Oral mucosal melanoma: conservative treatment including laser surgery.

Objective: To discuss the convenience of laser surgery as optimal treatment for melanoma of the oral mucosa.Patients and methods: A retrospective evaluation of four patients with primary oral melanomas treated at a single Cancer Institution in Mexico City.Results: Two patients were treated with resection of the melanoma with CO2 laser together with extraction of the involved dental organs and curettage of the alveolar walls. These two cases had melanoma in situ with multiple isolated foci. The third patient had a lesion with vertical growth, who was submitted to partial maxillectomy along with selective dissection of bilateral neck levels I-V with a negative report and the fourth patient had a history of oral nodular melanoma and presented with lymph node metastasis. According to follow-up status, there was no distant metastasis in any of the patients reported here.Conclusion: In our experience, conservative management with CO2 laser is adequate for melanomas of the oral mucosa with extraction of the dental organs and curettage of the alveoli to achieve complete surgical resection microscopically without sacrifice of the quality of life. Management of the neck is controversial. We recommend selective therapeutic resection of the neck only if it is found to be clinically positive. Elective dissection has not shown to have an impact in overall survival.

From the Cover: Nanoparticle conjugation of antigen enhances cytotoxic T-cell responses in pulmonary vaccination.

The ability of vaccines to induce memory cytotoxic T-cell responses in the lung is crucial in stemming and treating pulmonary diseases caused by viruses and bacteria. However, most approaches to subunit vaccines produce primarily humoral and only to a lesser extent cellular immune responses. We developed a nanoparticle (NP)-based carrier that, upon delivery to the lung, specifically targets pulmonary dendritic cells, thus enhancing antigen uptake and transport to the draining lymph node; antigen coupling via a disulfide link promotes highly efficient cross-presentation after uptake, inducing potent protective mucosal and systemic CD8(+) T-cell immunity. Pulmonary immunization with NP-conjugated ovalbumin (NP-ova) with CpG induced a threefold enhancement of splenic antigen-specific CD8(+) T cells displaying increased CD107a expression and IFN-γ production compared with immunization with soluble (i.e., unconjugated) ova with CpG. This enhanced response was accompanied by a potent Th17 cytokine profile in CD4(+) T cells. After 50 d, NP-ova and CpG also led to substantial enhancements in memory CD8(+) T-cell effector functions. Importantly, pulmonary vaccination with NP-ova and CpG induced as much as 10-fold increased frequencies of antigen-specific effector CD8(+) T cells to the lung and completely protected mice from morbidity following influenza-ova infection. Here, we highlight recruitment to the lung of a long-lasting pool of protective effector memory cytotoxic T-cells by our disulfide-linked antigen-conjugated NP formulation. These results suggest the reduction-reversible NP system is a highly promising platform for vaccines specifically targeting intracellular pathogens infecting the lung.

Primary testicular lymphoma: review

Primary testicular lymphoma is a rare form of non-Hodgkin's lymphoma. It occurs more frequently in older patients, and it is a potentially lethal disease. For early stages (I and II), the management consists of orchidectomy followed by chemotherapy combined with monoclonal antibodies directed against the CD20 antigen and scrotal radiotherapy (sanctuary site) with/or without iliac and/or paraaortic lymph node radiotherapy. For advanced stages (III and IV), chemo-immunotherapy is the treatment of choice while scrotal radiotherapy can be discussed. Both in early or advanced disease, intrathecal chemotherapy is necessary to prevent central nervous system relapse. New molecular approaches and/or more aggressive treatments are to be explored in this rare disease. To cite this journal: Oncologie 13 (2011).

Analysis of the cytolytic T lymphocyte response of melanoma patients to the naturally HLA-A*0201-associated tyrosinase peptide 368-376.

The human tyrosinase gene codes for two distinct antigens that are recognized by HLA-A*0201-restricted CTLs. For one of them, tyrosinase peptide 368-376, the sequence identified by mass spectrometry in melanoma cell eluates differs from the gene-encoded sequence as a result of posttranslational modification of amino acid residue 370 (asparagine to aspartic acid). Here, we used fluorescent tetrameric complexes ("tetramers") of HLA-A*0201 and tyrosinase peptide 368-376 (YMDGTMSQV) to characterize the CD8+ T-cell response to this antigen in lymphoid cell populations from HLA-A2 melanoma patients. Taking advantage of the presence of significant numbers of tetramer-positive CD8+ T cells in tumor-infiltrated lymph node cells from a melanoma patient, we derived polyclonal and monoclonal tyrosinase peptide 368-376-specific CTLs by tetramer-guided flow cytometric sorting. These CTLs efficiently and specifically lysed HLA-A*0201- and tyrosinase-positive melanoma cells. As assessed with tyrosinase peptide variants, the fine antigen specificity of the CTLs was quite diverse at the clonal level. Flow cytometric analysis of PBMCs stained with tetramers showed that tyrosinase peptide 368-376-specific CD8+ T cells were hardly detectable in peripheral blood of melanoma patients. However, significant numbers of such cells were detected after short-term stimulation of CD8+ lymphocytes with tyrosinase peptide 368-376 in 6 of 10 HLA-A2 melanoma patients. Taken together, these findings emphasize the significant contribution of the natural tyrosinase peptide 368-376 to the antigenic specificities recognized by the tumor-reactive CTLs that may develop in HLA-A2 melanoma patients.

Development of T-B cell collaboration in neonatal mice.

The neonatal immune response is impaired during the first weeks after birth. To obtain a better understanding of this immaturity, we investigated the development of T cell interactions with B cells in mice. For this purpose, we analyzed the immune response to three T-dependent antigens in vivo: (i) the polyclonal antibody response induced by vaccinia virus; (ii) the production of polyclonal and specific antibodies following immunization with hapten-carrier conjugates; (iii) the mouse mammary tumor virus superantigen (sAg) response involving an increase in sAg-reactive T cells and induction of polyclonal antibody production. After vaccinia virus injection into neonates, the polyclonal antibody response was similar to that observed in adult mice. The antibody response to hapten-carrier conjugates, however, was delayed and reduced. Injection with sAg-expressing B cells from neonatal or adult mice allowed us to determine whether B cells, T cells or both were implicated in the reduced immune response. In these sAg responses, neonatal T cells were stimulated by both neonatal and adult sAg-presenting B cells but only B cells from adult mice differentiated into IgM- and IgG-secreting plasma cells in the neonatal environment in vivo. Injecting neonatal B cells into adult mice did not induce antibody production. These results demonstrate that the environment of the neonatal lymph node is able to support a T and B cell response, and that immaturity of B cells plays a key role in the reduced immune response observed in the neonate.

New insights into dendritic cell biology and histiocytosis through a transgenic tumor model

SUMMARY The effective development of an immune response depends on the careful interplay and the regulation between innate and adaptive immunity. As the dendritic cells (DCs) are equipped with many receptors, such as Toll-like receptors, which can detect the presence of infection by recognizing different component of bacteria, fungi and even viruses, they are the among the first cells to respond to the infection. Upon pathogen challenge, the DCs interpret the innate system activation as a maturation signal, resulting in the migration of the DCS to a draining lymph node site. There, activated DCs present efficiently antigens to naïve T cells, which are in turn activated and initiate adaptive immunity. Therefore, DCs are the main connectors between innate and adaptive immune systems. In addition to be the most efficient antigen- presenting cells, DCs play a central role in the regulation of immune responses and immune tolerance. Despite extensive research, many aspects related to DC biology are still unsolved and/or controversial. The low frequency of DCs in vivo often hamper study of DC biology and in vitro-derived DCs are not suited to address certain questions, such as the development of DC. We sought of transforming in vivo the DCs through the specific expression of an oncogene, in order to obtain unlimited numbers of these cells. To achieve this goal, transgenic mouse lines expressing the SV40 Large T oncogene under the control of the CD1 1 c promoter were generated. These transgenic mice are healthy until the age of three to four months without alterations in the DC biology. Thereafter transgenic mice develop a fatal disease that shows features of a human pathology, named histiocytosis, involving DCs. We demonstrate that the disease development in the transgenic mice correlates with a massive accumulation of transformed DCs in the affected organs. Importantly, transformed DCs are immature and fully conserve their capacity to mature in antigen presenting cells. We observe hyperproliferation of transformed DCs only in the sick transgenic mice. Surprisingly, transformed DCs do not proliferate in vitro, but transfer of the transformed DCs into immunodeficient or tolerant host leads to tumor formation. Altoghether, the transgenic mouse lines we have generated represent a valuable tumor model for human histiocytosis, and provide excellent tools to study DC biology. RESUME Le développement d'une réponse immunitaire efficace dépend d'une minutieuse interaction et régulation entre l'immunité innée et adaptative. Comme les cellules dendritiques (DCs) sont équipées de nombreux récepteurs, tels que les récepteurs Toll-like, qui peuvent détecter la présence d'une infection en reconnaissant différents composants bactériens, issus de champignons ou même viraux, elles sont parmi les premières cellules à répondre à l'infection. Suite à la stimulation induite par le pathogène, les DCs interprètent l'activation du système immunitaire inné comme un signal de maturation, résultant dans la migration des DCs vers le ganglion drainant le site d'infection. Là, les DCs actives présentent efficacement des antigènes aux cellules T, qui sont à leur tour activées et initient les systèmes d'immunité adaptative. Ainsi, les DCs forment le lien principal entre les réponses immunitaires innées et adaptatives. En plus d'être les cellules présentatrices d'antigènes les plus efficaces, les DCs jouent un rôle central dans la régulation du système immunitaire et dans le phénomène de tolérance. Malgré des recherches intensives, de nombreux aspects liés à la biologie des DCs sont encore irrésolus et/ou controversés. La faible fréquence des DCs in vivo gêne souvent l'étude de la biologie de ces cellules et les DCs dérivées in vitro ne sont pas adéquates pour adresser certaines questions, telles que le développement des DCs. Afin d'obtenir des quantités illimitées de DCs, nous avons songé à transformer in vivo les DC grâce à l'expression spécifique d'un oncogène. Afin d'atteindre ce but, nous avons généré des lignées de souris transgéniques qui expriment l'oncogène SV40 Large T sous le contrôle du promoter CD1 le. Ces souris transgéniques sont saines jusqu'à l'âge de trois à quatre mois et ne présentent pas d'altération dans la biologie des DCs. Ensuite, les souris transgéniques développent une maladie présentant les traits caractéristiques d'une pathologie humaine nommée histiocytose, qui implique les DCs. Nous montrons que le développement de cette maladie corrèle avec une accumulation massive des DCs transformées dans les organes touchés. De plus, les DCs transformées sont immatures et conservent leur capacité à différencier en cellules présentatrices d'antigène. Nous observons une hyper-prolifération des DCs transformées seulement dans les souris transgéniques malades. Etonnament, les DC transformées ne prolifèrent pas in vitro, par contre, le transfert des DCs transformées dans des hôtes immuno-déficients ou tolérant conduit à la formation de tumeurs. Globalement, les lignées de souris transgéniques que nous avons générées représentent un modèle valide pour l'histiocytose humaine, et de plus, offrent d'excellents outils pour étudier la biologie des DCs.

TLR 2 modulates inflammation in zymosan-induced arthritis in mice

Résumé L'objectif de cette étude est la compréhension des mécanismes sous-jacents à l'inflammation articulaire dans un modèle murin d'arthrite induite par le zymosan (ZIA). En particulier, la participation du récepteur Toll 2 (TLR2) et du complément C3 a été recherchée. L'inflammation articulaire a été quantifiée par l'accumulation de Technetium (Tc) in vivo, et par histologie des articulations arthritiques. Les réponses humorales et cellulaires induites par le zymosan ont été quantifiées par la prolifération lymphocytaire in vitro et par la mesure de la production d'anticorps dirigés contre le zymosan in vivo. L'inflammation associée à l'arthrite induite au zymosan est, d'après le Tc-uptake, d'aspect biphasique, avec un pic après 1 jour, puis une deuxième phase plus tardive. La deuxième phase persiste jusqu'au 24 ème jour et est associée au développement d'une immunité spécifique contre le zymosan. Les souris déficientes pour TLR-2 présentent une réduction significative de l'inflammation articulaire précoce (jour 1) et tardive (jour 24), ainsi qu'une nette diminution de l'infiltrat inflammatoire dans la membrane synoviale. De plus, la prolifération de cellules du ganglion lymphatique ainsi que le taux d'IgG dirigés contre le zymosan sont diminués de façon significative après 25 jour d'arthrite chez les souris déficientes en TLR2 par rapport aux souris sauvages contrôles. Par contraste, chez les souris déficientes pour C3 on n'observe pas de différence dans l'uptake de Tc ou le scoring histologique par rapport à la lignée sauvage. Ces résultats montrent que l'arthrite induite au zymosan n'est pas seulement un modèle d'inflammation aigue, mais que l'inflammation synoviale persiste même après 25 jours. Ce modèle implique à la fois des mécanismes d'immunité innée et acquise. Le signalling via TLR 2 semble jouer in rôle dans l'immunité au zymosan et pourrait être responsable de la nature biphasique de ce modèle d'arthrite. Abstract The interplay between the innate and acquired immune systems in chronic inflammation is not well documented. We have investigated the mechanisms of inflammation in murine zymosan-induced arthritis (ZIA) in the light of recent data on the roles of Toll-like receptor 2 (TLR2) and Dentin-1 in the activation of monocyte/macrophages by zymosan. The severity of inflammation, joint histology, lymphocyte proliferation and antibody production in response to zymosan were analyzed in mice deficient in TLR2 and complement C3, and the effects of Dentin-1 inhibition by laminarin were studied. In comparison with wild-type animals, TLR2-deficient mice showed a significant decrease in the early (day 1) and late phases (day 24) of joint inflammation. C3-deficient mice showed no differences in technetium uptake or histological scoring. TLR2-deficient mice also showed a significant decrease in lymph node cell proliferation in response to zymosan and a lower IgG antibody response to zymosan at day 25 in comparison with wild-type controls, indicating that TLR2 signalling has a role in the development of acquired immune responses to zymosan. Although laminarin, a soluble β-glucan, was able to significantly inhibit zymosan uptake by macrophages in vitro, it had no effect on ZIA in vivo. These results show that ZIA is more prolonged than was originally described and involves both the innate and acquired immune pathways. C3 does not seem to have a major role in this model of joint inflammation.

Second non-breast primary cancer following adjuvant therapy for early breast cancer: a report from the International Breast Cancer Study Group.

The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of the first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for 5 years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of 8 years and endocrine therapy (toremifene or tamoxifen) versus chemo-endocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular, the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemo-endocrine therapy compared with endocrine therapy.

Stringent V beta requirement for the development of NK1.1+ T cell receptor-alpha/beta+ cells in mouse liver.

The liver of C57BL/6 mice contains a major subset of CD4+8- and CD4-8- T cell receptor (TCR)-alpha/beta+ cells expressing the polymorphic natural killer NK1.1 surface marker. Liver NK1.1+TCR-alpha/beta+ (NK1+ T) cells require interaction with beta2-microglobulin-associated, major histocompatibility complex I-like molecules on hematopoietic cells for their development and have a TCR repertoire that is highly skewed to Vbeta8.2, Vbeta7, and Vbeta2. We show here that congenic C57BL/6.Vbeta(a) mice, which lack Vbeta8- expressing T cells owing to a genomic deletion at the Vbeta locus, maintain normal levels of liver NK1+ T cells owing to a dramatic increase in the proportion of cells expressing Vbeta7 and Vbeta2 (but not other Vbetas). Moreover, in C57BL/6 congenic TCR-V Vbeta3 and -Vbeta8.1 transgenic mice (which in theory should not express other Vbeta, owing to allelic exclusion at the TCR-beta locus), endogenous TCR-Vbeta8.2, Vbeta7, and Vbeta2 (but not other Vbetas) are frequently expressed on liver NK1+T cells but absent on lymph node T cells. Finally, when endogenous V beta expression is prevented in TCR-Vbeta3 and Vbeta8.1 transgenic mice (by introduction of a null allele at the C beta locus), the development of liver NK1+T cells is totally abrogated. Collectively, our data indicate that liver NK1+T cells have a stringent requirement for expression of TCR-Vbeta8.2, Vbeta7, or Vbeta2 for their development.

Selectively impaired development of intestinal T cell receptor gamma delta+ cells and liver CD4+ NK1+ T cell receptor alpha beta+ cells in T cell factor-1-deficient mice.

T cell factor-1 (Tcf-1) is a transcription factor that binds to a sequence motif present in several T cell-specific enhancer elements. In Tcf-1-deficient (Tcf-1-/-) mice, thymocyte development is partially blocked at the transition from the CD4-8+ immature single-positive stage to the CD4+8+ double-positive stage, resulting in a marked decrease of mature peripheral T cells in lymph node and spleen. We report here that the development of most intestinal TCR gamma delta+ cells and liver CD4+ NK1.1+TCR alpha beta+ (NK1+T) cells, which are believed to be of extrathymic origin, is selectively impaired in Tcf-1-/- mice. In contrast, thymic and thymus-derived (splenic) TCR gamma delta+ cells are present in normal numbers in Tcf-1-/- mice, as are other T cell subsets in intestine and liver. Collectively, our data suggest that Tcf-1 is differentially required for the development of some extrathymic T cell subsets, including intestinal TCR gamma delta+ cells and liver CD4+ NK1+T cells.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Prognostic value of arginase-II expression and regulatory T-cell infiltration in head and neck squamous cell carcinoma.

Tumor-infiltrating lymphocytes are present in a variety of tumors and play a central role in antitumor immune responses. Nevertheless, most cancers progress probably because tumors are only weakly immunogenic and develop multiple immunosuppressive mechanisms. In the present study, on head and neck squamous cell carcinoma, we found high intraepithelial infiltration of regulatory FOXP3(+) T cells, and relatively high levels of BDCA2(+) and FOXP3(+) cells in stromal (peripheral) regions of the tumors. Tumor-infiltrating (intraepithelial) FOXP3(+) T cells were significantly more frequent in patients with oropharynx and oral cavity squamous cell carcinoma and in patients without lymph node metastasis. Furthermore, arginase-II (ARG2) was expressed by 60%, inducible nitric oxide synthetase by 9%, cyclooxygenase-2 by 43%, and B-cell lymphoma 2 (BCL2) by 26% of tumors. Interestingly, the absence of ARG2 expression, enhanced stromal infiltration of CD11c(+) myeloid dendritic cells, and high numbers of FOXP3(+) T cells were each significantly associated with prolonged overall survival, and the latter two parameters were also confirmed by multivariate analysis. For disease-free survival, multivariate analysis revealed significant negative correlations with BCL2 and ARG2 expression by tumor cells. These findings shed new light on mechanisms of cancer progression, and provide rationales for therapeutic inhibition of immunosuppressive mechanisms in head and neck squamous cell carcinoma.

An unusual uterine tumor with signet ring cell features.

In 2004, a 56-year-old woman was diagnosed with Stage IA follicular lymphoma in a cervical lymph node biopsy. The patient experienced total remission after local radiation therapy. In 2009, a control computed tomography scan evidenced a pelvic mass, prompting total hysterectomy. The latter harbored a 4.8-cm intramural uterine tumor corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells, with extensive, periodic acid-Schiff negative, signet ring cell changes, and a pan-keratin negative, CD20+, CD10+, Bcl2+, Bcl6+ immunophenotype. Molecular genetic studies showed the same clonal IGH gene rearrangement in the lymph node and the uterus, establishing the uterine tumor as a relapse of the preceding follicular lymphoma, although no signet ring cells were evidenced at presentation. Uterine localization of lymphomas is rare, and lymphomas with signet ring cell features are uncommon. This exceptional case exemplifies a diagnostically challenging situation and expands the differential diagnosis of uterine neoplasms displaying signet ring cell morphology.

Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC

Résumé : Objectif: Analyse d'un traitement de chimiothérapie à base de cisplatine de type néoadjuvant en comparaison à un traitement de radio-chimiothérapie suivi de la résection chirurgicale chez des patients présentant un carcinome pulmonaire non à petites cellules de stade Ill (N2) prouvé histologiquement par médiastinoscopie. Evaluation de la morbidité postopératoire, du down-staging ganglionnaire, des taux de survie globale et sans récidive ainsi que du site de récidive. Matériel et méthodes : 82 patients ont été inclus dans l'étude entre Janvier 1994 et Juin 2003, parmi eux 36 ont été traités avec une chimiothérapie néoadjuvante à base de cisplatine et doxétacel (groupe l). Les autres 46 patients ont été soumis à une radio-chimiothérapie néoadjuvante avec administration de 44 Gy (groupe II), soit de façon séquentielle (25 cas) soit concomitante (21 cas). Dans tous les cas des métastases à distance ont été exclues par une évaluation préopératoire comprenant une scintigraphie osseuse, un Ct scan thoraco-abdominal, ou un examen PET scan ainsi qu'une IRM cérébrale. La médiastinoscopie effectuée avant le traitement d'induction chez la totalité des patients, de même que la résection chirurgicale de la tumeur pulmonaire et la lymphadenectomie médiastinale ont été effectuées par le même chirurgien. Résultats : La tumeur pulmonaire était de stade Ti à T2 dans respectivement 47% et 28% des patients des groupes (e II, T3 dans 45% et 41% et T4 dans 8% et 31% des cas. Le type de résection effectué (lobectomie, lobectomie en manchon, pneumonectomie) était comparable dans les deux collectifs (p=0.03) Le taux de mortalité postopératoire à 90 jours était de respectivement 3% et 4 "Vo (p=0.6). Une résection complète (RO) a pu être obtenue dans 92% et 94% des cas (p=0.6) avec un downstaging ganglionnaire médiastinal dans 61% et 78% des patients respectivement (p<0.001). Les taux de survie globale à 5 ans et de survie sans récidive à 5 ans s'élevaient à 40% et à 36% respectivement, sans différence significative entre des tumeurs de stade Ti à T3 et T4. Le taux de survie globale n'était pas significativement différent entre les deux modalités de traitement d'induction, toutefois après radio-chimiothérapie on observait une plus longue survie sans récidive (p.0.04). Il n'y avait par ailleurs pas de différence significative, en termes de morbidité post-opératoire, résecabilité, downstaging ganglionnaire, survie globale et sans récidive, entre les patients traités par radio-chimiothérapie séquentielle ou concomitante. Conclusions : En cas de carcinome pulmonaire non à petites cellules de stade III (N2) un traitement d'induction par radio chimiothérapie suivi de la résection chirurgicale est associé avec un meilleur downstaqing médiastinal ainsi qu'une plus longue survie sans récidive en comparaison au traitement d'induction par chimiothérapie seule. Abstract : Objective: Comparison of prospectively treated patients with neoadjuvant cisplatin-based chemotherapy vs radiochemotherapy followed by resection for mediastinoscopically proven stage III NZ non-small cell lung cancer with respect to postoperative morbidity, pathological nodal downstaging, overall and disease-free survival, and site of recurrence. Methods: Eighty-two patients were enrolled between January 1994 to June 2003, 36 had cisplatin and doxetacel-based chemotherapy (group I) and 46 cisplatin-based radiochemotherapy up to 44 Gy (group II), either as sequential (25 patients) or concomitant (21 patients) treatment. All patients had evaluation of absence of distant metastases by bone scintigraphy, thoracoabdominal CT scan or PET scan, and brain MRI, and all underwent pre-induction mediastinoscopy, resection and mediastinal lymph node dissection by the same surgeon. Results: Group I and II comprised T1/2 tumors in 47 and 28%, 13 tumors in 45 and 41%, and 14 tumors in 8 and 31% of the patients, respectively (P=0.03). There was a similar distribution of the extent of resection (lobectomy, sleeve lobectomy, left and right pneumonectomy) in both groups (P=0.9). Group I and II revealed a postoperative 90-d mortality of 3 and 4% (P=0.6), a RO-resection rate of 92 and 94% (P=0.9), and a pathological mediastinal downstaging in 61 and 78% of the patients (P<0.01), respectively. 5y-overall survival and disease-free survival of all patients were 40 and 36%, respectively, without significant difference between T1-3 and T4 tumors. There was no significant difference in overall survival rate in either induction regimens, however, radiochemotherapy was associated with a longer disease-free survival than chemotherapy (P=0.04). There was no significant difference between concurrent vs sequential radiochemotherapy with respect to postoperative morbidity, resectability, pathological nodal downstaging, survival and disease-free survival. Conclusions: Neoadjuvant cisplatin-based radiochemotherapy was associated with a similar postoperative mortality, an increased pathological nodal downstaging and a better disease-free survival as compared to cisplatin doxetacel-based chemotherapy in patients with stage III (N2) NSCLC although a higher number of 14 tumors were admitted to radiochemotherapy.

Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response.

Mice with homologous disruption of the gene coding for either the p35 subunit or the p40 subunit of interleukin-12 (IL-12) and derived from a strain genetically resistant to infection with Leishmania major have been used to study further the role of this cytokine in resistance to infection and the differentiation of functional CD4+ T cell subsets in vivo. Wild-type 129/Sv/Ev mice are resistant to infection with L. major showing only small lesions which resolve spontaneously within a few weeks and develop a type 1 CD4+ T cell response. In contrast, mice lacking bioactive IL-12 (IL-12p35-/- and IL-12p40-/-) developed large, progressing lesions. Whereas resistant mice were able to mount a delayed-type hypersensitivity (DTH) response to Leishmania antigen, susceptible BALB/c mice as well as IL-12-deficient 129/Sv/Ev mice did not show any DTH reaction. To characterize the functional phenotype of CD4+ T cells triggered in infected wild-type mice and IL-12-deficient mice, the expression of mRNA for interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in purified CD4+ lymph node cells was analyzed. Wild-type 129/Sv/Ev mice showed high levels of mRNA for IFN-gamma and low levels of mRNA for IL-4 which is indicative of a Th1 response. In contrast, IL-12- deficient mice and susceptible BALB/c mice developed a strong Th2 response with high levels of IL-4 mRNA and low levels of IFN-gamma mRNA in CD4+ T cells. Similarly, lymph node cells from infected wild-type 129 mice produced predominantly IFN-gamma in response to stimulation with Leishmania antigen in vitro whereas lymph node cells from IL-12-deficient mice and susceptible BALB/c mice produced preferentially IL-4. Taken together, these results confirm in vivo the importance of IL-12 in induction of Th1 responses and protective immunity against L. major.