Risk factors for early mortality from lung cancer: evolution over the last 20 years in the French nationwide KBP cohorts.

BACKGROUND: The impact of the most recent advances, including targeted therapies and immune checkpoint inhibitors, on early (3-month) mortality in lung cancer is unknown. The aims of this study were to evaluate the real-world rate of and risk factors for early mortality, as well as trends in early mortality over the last 20 years. MATERIALS AND METHODS: The KBP prospective observational multicenter studies have been conducted every 10 years since 2000. These studies collect data on all newly diagnosed patients with lung cancer (all stages and histologies) over 1 year in non-academic public hospital pulmonology or oncology units in France. In this study, we analyzed data on patient and tumor characteristics from participants in the KBP-2020 cohort and compared the characteristics of patients who died within 3 months of diagnosis with those of all other patients within the cohort. We also carried out a comparative analysis with the KBP-2000 and KBP-2010 cohorts. RESULTS: Overall, 8999 patients from 82 centers were included in the KBP-2020 cohort. Three-month survival data were available for 8827 patients, of whom 1792 (20.3%) had died. Risk factors for early mortality were: male sex, age >70 years, symptomatic disease at diagnosis, ever smoker, weight loss >10 kg, poor Eastern Cooperative Oncology Group performance status (≥1), large-cell carcinoma or not otherwise specified, and stage ≥IIIC disease. The overall 3-month mortality rate was found to have decreased significantly over the last 20 years, from 24.7% in KBP-2000 to 23.4% in KBP-2010 and 20.3% in KBP-2020 (P < 0.0001). CONCLUSION: Early mortality among patients with lung cancer has significantly decreased over the last 20 years which may reflect recent improvements in treatments. However, early mortality remained extremely high in 2020, particularly when viewed in light of improvements in longer-term survival. Delays in lung cancer diagnosis and management could contribute to this finding.

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

[Second- or third-line treatment with erlotinib in EGFR wild-type non-small cell lung cancer: Real-life data]. / Erlotinib en 2e ou 3e ligne pour les cancers bronchiques non à petites cellules sans mutation de l'EGFR : données en vie réelle.

INTRODUCTION: The benefit of tyrosine kinase inhibitors for patients with an EGFR wild-type non-small cell lung cancer (NSCLC) remains controversial. METHODS: The survival of patients with an EGFR wild-type NSCLC who received second- or third-line erlotinib treatment was assessed using real-life data that had been collected in a prospective, national, multicenter, non-interventional cohort study. RESULTS: Data from 274 patients were analysed, 185 (68%) treated with erlotinib and 89 (32%) treated with supportive care only. The median overall survival was 4.2months (95% CI [3.5; 5.4]) with erlotinib, and 1.3months (95% CI [1.0; 1.8]) with supportive care. Survival rate at 3, 6, and 12months was 62%, 37%, and 17%, respectively, with erlotinib, versus 20%, 8%, et 3%, with exclusive supportive care. Significant predictive factors for longer overall survival were the presence of adenocarcinoma, and use of 1st line chemotherapy including either taxanes, pemetrexed or vinorelbine (P<0.05). CONCLUSION: Erlotinib remains a valuable therapeutic option to treat inoperable locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen in fragile patients who are not eligible for chemotherapy.

[Clomipramine hypersensitivity with predominantly pulmonary involvement]. / DRESS syndrome avec atteinte pulmonaire prédominante sous clomipramine.

Drug hypersensitivity (DRESS syndrome) is a rare disorder with diverse systemic and visceral manifestations. Pulmonary involvement is uncommon and is mainly characterized by eosinophilic infiltration. We report a case of DRESS syndrome induced by clomipramine with predominant pulmonary involvement.

Feasibility of a PB CD34+ cell transplantation procedure using standard leukapheresis products in very small children.

To evaluate the feasibility and efficacy of CD34+ cell immunoselection from routine peripheral blood stem cell (PBSC) harvests in very small children a prospective study was performed in 15 children with advanced neuroblastoma weighing 20 kg or less. Products of two consecutive leukaphereses carried out on a COBE Spectra separator after G-CSF alone mobilization were pooled for immunoselection on Ceprate column. The median number of CD34+ cells and total CFU-GM collected were respectively 5.9 x 10(6)/kg (range 2.3-23.4) and 126.9 x 10(4)/kg (range 52.9-559.9). After separation the median number of CD34+ cells in the adsorbed fraction was 2.6 x 10(6)/kg (range 1-9.8) with a median purity of 54% (range 21-82) and a median of 95.7-fold (range 35-250) enrichment. Thirteen patients underwent autografts with CD34+ PBSCs after a busulfan 600 mg/m2 + melphalan 180 mg/m2 preparative regimen. The median number of days to achieve an absolute granulocyte count of 0.5 x 10(9)/l and a platelet count of 20 x 10(9)/l were respectively, 12 (range 10-24) and 35 (range 25-43). The median number of platelet transfusions was nine (range 2-15). We conclude that safe and effective immunoselection and transplantation of CD34+ PBSC can be accomplished in children with low body mass.

Comparative analysis of CD4-mediated down-regulation of T cell adhesion to B cells by flow cytometry and fluorescence microscopy.

We have previously shown by means of fluorescence microscopy that antigen-independent adhesion of resting CD4 T cells to EBV-transformed B cells can be down-regulated by ligand interaction with CD4. In this study we used flow cytometry analysis of conjugate formation to confirm these findings. No conjugates between resting CD4 + T cells and B cells were initially detected in the latter method, because flow velocity in the flow chamber induces hydrodynamic elongation forces which disrupt low-affinity conjugates. After forcing cell conjugation by low-speed centrifugation of T and B cells, conjugates became detectable although in smaller numbers than in fluorescence microscopy. "Forced" cell conjugates had similar characteristics to their unforced counterparts, i.e., 37 degrees C temperature dependency, mediation by LFA-1/ICAM-1 and CD2/LFA-3 pathways, and transiency. The latter characteristic was at least partly mediated by CD4/HLA class II interaction, since adhesion of CD4 + T cells to HLA class II-B cells was more stable. In addition, adhesion was inhibited by anti-CD4 antibodies but not by an HLA DR-derived peptide known to inhibit unforced CD4 + T cell adhesion to B cells. This blocking effect was partially reproduced by reducing the centrifugation time prior to the adhesion assay. These results show that a) CD4-mediated down-regulation of T cell adhesion can be observed by means of two different techniques, and b) analysis of cell-cell adhesion after increasing centrifugation times (and possibly speeds) is a simple way of measuring adhesion forces semiquantitatively.

Characteristics of antigen-independent and antigen-dependent interaction of dendritic cells with CD4+ T cells.

Dendritic cells (DC) are the main antigen-presenting cells for the initiation of primary T cell-mediated immune responses. In the first stage of activation, T cells bind to DC in an antigen-independent manner. We studied the adhesion characteristics of human CD4+ T cells to DC generated from CD34+ hematopoietic progenitors following 12 to 13 days of culture in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor-alpha. A majority of these cells had the morphology, phenotype and functions of DC. CD4+ T/DC adhesion was measured by means of fluorescence microscopy and flow cytometry. Four independent receptor/ligand pathways, LFA-1/ICAM, ICAM/LFA-1, CD2/LFA-3 and CD28/CD80, were involved in the transient adhesion of DC to CD4+ T cells in antigen-independent and specific alloantigen-dependent situations, as shown by blocking experiments using monoclonal antibodies. The antibodies also blocked a primary mixed lymphocyte reaction (MLR) in which DC were used as stimulatory cells. Adhesion of alloreactive CD4+ T cells to antigen-presenting DC was stronger than that of resting CD4+ T cells, while peak adhesion occurred after 5 and 20 min, respectively. The LFA-1 ligands involved in adhesion of resting CD4 T cells to DC and alloreactive CD4+ T cells to specific DC differed in part, since ICAM-3 on resting T cells and ICAM-1 on alloreactive T lymphocytes preferentially bound LFA-1. Studies of interactions between DC and phorbol ester-activated T cells expressing the CD40 ligand revealed a fifth independent adhesion pathway, CD40/CD40 ligand. CD4-mediated regulation of CD4+ T/DC adhesion was suggested by the observation that preincubation of CD4+ T cells and DC individually with anti-CD4 antibodies inhibited adhesion. In addition, antibodies specific for HLA class II molecules inhibited adhesion when used to pretreat DC but not alloactivated CD4+ T cells.

Role of LFA-1, CD2, VLA-5/CD29, and CD43 surface receptors in CD4+ T cell adhesion to B cells.

We investigated the adhesion to B cells of CD4+ T cells both in the resting state and following activation by CD3 cross-linking or stimulation by PMA/ionomycine/IL2 for 6 days. Both resting and activated CD4+ T cell adhesion were inhibited by anti-LFA-1, -CD2, -VLA-5/CD29, and -CD43 antibodies, suggesting coordinated upregulation of T cell adhesion. The CD2 and LFA-1 adhesion pathways were found to act independently, as CD2 was functional in T cells not expressing LFA-1, and vice versa, and as specific antibodies had additive effects. In contrast, LFA-1- and VLA-5/CD29-specific antibodies did not have an additive blocking effect on CD4+ T cell adhesion, suggesting that efficient adhesion requires a competitive association of integrins with cytoskeleton elements. Although the involvement of fibronectin (coated to B cells via VLA-4) in VLA-5-mediated T cell adhesion to B cells is feasible, an anti-fibronectin and a VLA-4-specific antibody had no blocking effect. The involvement of an unidentified B cell ligand can also be envisaged.

GF109203X, a specific PKC inhibitor, abrogates anti-CD3 antibody-induced upregulation of CD4+ T cell adhesion to B cells.

Antigen-independent adhesion of CD4+ T lymphocytes to Epstein-Barr virus transformed B cells is mainly mediated by LFA-1 (CD11a/CD18) and CD2 molecules. Low-affinity binding of resting T cells can be transiently upregulated by cross-linking of CD3-TCR (T cell receptor) complexes. This inside-out signaling influences integrin (beta 1 and beta 2) adhesion capacity. Studies using the nonspecific inhibitor staurosporine have suggested that this phenomenon is dependent on protein kinase C activation. We found that the upregulation of anti-CD3-activated CD4+ T cell adhesion was inhibited strongly and in a concentration-dependent manner by GF109203X, a compound described as a potent and selective inhibitor of PKC. Comparative studies showed that GF109203X and staurosporine had similar inhibitory effects on the upregulation of activated CD4+ T cell adhesion. However, staurosporine is a nonselective kinase inhibitor. PMA-activated CD4+ T cell adhesion was also inhibited by GF109203X. In contrast, passive enhancement of adhesion by treatment with the CD11a-specific antibody NKI-L16 was unaffected by GF109203X. Taken together, these results show that PKC is involved in upregulating the adhesion of CD4+ T cells to B cells following activation of the former by CD3 cross-linking. PKC-dependent upregulation of CD4+ T cell adhesion to B cells is exclusively LFA-1-dependent, as GF109203X had no additional inhibitory effect on anti-LFA-1 antibody-pretreated T cells activated by the anti-CD3 antibody OKT3 and had no effect on the adhesion of LFA-1(-) CD4+ T cells. Finally, PKC inhibition did not alter CD2-mediated adhesion. This points to a limited participation of CD2 in T-B cell interactions after TCR/CD3 cross-linking.

Regulation of LFA-1-mediated T cell adhesion by CD4.

Heterotypic adhesion of T lymphocytes to monocytes, B lymphocytes, or other target cells is mainly mediated by LFA-1 and CD2 molecules. Low-affinity binding of resting T cells can be transiently up-regulated by cross-linking of CD3. We have previously found that binding of specific ligands to CD4 can down-regulate adhesion of resting T cells to B cells. We now show that the enhanced adhesiveness of CD4+ T cells induced by CD3 cross-linking using plastic-bound anti-CD3 antibody can also be inhibited by several CD4 ligands. i.e. anti-CD4 antibodies, the gp160 env protein of human immunodeficiency virus, as well as by putative CD4 ligands, i.e. synthetic peptides analogous to the gp160-binding site to CD4 (positions 418-434 and 449-464) and a 12-mer synthetic peptide (DR-12) analogous to positions 35-46 of HLA class II beta subunit and including the highly conserved Arg-Phe-Asp-Ser (RFDS) sequence. After CD3 cross-linking, maximal binding of T cells to HLA class II-positive and -negative B cells was similar, although binding to HLA class II-negative B cells was more prolonged. T cells that were passively induced to up-regulate adhesion by binding of a CD11a-specific antibody NKIL16, known to enhance LFA-1-dependent adhesiveness, were less sensitive to the inhibitory effect of the DR-12 peptide, whereas the inhibitory effects of gp160 were preserved. The kinetics of adhesion of NKIL16-pretreated T cells was not influenced by HLA class II expression at the B cell surface. Together, these results strongly suggest that CD4-HLA class II interaction may down-regulate low-affinity adhesion of resting T cells and, to some extent, high-affinity adhesion of T cells actively induced by CD3 cross-linking but not passively induced by an anti-CD11a antibody.