Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.

Background: Various programed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 testing in non-small-cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDTs). Methods: IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers) platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For nonmatching platforms and other antibodies, LDTs were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively. Results: 28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the five Dako or Ventana platforms. Among 27 LDTs developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance when compared with reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms. Lower concordance was observed for immune cells staining when using a four categories scale. Conclusion: 28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across seven centers. Some LDTs on Dako, Ventana and Leica platforms achieved similar concordance, but caution is warranted for their validation. These LDTs will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.

Administration of low doses of IL-2 combined to rapamycin promotes allogeneic skin graft survival in mice.

Human CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) prevent allogeneic graft rejection by inhibiting T cell activation, as has been shown in mouse models. Recently, low-dose IL-2 administration was shown to specifically activate Tregs but not pathogenic conventional T cells, leading to resolution of type 1 diabetes in nonobese diabetic mice. We therefore tested the ability of low-dose IL-2 to prevent allogeneic skin graft rejection. We found that while IL-2 alone was inefficient in preventing rejection, combined with rapamycin, IL-2 treatment promoted skin graft survival both in minor disparate and semi-allogeneic skin graft combinations. Tregs are activated by this combined treatment while conventional CD4(+) cell expansion and activation are markedly inhibited. Co-administration of anti-CD25 antibodies dramatically reduces the effect of the IL-2/rapamycin treatment, strongly supporting a central role for Treg activation. Thus, we provide the first preclinical data showing that low-dose IL-2 combined with rapamycin can significantly delay transplant rejection in mice. These findings may form the rational for clinical evaluation of this novel approach for the prevention of transplant rejection.

Prognostic Significance of the Microenvironment in Human Papillomavirus Oropharyngeal Carcinoma: A Systematic Review.

OBJECTIVE: The immune microenvironment of HPV-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) (HPV+OPSCCs) differs from that of HPV-independent oropharyngeal cancers (HPV-independent OPSCCs). The literature on the subject is very abundant, demanding an organized synthesis of this wealth of information to evaluate the hypothesis associating the favorable prognosis of HPV+OPSCC patients with a different immune microenvironment. A systematic review of the literature was conducted regarding the microenvironment of HPV+OPSCCs. DATA SOURCE: MEDLINE/PubMed, Embase, and Cochrane Library databases. REVIEW METHODS: A literature search was performed following PRISMA guidelines (Moher D. PLoS Med. 2009). The PEO (Population, Exposure, and Outcome) framework is detailed as follows: P: patients with oropharyngeal squamous cell carcinomas, E: human papillomavirus (HPV), and O: histological and immunological composition of the tumoral microenvironment (TME). No meta-analysis was performed. RESULTS: From 1,202 studies that were screened, 58 studies were included (n = 6,474 patients; n = 3,581 (55%) HPV+OPSCCs and n = 2,861(45%) HPV-independent OPSCCs). The presence of tumor-infiltrating lymphocytes (TIL), CD3+ in 1,733 patients, CD4+ in 520 patients, and CD8+ (cytotoxic T lymphocytes (CTL)) in 3,104 patients, and high levels of PD-L1 expression in 1,222 patients is strongly correlated with an improved clinical outcome in HPV+OPSCCs. CONCLUSION: This systematic review provides the most comprehensive information on the immune microenvironment of HPV+OPSCCs to date. Tumor-infiltrating lymphocytes and PD-L1 expression are associated with a favorable prognosis. B, CD8+ and resident memory cells densities are higher in HPV+OPSCCs. The importance of myeloid lineages is still a matter of debate and research. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1507-1516, 2024.

Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours.

BACKGROUND: Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified. DESIGN: Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology. RESULTS: Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations. CONCLUSION: Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT.

Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy.

The immune system regulates angiogenesis in cancer with both pro- and antiangiogenic activities. The induction of angiogenesis is mediated by tumor-associated macrophages and myeloid-derived suppressor cells (MDSC) which produce proinflammatory cytokines, endothelial growth factors (VEGF, bFGF…), and protease (MMP9) implicated in neoangiogenesis. Some cytokines (IL-6, IL-17…) activated Stat3 which also led to the production of VEGF and bFGF. In contrast, other cytokines (IFN, IL-12, IL-21, and IL-27) display an antiangiogenic activity. Recently, it has been shown that some antiangiogenic molecules alleviates immunosuppression associated with cancer by decreasing immunosuppressive cells (MDSC, regulatory T cells), immunosuppressive cytokines (IL-10, TGFß), and inhibitory molecules on T cells (PD-1). Some of these broad effects may result from the ability of some antiangiogenic molecules, especially cytokines to inhibit the Stat3 transcription factor. The association often observed between angiogenesis and immunosuppression may be related to hypoxia which induces both neoangiogenesis via activation of HIF-1 and VEGF and favors the intratumor recruitment and differentiation of regulatory T cells and MDSC. Preliminary studies suggest that modulation of immune markers (intratumoral MDSC and IL-8, peripheral regulatory T cells…) may predict clinical response to antiangiogenic therapy. In preclinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy which may be explained by an improvement of immune status in tumor-bearing mice after antiangiogenic therapy. In preclinical models, antiangiogenic molecules promoted intratumor trafficking of effector cells, enhance endogenous anti-tumor response, and synergyzed with immunotherapy protocols to cure established murine tumors. All these results warrant the development of clinical trials combining antiangiogenic drugs and immunotherapy.

Extraosseous plasmacytoma of the lacrimal duct.

OBJECTIVE: Extraosseous plasmacytoma (EOP) is a rare plasma cell proliferative disorder that commonly affects the head and neck region. We report the first case of a plasmacytoma of the lacrimal duct. METHODS: A 66-year-old man presented with an isolated plasmacytoma of the right lacrimal duct and was treated surgically. RESULTS: The tumour grew slowly for a few months. CT scan and MRI showed a right lateral nasal mass extending from the right lacrimal duct toward the floor of the right maxillary sinus. The lesion was removed completely by endoscopic nasal surgery. DISCUSSION: EOP accounts for up to 3% of all plasma cell tumours. Management of this rare lesion involves surgery and radiotherapy with or without adjuvant chemotherapy. Guided by a literature review, we discuss the diagnostic and therapeutic management of EOP.

[Unilateral laryngeal paralysis after intra capsular loboisthmectomy without laryngeal nerve dissection]. / Paralysie laryngée unilatérale après lobo-isthmectomie intra capsulaire sans repéérage du nerf laryngé inférieur.

OBJECTIVES: To document the incidence, outcome and variables that increase the risk for unilateral laryngeal paralysis after loboisthmectomy performed according to the intracapsular dissection technique. MATERIALS AND METHODS: A retrospective analysis of an inception cohort of 317 loboisthmectomies consecutively performed at a single institution by the same surgeon during the years 2002-2007 using the intra capsular dissection without laryngeal nerve dissection, neuromonitoring and modern hemostasis techniques (Ligasure, Ultracision). The immediate and definite rate for unilateral laryngeal nerve paralysis is documented. A statistical analysis is performed for potential relation between these events and the following variables: age, gender, comorbidity, tracheal compression and intrathoracic characteristics of the thyroid lesion, side of the loboisthmectomy, etiology of the thyroid lesion (benign, malignant, hyperthyroidy), associated thyroiditis, size of the largest resected nodule and weight of the resected lobe. RESULTS: The immediate unilateral laryngeal nerve paralysis incidence was 1,2%. Recovery of motion occurred by the 1st, 3rd, 5th or 9th post operative month resulting in a 0% incidence for definitive unilateral laryngeal nerve paralysis. No significant statistical relation was noted between immediate unilateral laryngeal nerve paralysis and the variables under analysis. CONCLUSION: Based on the current series and the review of the medical literature, it appears that the loboisthmectomy according to the intra capsular technique without inferior laryngeal nerve identification, in patients not previously operated, performed according to is a surgical technique whose goal is to ascent the thyroid lobe and dissect the region of the nerve penetration within the larynx by the end of the resection, does not increase the risk for transient or permanent unilateral laryngeal nerve paralysis.

Progressive clinical case-based multiple-choice questions: An innovative way to evaluate and rank undergraduate medical students.

INTRODUCTION: In France, at the end of the sixth year of medical studies, students take a national ranking examination including progressive clinical case-based multiple-choice questions (MCQs). We aimed to evaluate the ability of these MCQs for testing higher-order thinking more than knowledge recall, and to identify their characteristics associated with success and discrimination. METHODS: We analysed the 72 progressive clinical cases taken by the students in the years 2016-2019, through an online platform. RESULTS: A total of 72 progressive clinical cases (18 for each of the 4 studied years), corresponding to 1059 questions, were analysed. Most of the clinical cases (n=43, 60%) had 15 questions. Clinical questions represented 89% of all questions, whereas basic sciences questions accounted for 9%. The most frequent medical subspecialties were internal medicine (n=90, 8%) and infectious diseases (n=88, 8%). The most frequent question types concerned therapeutics (26%), exams (19%), diagnosis (14%), and semiology (13%). Level 2 questions ("understand and apply") accounted for 59% of all questions according to the Bloom's taxonomy. The level of Bloom's taxonomy significantly changed over time with a decreasing number of level 1 questions ("remember") (P=0.04). We also analysed the results of the students among 853 questions of training ECNi. Success and discrimination significantly decreased when the number of correct answers increased (P<0.0001 both). The success, discrimination, mean score, and mean number of discrepancies did not differ according to the diagnosis, exam, imaging, semiology, or therapeutic type of questions. CONCLUSION: Progressive clinical case-based MCQs represent an innovative way to evaluate undergraduate students.

Evaluation of robotic surgery for transoral resection of T1-2 squamous cell carcinoma of the tonsillar fossa.

GOAL: To evaluate transoral robotic surgery (TORS) for isolated previously untreated squamous cell carcinoma (SCC) of the tonsillar fossa classified as T1-2. METHOD: Retrospective analysis of two cohorts of isolated untreated T1-2 tonsillar fossa SCC consecutively operated on by a transoral approach, with (R=21) and without (NR=24) robotic assistance, in the period 2006-2014. Three main (survival, local control, and operative morbidity) and three secondary (pathologic data, incidence and duration of tracheotomy and nasogastric intubation, and hospital stay) endpoints were compared between groups. The significance threshold was set at P< .005. RESULTS: Three- and five-year actuarial survival estimates were 80.2% and 74.5% respectively in group R, and 91.5% and 82.5% respectively in group NR (NS: P=.34). Three- and five-year actuarial local control estimates were 90% and 90% respectively in group R, and 95.8% and 91% respectively in group NR (NS: P=.81). There were no significant differences in morbidity, tracheotomy/nasogastric intubation time, or hospital stay. Positive resection margins (R1) were noted in 38.1% and 16.7% in groups R and NR, respectively (NS: P=.05) without significant impact on 5-year actuarial local control (P=0.78). CONCLUSION: Robotic assistance in transoral lateral oropharyngectomy for T1-2 tonsillar fossa SCC did not significantly impact oncologic or functional outcome.

Predominant Th1 and cytotoxic phenotype in biopsies from renal transplant recipients with transplant glomerulopathy.

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4+ T cells including Th1 (T-bet and INFgamma), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and RORgammat) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IF/TA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INFgamma, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.

Skin metastasis of head and neck carcinoma predictive for dismal outcome.

A 64-year-old female with locally advanced oropharyngeal carcinoma presented with an innocuous appearing macule on the abdomen. The lesion rapidly enlarged over 2 weeks into an inflammatory 5 cm fleshy nodule that was diagnosed as squamous cell carcinoma (SCC) and was found to overexpress epidermal growth factor receptor (EGFR). A fatal outcome occurred 3 months after the initial diagnosis of cancer, in spite of chemotherapy and treatment with EGFR inhibitors (cetuximab). Cutaneous metastases occur in 10 percent of squamous cell carcinomas of the head and neck. Contiguous cutaneous metastases in the head and neck areas are by far the most common. Conversely, isolated infradiaphragmatic cutaneous metastases are exceedingly rare and are associated with an aggressive clinical course. In a patient with cancer, the possibility of distant skin metastasis should be considered whenever new cutaneous nodules appear.

[Sinonasal hemangiopericytomas]. / Hémangiopéricytomes nasosinusiens.

OBJECTIVES: The aim of this study was to report on the clinical, radiological and histological characteristics of hemangiopericytomas, and to discuss our experience with their treatment. MATERIAL AND METHODS: The authors reexamined two recent cases of patients presenting with sinonasal hemangiopericytomas (semiology, CT and MRI results, treatment and follow-up). RESULTS AND DISCUSSION: There was substantial variability of hemangiopericytoma presentation depending on location. Hemangiopericytomas of the nose and paranasal sinuses are considered a distinct entity with a good prognosis. Treatment is based on endoscopic sinus surgery. The histological approach requires the use of immunohistochemistry. Recurrences vary in the literature depending on the initial resection quality. Metastases are rare.

[Multidisciplinary consultation for patients with HPV-related invasive carcinoma or precancerous lesions]. / Consultation multidisciplinaire pour les patients atteints d'une pathologie tumorale (carcinome infiltrant ou lésion précancéreuse) liée à HPV : la consultation multidisciplinaire papillomavirus.

Given the recent increase in the number of human papillomavirus (HPV)-induced cancers in other locations than gynaecological, the number of patients with two cancers at distinct sites, and because of the lack of exhaustive data, we decided to create a multidisciplinary network around an HPV consultation at the Georges-Pompidou European Hospital (HEGP). This network aims to set up the best tools for detecting HPV-associated "multisite" precancerous lesions in order to determine the possible impact of dedicated care for this at-risk population. This monthly consultation was created at the HEGP in June 2014. It is currently organized around five consultations: gynaecological, ENT, urological, digestive and immunological. Every patient who has been diagnosed with HPV-related cancer and whose care is provided at the HEGP is offered this particular follow-up: systematically, once the initial lesion has been treated, the patient is convened annually for a day during which it benefits from the consultations mentioned above. A consultation with a psychologist is systematically proposed. Local samples are taken at each site: a cytological examination, the analysis of known predictive and prognostic virological markers are carried out. This study fits more broadly in a theme of clinical and fundamental research around cancers related to HPV.

The keys to conservative treatment of early-stage squamous cell carcinoma of the tonsillar region.

To analyze the medical literature devoted to work-up, epidemiology, local control, survival, complications and sequelae after conservative treatment for early-stage squamous cell carcinoma of the tonsillar region. An analysis of the PubMed (1975-2016) database was performed using the following keywords and associations: "tonsil/tonsillar region/oropharynx" AND "squamous cell carcinoma" AND "early-stage (I-II; T1-2N0M0)" AND "radiation therapy/radiotherapy" OR "conservative surgery/oropharyngectomy/transoral surgery/radical tonsillectomy". The search retrieved 10 retrospective series documenting local control and/or survival in series with more than 50 cases and a minimum 2 years' follow-up after conservative treatment; no prospective studies, meta-analyses and/or Cochrane analyses were found. Magnetic resonance imaging is the key radiological exam for local extension assessment. Human papilloma virus infection (HPV) is a risk factor that must be screened for systematically, since it induces tumoral radio-sensitivity and increases the risk of specific synchronous and metachronous second primaries. Whatever conservative treatment used, local control and survival rates higher than 85% were achieved. Implementing intensity-modulated radiation therapy reduced the incidence and severity of radiation-related complications and sequelae. Transoral surgery yielded very low morbidity/mortality rates, enabled association to ipsilateral neck dissection, and allowed radiation therapy to be reserved for the management of metachronous second primaries. Transoral surgery appeared to be the first-line option in the majority of cases. Lifetime follow-up adapted to HPV status is mandatory. The development of HPV vaccination does not mean that campaigns against smoking and alcohol abuse are of diminished importance.

[Granular cell tumours (Abrikossoff's tumour) of the parotid region]. / Tumeur à cellules granuleuses (tumeur d'Abrikossoff) de la loge parotidienne.

BACKGROUND: Granular cell tumour (Abrikossoff's tumour) was first described by Abrikossoff in 1926. These tumours are rare and usually presents as a solitary lesion, located mainly in the subcutaneous tissue of the head and neck, and in the oral cavity (tongue). CASE REPORT: We report a rare case of a granular cell tumor of the parotid gland, in a 55-year old woman, who was referred with a left preauricular mass that had rapidly increased in size over 2 months. There was no cervical lymph adenopathy. RMI demonstrated a solitary lesion of the parotid gland. Surgical resection was performed. CONCLUSION: We discuss the classification, pathophysiology and the treatment of granular cell tumours through a review of the literature.

Warthin's tumor of parotid gland: Surgery or follow-up? Diagnostic value of a decisional algorithm with functional MRI.

PURPOSE: Warthin's tumor is the second most frequent benign tumor of the parotid gland, with no risk of malignant evolution. That is why surgery should be avoided if the preoperative diagnosis is certain. The aim of the study was to assess the added value of a decisional algorithm for the preoperative diagnosis of Warthin's tumor. MATERIALS AND METHODS: This retrospective IRB-approved study included 75 patients who underwent standardised MRI with conventional sequences (T1- and T2-weighted images, and T1 post-contrast sequences with fat saturation) and functional sequences: diffusion (b0, b1000) and perfusion MR. Two independent readers reviewed the images using the decisional algorithm. The conclusion of each reader was: the lesion is or is not a Warthin's tumor. The MRI conclusion was compared with histology or with cytology and follow-up. We calculated the Cohen's kappa coefficient between the two observers and the sensitivity and specificity of the algorithm-helped-reading for the diagnosis of Warthin's tumor. RESULTS: Seventy-five patients; histology (n=61) or cytology and follow-up (n=14) results revealed 20 Warthin's tumors and 55 other tumors. Using the algorithm, sensitivity and specificity were 80-96%, and 85-100%, respectively for readers 1 and 2. The Cohen's kappa coefficient between the two observers was 0.79 (P<0.05) for the diagnosis of Warthin's tumor. CONCLUSION: Our decisional algorithm helps the preoperative diagnosis of Warthin's tumor. The specificity of the technique is sufficient to avoid surgery if a parotid gland tumor presents all the MRI characteristics of a Warthin's tumor.

[Cancer immunotherapy: Rational and recent breakthroughs]. / Immunothérapie des cancers : rationnel et avancées récentes.

Cancer immunotherapy has occupied a marginal therapeutic option in cancer despite strong arguments documenting the role of the immune system in controlling the proliferation of cancers. The recent success of immunotherapy results from a change in the past paradigm. From now on, the goal is not only to activate the immune system against tumor, but also to take account of the immunosuppressive tumor microenvironment Among these mechanisms, negative costimulatory molecules (CTLA-4, PD-1, etc.) expressed by T cells in the tumor could explain their lack of effectiveness in inhibiting tumor growth. Blocking these molecules allowed the reactivation of anti-tumor T cells. Clinically, the administration of anti-CTLA-4 antibody (ipilimumab: Yervoy®) was granted marketing authorization for patients with metastatic melanoma. The anti-PD-1 antibodies (nivolumab: Opdivo®, pembrolizumab: Keytruda®) have demonstrated clinical efficacy when compared to the standard therapy in metastatic melanomas, advanced lung cancers and metastatic renal cell carcinoma. In phase I and II clinical trials, other tumors (Hodgkin's disease, head and neck cancers, bladder cancer, gastric cancer, etc.) appear to be responsive to these immunomodulators. These treatments were associated with the occurrence of side effects dominated by autoimmunity predictable by unlocking the breaks exerted by immune system to maintain tolerance against self-antigen. The optimization of therapeutic combination based on these molecules and the search for biomarkers associated with these treatments constitute a challenge for the future for this new therapeutic class of drugs for oncology.

Identification of a novel cDNA, encoding a cytoskeletal associated protein, differentially expressed in diffuse large B cell lymphomas.

Diffuse large B-cell lymphomas (DLBL) constitute an heterogeneous clinico-pathological entity. To characterize molecular events related to histological subtypes, clinical presentation or outcome, we compared the mRNAs expressed in a limited series of DLBL by Differential display-reverse transcription (DDRT) and cloned a differential cDNA, that we called LB1. LB1 open reading frame encodes a 683 amino-acid polypeptide that does not show significant homology upon comparison to protein databases, nor any structural domain relating LB1 to an already known protein family. Immunofluorescence analysis of transfected COS cells showed a cytoplasmic filamentous staining, indicating that LB1 protein is tightly associated with cytoskeletal fibers. Two LB1 transcripts, a major 3.6-3.9 Kb and a minor 2.2 Kb transcripts, were detected among human haematopoietic and non-haematopoietic lines and tissues. LB1 transcripts were abundant in testis, thymus and in tumour derived cell lines, while barely detectable in liver, prostate and kidney. Concerning DLBL, LB1 expression was high in two cases of DLBL, and low or undetectable in four others, confirming the differential expression previously observed in the DDRT experiment. Furthermore, LB1 gene mapped to chromosome 13q14, a region that has been involved as a chromosomal breakpoint in DLBL. The cellular function of LB1 and its relationship with B cell maturation and/or oncogenesis remain to be established.