Afatinib as first-line treatment in patients with EGFR-mutated non-small cell lung cancer in routine clinical practice.

BACKGROUND: Lung cancer is a leading cause of cancer-related death in Germany and worldwide. Non-small cell lung cancer (NSCLC) comprises ~80% of lung cancer diagnoses; in White patients, around 10% of NSCLC cases are epidermal growth factor receptor mutation-positive (EGFRm+). Head-to-head clinical trials have demonstrated superior efficacy with second-/third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) versus first-generation EGFR TKIs in EGFRm+ NSCLC. Data from routine clinical practice are necessary to confirm that clinical trial findings are transferable to real-world populations. METHODS: In NCT02047903, a prospective non-interventional study in Germany, patients with EGFRm+ NSCLC received first-line afatinib until disease progression or intolerable adverse events. Key objectives were progression-free survival (PFS) rate at 12 months, objective response rate (ORR) and overall survival (OS). Safety/tolerability was also assessed. RESULTS: Of 152 patients, 106 (69.7%) were female, 20 (13.1%) patients had an uncommon EGFR mutation and 51 patients (33.6%) had brain metastases. A starting dose of <40 mg was received by 39 (25.7%) patients. Overall, the 12-month PFS rate was 50.2% while the median PFS was 12.2 months. The ORR was 74.6% and the median OS was 30.4 months. In patients with brain metastases and uncommon mutations, the median PFS was 10.5 and 10.7 months, and the ORR was 77.3% and 83.3%, respectively. Treatment effectiveness was similar in patients with a starting dose of <40 mg (median PFS: 16.4 months; ORR, 81.3%) and a starting dose of 40 mg (median PFS: 10.8 months; ORR, 72.1%). Adverse drug reactions were manageable and consistent with the known afatinib safety profile. CONCLUSION: The results support clinical trial data for afatinib in routine clinical practice, including in patients generally excluded from clinical trials. Outcomes were positive in patients with uncommon EGFR mutations and in those with brain metastases. Treatment benefit was also seen in patients receiving a <40 mg afatinib starting dose, supporting patient-tailored dosing.

Returning to work in lung cancer survivors-a multi-center cross-sectional study in Germany.

PURPOSE: To investigate the work situation of lung cancer survivors and to identify the factors associated with their returning to work. METHODS: Descriptive analysis and logistic regression were used to evaluate study population characteristics and independent factors of subsequently returning to work. To analyze time to return to work, Cox regression was used. RESULTS: The study sample included 232 lung cancer survivors of working age from 717 enrolled participants in the multi-center cross-sectional LARIS (Quality of Life and Psychosocial Rehabilitation in Lung Cancer Survivors) study. About 67% of the survivors were not employed during the survey. More than 51% of the survivors who were employed before their illness did not return to their work. The survivors who had returned to their careers were younger, associated with higher household income, lower fatigue score, and stable relationship and vocational training. Patients who received social service counseling showed a higher chance of regaining their career. CONCLUSIONS: Lung cancer survivors were found to be associated with a high risk of unemployment and very low professional reintegration after interruption due to illness. More comprehensive studies are needed to support lung cancer survivors and targeting of patients in need of special attention in rehabilitation that would benefit from the findings in the present study.

Use of psychosocial services by lung cancer survivors in Germany : Results of a German multicenter study (LARIS).

PURPOSE: Little is known about the use of psychosocial services in lung cancer survivors and patients who have survived the diagnosis for at least one year. We investigated the frequency of use, stratified by radiation therapy received, its associated factors, and the reasons for non-use of those services. METHODS: We performed a multicenter (n = 6 hospitals) cross-sectional study using data from medical records, patient reported questionnaires, and computer-assisted telephone interviews. Odds ratios (OR) for factors potentially associated with the use of any type of psychosocial services were calculated using multivariable logistic regression. RESULTS: We included 604 lung cancer patients/survivors. Of them, 60% (69% of those who had received radiotherapy) had used some kind of psychological and/or social service in the past (47% psychological, 42% social); 39% had used inpatient care, 24% outpatient care (cancer counselling center, general counselling center, psychological counselling by family doctor, psychotherapy, patient support group, pastoral work). Of those who visited a rehabilitation clinic, 66% received psychosocial care there. Factors associated with using psychosocial services in general were female gender (OR 1.96, 95% CI 1.32-2.93), poor emotional functioning (per unit decrease: OR 0.99, 95% CI 0.98-0.996), and younger age (per year decrease: OR 0.95, 95% CI 0.93-0.97). CONCLUSIONS/IMPLICATIONS: The high proportion of psychosocial care users among lung cancer survivors in Germany indicates that patients are interested in using it and that an unmet need exists. The creation of a broad spectrum of easily accessible services with high quality is important to enable and facilitate use.

Impact of EMT in stage IIIB/IV NSCLC treated with erlotinib and bevacizumab when compared with cisplatin, gemcitabine and bevacizumab.

The aim of the present study was to assess the expression of epithelial-mesenchymal transition biomarkers (E-cadherin and vimentin) and their potential significance as prognostic markers in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) enrolled in the INNOVATIONS trial, receiving treatment with either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). The tumor tissues of 104 patients were retrospectively analyzed using immunohistochemistry to assess the expression of E-cadherin and vimentin. The distribution between the treatment arms was 46 patients in the EB-arm and 58 in the PGB-arm. Comparing the treatment arms according to E-cadherin and vimentin expression, the analysis revealed that progression-free survival (PFS) was increased in the PGB treatment group when compared with EB treatment in patients with low expression of E-cadherin [hazard ratio (HR)=0.353; 95% confidence interval (CI) 0.189- 0.658; log-rank P=0.0007] and in those with high expression of vimentin [HR=0.276 (95% CI, 0.115- 0.659), log-rank P=0.0021]. In patients that exhibited high E-cadherin and were negative for vimentin, there was no difference in the PFS between the PGB and EB treatment groups. In conclusion, in non-squamous NSCLC with downregulated E-cadherin and upregulated vimentin, the efficacy of chemotherapy with PGB was superior compared with EB; but the same effect was not observed in patients with high E-cadherin and low vimentin. Although increased PFS was observed in patients with PGB treatment compared with EB treatment in the whole analysis populations, in the subgroup of patients with the mesenchymal phenotype, no prognostic or predictive value of either biomarker could be identified. The potential role of bevacizumab in overcoming chemotherapy resistance in the population with the mesenchymal phenotype has to be further explored.

Quality of Life in NSCLC Survivors - A Multicenter Cross-Sectional Study.

INTRODUCTION: The objective was to assess quality of life (QoL) in lung cancer survivors, compare it to the general population, and identify factors associated with global QoL, physical functioning, emotional functioning, fatigue, pain, and dyspnea. METHODS: Data from NSCLC patients who had survived 1 year or longer after diagnosis were collected cross-sectionally in a multicenter study. QoL was assessed with the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the lung cancer module QLQ-LC13 across different clinical subgroups and compared to age- and sex-standardized general population reference values. Multivariable linear regression analyses were performed to test the associations of patient-, tumor-, and treatment-related factors with the six primary QoL scales. RESULTS: Six hundred fifty-seven NSCLC patients participated in the study with a median time since diagnosis of 3.7 years (range, 1.0-21.2 years). Compared to the age- and sex-standardized general population, clinically meaningful differences in the QoL detriment were found on almost all domains: lung cancer survivors had clinically relevant poorer global QoL (10 points, p < 0.001). Whereas in 12 months or longer treatment-free patients this detriment was small (8.3), it was higher in patients currently in treatment (16.0). Regarding functioning and symptom scales, respective detriments were largest for dyspnea (41 points), role function (33 points), fatigue (27 points), social function (27 points), physical function (24 points), and insomnia (21 points) observed across all subgroups. The main factor associated with poorer QoL in all primary QoL scales was mental distress (ß |19-31|, all p < 0.001). Detriments in QoL across multiple primary QoL scales were also observed with current treatment (ß |8-12|, p < 0.01), respiratory comorbidity (ß |4-5|, p < 0.01), and living on a disability pension (ß |10-11|, p < 0.01). The main factor associated with better QoL in almost all primary QoL scales was higher physical activity (ß |10-20|, p < 0.001). Better QoL was also observed in patients with high income (ß |10-14|, p < 0.01). CONCLUSIONS: Lung cancer survivors experience both functional restrictions and symptoms that persist long term after active treatment ends. This substantiates the importance of providing long-term supportive care.

ERCC1 assessment in upfront treatment with and without cisplatin-based chemotherapy in stage IIIB/IV non-squamous non-small cell lung cancer.

Prior studies have demonstrated an association between excision repair cross-complementation group 1 (ERCC1) expression level and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. The aim of this study was to assess the impact of ERCC1 on survival for patients with stage IIIB/IV non-squamous NSCLC (NS-NSCLC) enrolled in the INNOVATIONS trial, thus receiving as treatment either erlotinib/bevacizumab (EB) or cisplatin/gemcitabine/bevacizumab (PGB). We retrospectively analyzed tumor tissue of 72 patients using immunohistochemistry to assess the expression of ERCC1. The distribution between treatment arms was equal (36 patients each). Two different H scores were calculated and correlated with survival. In ERCC1-positive patients, no significant difference in terms of progression-free survival (PFS) between treatment arms has been detected. ERCC1-negative patients benefited from PGB compared to EB arm (H score: HR = 0.377, 95% CI [0.167-0.849], p = 0.0151; modified H score: HR = 0.484, 95% CI [0.234-1.004], p = 0.0468). With respect to the scoring system, in the EB-arm, a significant superior PFS turned out in ERCC1-positive patients when employing the H-score (HR = 0.430, 95% CI [0.188-0.981], p = 0.0397; median 4.9 vs. 3.9 months), but not with the modified H-score. Our findings support the hypothesis that NS-NSCLC displaying a low ERCC1 expression might benefit from cisplatin-based chemotherapy. High expression indicated better PFS in the EB arm supporting the prognostic impact. However, as impact of ERCC1-assessment even might depend on scoring systems differences, the need in standardization of assessment methodology is emphasized.

65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer.

BACKGROUND: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). RESULTS: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0-1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03-1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195-2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS. CONCLUSION: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0-1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy.

Comprehensive Biomarker Analyses in Patients with Advanced or Metastatic Non-Small Cell Lung Cancer Prospectively Treated with the Polo-Like Kinase 1 Inhibitor BI2536.

BACKGROUND: Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established. To this end, we conducted a post-hoc biomarker analysis of tumor samples from non-small cell lung cancer (NSCLC) patients treated with the PLK1 inhibitor BI2536 in a phase II study. METHODS: We analyzed formalin-fixed paraffin-embedded surplus tumor tissue from 47 study patients using immunohistochemistry (IHC) and DNA sequencing of KRAS, EGFR, BRAF, and PIK3CA. RESULTS: KRAS-mutated patients showed numerically prolonged progression-free survival, but statistical significance was not established. Interestingly, when pathways rather than single genes were analyzed, a positive correlation between IHC staining of activated ERK (p-ERK) and mutated KRAS was detected, whereas KRAS mutation status was found to be negatively correlated with activated AKT (p-AKT). CONCLUSION: With this hypothesis-generating study in BI2531-treated patients, we could not establish a correlation between KRAS mutations and relevant clinical endpoints. Future clinical trials with concomitant systematic biosampling and comprehensive molecular analyses are required to identify biomarkers predictive for response to PLK1 inhibitors.

Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected nonsquamous nonsmall cell lung cancer.

Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab. Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg·m(-2) on day 1, every 3 weeks) and gemcitabine (1250 mg·m(-2) on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (PGB) until progression. 224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39-2.45; p<0.0001) and overall survival (median 12.6 versus 17.8 months; HR 1.41, 95% CI 1.01-1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB. Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.

The gefitinib long-term responder (LTR)--a cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP).

BACKGROUND: In selected patients with advanced non-small cell lung cancer (NSCLC) the EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor (TKI) gefitinib (IRESSA) shows response rates of ≥ 70% and a significant prolongation of progression free survival (PFS). However, cogent biomarkers predicting long-term response to EGFR-TKIs are yet lacking. Cancer stem-like cells (CSC) are thought to play a pivotal role in tumor regeneration and appear to be influenced by the EGFR-pathway. This makes them a promising candidate for predicting long-term response to EGFR-TKIs. MATERIALS AND METHODS: We analyzed pre-therapeutic tissue specimens of a rare and specific subset of previously treated German patients with advanced NSCLC who experienced ≥ 3 year response to gefitinib within the International IRESSA EAP. 11/20 identified long-term responders (LTRs) had appropriate tissue specimens available. Those were analyzed for EGFR and k-ras (Kirsten rat sarcoma) mutations, EGFR and c-met (met proto-oncogene) amplifications and protein expression of EGFR, E-cadherin/vimentin and the CSC antigens CD133 and BCRP1 (breast cancer resistance protein 1). The results were compared to primary resistant patients (RPs) and intermediate responders (IRs) showing a median response of 8.6 months. RESULTS: Each group consisted of 6 women and 5 men, with 1 squamous cell carcinoma (SCC) and 10 adenocarcinoma (AC). Along the LTRs, all but the SCC had EGFR mutations, whereas the RPs had no EGFR, but k-ras mutations in 5/11 cases. 8/11 IRs had EGFR and 3/11 k-ras mutations, of which 2 occurred concomitantly. One patient of each group had an EGFR and/or c-met amplification. EGFR and E-cadherin/vimentin expression was not different between the groups, whereas CD133 was expressed only in 4/10 LTRs and BCRP1 predominantly in responders. The LTRs showed a substantially longer mean PFS to previous therapies, a substantially lower number of metastatic sites and almost exclusively pulmonary or pleural metastasis. CONCLUSION: LTRs display established properties of EGFR-TKI responders. Antigens characterizing CSC might identify a fraction of LTRs and matter of interest for further evaluation.

Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study.

BACKGROUND: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. METHODS: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). INTERPRETATION: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. FUNDING: Merck KGaA.

The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial.

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer. METHODS: Ninety-five patients were randomized to intravenous BI 2536 on day 1 (200 mg) or days 1 to 3 (50 or 60 mg) of a 21-day treatment course. BI 2536 doses were escalated beyond course 2 if well tolerated. The primary objective was response, and the secondary objectives were progression-free survival (PFS) and overall survival (OS), quality of life, safety, and pharmacokinetics. Primary statistical aim was to demonstrate the difference in objective response rate to historical placebo for both treatment groups. RESULTS: Four patients (4.2%) had a partial response; two were confirmed by independent review. Median PFS was 8.3 weeks (58 days 95% confidence interval [CI]: 48-85) and 7 weeks (49 days 95% CI: 46-70) assessed by investigator and independent review, respectively. Median OS was 28.7 weeks (201 days 95% CI: 180-305). No statistically significant difference was observed between the two treatment schedules regarding clinical benefit, PFS, or OS. Grade 4 neutropenia occurred in 37% of patients; common nonhematologic adverse events were fatigue (31%) and nausea (27%). Two deaths (pulmonary hemorrhage and sepsis) were considered drug related. There was a trend in favor of the days 1 to 3 dosing schedule in quality of life. BI 2536 displayed moderate interpatient variability. CONCLUSIONS: BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication.

A phase II study of irinotecan (CPT-11) and carboplatin in patients with limited disease small cell lung cancer (SCLC).

PURPOSE: The aim of this phase II trial was to evaluate the efficacy and safety of a combination chemotherapy containing irinotecan (CPT-11) and carboplatin as first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: From December 2002 to May 2004 61 patients with limited disease (IASLC classification) were enrolled who were not suitable for concurrent chemo-radiotherapy. Eighteen of the 61 patients (29.5%) had malignant pleural or pericardial effusion and 4 patients (6.6%) had involved supra- or infraclavicular lymph nodes. Patients received irinotecan 50mg/m(2) on days 1, 8 and 15 and carboplatin AUC 5 on day 1, every 4 weeks. RESULTS: A total of 233 chemotherapy cycles were administered. The median number of cycles per patient was 4. The overall response rate to chemotherapy on an intention-to-treat basis was 64%. The median overall survival was 13.8 months, the median disease-free survival 8.0 months, the 1-year survival rate 53.5%, and the 2-year survival rate 17.9%. Haematological and non-hematogical toxicities were low (CTC-grade 3 neutropenia 14.8%, grade 3 thrombocytopenia 5.2%, grade 3/4 anemia 5.1%, grade 3 nausea/vomiting 5.1%, grade 3 diarrhea 3.6%, grade 3 alopecia 3.6% of pts). CONCLUSION: The results suggest that the combination of irinotecan (CPT-11) and carboplatin is active and well tolerable in patients with limited disease SCLC who were not suitable for concurrent chemotherapy.

Dysfunctional inhibitory muscarinic receptors mediate enhanced histamine release in isolated human bronchi.

In human airways mucosal mast cells are under the control of inhibitory muscarinic receptors. The described experiments tested, whether the inhibitory potency of two muscarinic receptor agonists (oxotremorine, acetylcholine) becomes impaired in advanced chronic obstructive pulmonary disease (COPD). Isolated human bronchi obtained from 26 patients with lung cancer were separated into two groups. Group 1 patients suffered from moderate COPD (mean FEV1 56%; range 34-71%; mean pack years of cigarette smoking 50, range 20-96; one non-smoker). Group 2 patients had no or only a mild form of COPD; mean FEV1 was 82% (62-97%) and the number of pack years 22 (6-45; 3 non-smoker). The calcium ionophore A23187 induced a maximal histamine release of 4100+/-870 pmol/g/5 min in group 1 bronchi, in contrast to only 1730+/-240 pmol/g/5 min in group 2 bronchi (p<0.02). Oxotremorine (1 nmol/L) reduced the stimulated histamine release by 81+/-5% in group 2 bronchi, but did not produce a significant effect in group 1 bronchi (11+/-14%). In conclusion, the present experiments show an enhanced histamine release in advanced COPD, which can be explained by a dysfunction of inhibitory muscarinic receptors.

Highly focused T cell responses in latent human pulmonary Mycobacterium tuberculosis infection.

The elucidation of the molecular and immunological mechanisms mediating maintenance of latency in human tuberculosis aids to develop more effective vaccines and to define biologically meaningful markers for immune protection. We analyzed granuloma-associated lymphocytes (GALs) from human lung biopsies of five patients with latent Mycobacterium tuberculosis (MTB) infection. MTB CD4+ and CD8+ T cell response was highly focused in the lung, distinct from PBL, as assessed by TCR-CDR3 spectratyping coupled with a quantitative analysis of TCR VB frequencies. GALs produced IFN-gamma in response to autologous macrophages infected with MTB and to defined MTB-derived HLA-A2-presented peptides Ag85a242-250, Ag85b199-207, early secreted antigenic target 6 (ESAT-6)28-36, 19-kDa Ag88-97, or the HLA-DR-presented ESAT-6(1-20) epitope. Immune recognition of naturally processed and presented MTB epitopes or the peptide ESAT-6(1-20) could be linked to specific TCR VB families, and in two patients to unique T cell clones that constituted 19 and 27%, respectively, of the CD4+ and 17% of the CD8+ GAL population. In situ examination of MTB-reactive GALs by tetramer in situ staining and confocal laser-scanning microscopy consolidates the presence of MHC class I-restricted CD8+ T cells in MTB granuloma lesions and supports the notion that clonally expanded T cells are crucial in immune surveillance against MTB.

Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial.

PURPOSE: To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with locally advanced or metastatic non-small cell lung cancer. EXPERIMENTAL DESIGN: Patients were randomly assigned to receive pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2) (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). All drugs were given on day 1 of a 21-day cycle for up to six cycles. Folic acid and vitamin B(12) were given to all patients to minimize pemetrexed-related toxicities. RESULTS: Forty-one patients received PemOx and 39 received PemCb. Objective tumor response rates were 26.8% for PemOx patients (95% confidence interval, 14.2-42.9) and 31.6% for PemCb patients (95% confidence interval, 17.5-48.7). Median time to progression was 5.5 and 5.7 months, respectively, for PemOx and PemCb. Median overall survival times were 10.5 months for both treatment groups (range, <1 to >20 months). The 1-year survival rate was 49.9% for PemOx patients and 43.9% for PemCb patients. Common toxicity criteria grade 3 or 4 hematologic toxicities among PemOx patients were grade 3 or 4 neutropenia (7.3%), grade 3 thrombocytopenia (2.4%), and grade 3 anemia (2.4%). PemCb patients experienced grade 3 or 4 neutropenia (25.6%), grade 3 or 4 thrombocytopenia (17.9%), and grade 3 anemia (7.7%). Grade 3 vomiting occurred in three PemOx patients and grade 3 fatigue occurred in three PemCb patients. One grade 3 neurosensory toxicity occurred in the PemOx group. Three patients (PemOx 1 and PemCb 2) experienced febrile neutropenia. CONCLUSIONS: Efficacy measures for both regimens seem similar to the most effective chemotherapies for advanced non-small cell lung cancer (platinum combinations) with less hematologic and nonhematologic toxicity. Comparing either of these two regimens to platinum-based therapies in a large randomized trial is warranted.

Longitudinal analysis of Mycobacterium tuberculosis 19-kDa antigen-specific T cells in patients with pulmonary tuberculosis: association with disease activity and cross-reactivity to a peptide from HIVenv gp120.

CD8(+) T cells play a central role in immune protection against infection with Mycobacterium tuberculosis. One of the target epitopes for anti-M. tuberculosis directed CD8(+) T cells is the HLA-A2-restricted 19-kDa lipoprotein peptide VLTDGNPPEV. T cell clones directed against this epitope recognized not only the nominal peptide ligand, but also a closely related peptide (VPTDPNPPEV) from the HIV envelope gp120 (HIV(env) gp120) protein characterized by IFN-gamma release. This cross-reactivity was confirmed in ex vivo in M. tuberculosis 19-kDa tetramer-sorted T cells from patients with tuberculosis and in HIVgp120 tetramer-reactive T cells sorted from HIV(+) patients. M. tuberculosis 19-kDa antigen-reactive T cells were present in HLA-A2(+) patients (10/10) with HIV infection with no evidence of M. tuberculosis infection, but they are absent in peripheral blood lymphocytes from healthy HLA-A2(+) individuals (10/10). M. tuberculosis 19-kDa antigen-reactive T cells were elevated in acute pulmonary tuberculosis, declined with response to therapy (7/10 patients) and resided in the terminally differentiated CD8(+) T cell subset. CD8(+) cross-reactive T cells recognizing HIV(env) or M. tuberculosis 19-kDa antigens may contribute to pathogenesis in individuals co-infected with both pathogens and may also present a marker for active tuberculosis.