanomas were located on the neck (n = 3), soles (n = 4), trunk (n = 13) and extremities (n = 14). Pathological examination showed 25 SSM, four acral lentiginous melanomas, three in situ melanomas, one nodular melanoma and one unclassified melanoma with a mean Breslow thickness of 0.57 mm. Histological tumour regression was observed in 26 over 34 cases and ulceration was found in one case. Clark levels were as follows: I (n = 3), II (n = 20), III (n = 9), IV (n = 2). Growth phase was available in 15 cases (seven radial and eight vertical). Mitotic rates, available in 24 cases, were: 0 (n = 9), 1 (n = 11), 2 (n = 2), 3 (n = 1), 6 (n = 1). One patient with histological tumour regression (2.9% of cases and 3.8% of cases with regressing tumours) had a metastatic SLN. One patient negative for SLN had a lung relapse and died of the disease. Mean follow-up was 26.2 months. Conclusion: The results of the present study and the analysis of the literature show that histological regression of the primary tumour does not seem predictive of higher risk of SLN involvement in thin melanomas. This suggests that screening for SLN is not indicated in thin melanomas, even those with histological regression.

Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression

The p120 RasGAP protein negatively regulates Ras via its GAP domain. RasGAP carries several other domains that modulate several signaling molecules such as Rho. RasGAP is also a caspase-3 substrate. One of the caspase-3-generated RasGAP fragments, corresponding to amino acids 158-455 and called fragment N2, was previously reported to specifically sensitize cancer cells to death induced by various anticancer agents. Here, we show that fragment N2 inhibits migration in vitro and that it impairs metastatic progression of breast cancer to the lung. Hence, stress-activated caspase-3 might contribute to the suppression of metastasis through the generation of fragment N2. These results indicate that the activity borne by fragment N2 has a potential therapeutic relevance to counteract the metastatic process.

Bloodmeal microfilariae density and the uptake and establishment of Wuchereria bancrofti infections in Culex quinquefasciatus and Aedes aegypti

The relationship between ingestion of microfilariae (mf), production of infective larvae (L3) and mf density in human blood has been suggested as an important determinant in the transmission dynamics of lymphatic filariasis. Here we assess the role of these factors in determining the competence of a natural vector Culex quinquefasciatus and a non vector Aedes aegypti to transmit Wuchereria bancrofti. Mosquitoes were infected via a membrane feeding procedure. Both mosquito species ingested more than the expected number of microfilariae (concentrating factor was 1.28 and 1.81 for Cx. quinquefasciatus and Ae. aegypti, respectively) but Cx. quinquefasciatus ingested around twice as many mf as Ae. aegypti because its larger blood meal size. Ae. aegypti showed a faster mf migration capacity compared to Cx. quinquefasciatus but did not allow parasite maturation under our experimental conditions. Similar proportions of melanized parasites were observed in Ae. aegypti (2.4%) and Cx. quinquefasciatus (2.1%). However, no relationship between rate of infection and melanization was observed. We conclude that in these conditions physiological factors governing parasite development in the thorax may be more important in limiting vectorial competence than the density of mf ingested.