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Unlabelled: We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment., Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease.

Introduction: Paraneoplastic Cushing's syndrome (CushingPS) in small-cell lung cancer is rare but severe., Methods: We studied 383 patients with small-cell lung cancer diagnosed between 1998 and 2012. Among them, 23 patients had CushingPS, 56 had other paraneoplastic syndrome (OtherPS), and 304 had no paraneoplastic syndrome (NoPS)., Results: After comparison of the three groups, we observed that CushingPS patients had more extensive disease: 82.6% versus 67.8% versus 53.3% (p = 0.005), respectively, with more than two metastatic sites: 63.2% versus 15.8% and 24.1% (p ≤ 0.001), a higher World Health Organization performance status (2-4): 73.9% versus 57.1% versus 43.7% (p = 0.006), greater weight loss (≥10%): 47.8% versus 33.9% versus 16.4% (p ≤ 0.001), reduced objective response to first-line treatment: 47.6% versus 74.1% versus 71.1% (p = 0.04), and poorer sensitivity to first-line treatment: 19% versus 38.9% versus 48.6% (p = 0.01). NoPS patients, with World Health Organization performance status of 3-4, had extensive disease at diagnosis, with response, sensitivity to first-line treatment, and survival similar to the CushingPS group. At relapse, the CushingPS group had no objective response to second-line treatment versus 25% versus 42.8% in OtherPS and NoPS groups, respectively (p = 0.005). The median survival of CushingPS patients was 6.6 months versus 9.2 months for OtherPS and 13.1 months for NoPS patients (p ≤ 0.001). CushingPS is a prognostic factor of death (hazard ratio, 2.31; p ≤ 0.001)., Conclusion: CushingPS is the worst form of the paraneoplastic syndromes with particularly extensive tumors. Reduced objective response and sensitivity to first-line treatment and no response to second-line treatment suggest starting palliative care early at first line and exclusively at relapse.

Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale "off-context" gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors.

Standard treatment of small-cell lung cancer (SCLC) is a combination of etoposide and platinum for patients with extensive disease, associated with radiotherapy for patients with limited disease (LD). Therapeutic strategies for relapse, although well characterized, are disappointing. Between 1997 and 2009, 300 patients were treated for SCLC at Grenoble University Hospital. We analyzed patients' characteristics and outcomes at different treatment steps, to determine prognostic factors and propose subsequent treatment strategies according to "sensitive", "resistant" or "refractory" status established after first-line treatment (L1). The median patient age was 63.2 years, 46.3% had LD, and 23% were female. The objective response rate (ORR) to first-line chemotherapy was 73% [CI(95%): 67.6-77.9] and median survival was 13 months. After L1, comparison between "refractory" and "sensitive" groups showed more extensive disease (76.6% vs. 34.3%, p=0.003), poorer Performance Status (PS 0-1: 48.4% vs. 67.8%, p=0.008), more endocrine paraneoplastic syndrome (18.7% vs. 8.4%, p=0.03) and more composite histology (17.2% vs. 4.9%, p=0.004) in "refractory" patients. After second line (L2), ORR was 55.8% [CI(95%): 45.2-66.0] in "sensitive", 18.2% [CI(95%): 8.2-32.7] in "resistant", and 14.7% [CI(95%): 4.9-31.0] in "refractory" groups; with partial response only for the last two groups. After L3 and L4, ORR was 24.0% [CI(95%): 14.9-35.2] in "sensitive", 9.1% [CI(95%): 11.2-29.2] in "resistant" with partial response only. No response was observed for "refractory". After L1, the median survival was respectively 23, 10 and 6.4 months for "sensitive", "resistant" and "refractory" groups (p<0.001). Multivariate analysis showed that LD and classical SCLC histology were positive predictors of belonging to the "sensitive" group. Positive factors for survival were sensitivity to L1, PS 0-1, LD, Charlson score <4, no endocrine paraneoplastic syndrome and no occupational exposure. Limited disease is the major predictive factor for sensitivity to treatments and survival. Factors linked to the patients' clinical presentation also impact on survival. With currently recommended drugs, the "sensitivity" of the patient determined by the response to L1 indicates that it is pointless to treat "sensitive" with L4, "resistant" with L3 and "refractory" with L2, except for a few selected patients after multidisciplinary group discussion., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex. In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits. Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51 versus 69 yrs; p < 0.001), more often had surgery (62.7% versus 39%; p = 0.01) and had a median (95% CI) estimated survival of 26.2 (18.1-49.2) versus 15.1 (12.8-22.2) months (p = 0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p < 0.001) and fewer had surgery (48.8%; p = 0.015), although the percentage of stage IIIb-IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0-18.5) months (p = 0.0024). Males smoked more than females (median 41 versus 30 pack-yrs; p < 0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p = 0.0035) and 8 yrs for males (p < 0.001). Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers.

Two thousand lung cancer patients were registered as Grenoble's university hospital joint oncology clinic from 1/1/1982 to 12/31/1991. These cases consisted of 449 small cell lung cancers (SCLC) and 1,551 non-small cell lung cancers (NSCLC). SCLC patients had a 4.6% and 2.9% survival rate at 5 and 10 years and only 7.2% of patients had a survival longer than 30 months. The main prognostic factors for survival were age, sex, TNM stage and WHO performance status. There was no increase in survival during the 2 periods of the study. NSCLC patients had a 14% and 7% survival rate at 5 and 10 years. Among 727 stage III or IV patients not treated with surgery, 2% were alive at 30 months. The main prognostic factors for survival were age, histology, TNM stage and WHO performance status. There was no increase in survival during the 2 periods of the study.

The prognosis of stage III non-small cell lung cancer (NSCLC) can be improved by a combination of radiotherapy (RT) and chemotherapy (CT). In this study, the GOTHA group evaluated the feasibility, tolerance, tumour response, pattern of failure and effect on survival of a combination alternating accelerated hyperfractionated (AH) RT and CT in patients with tumour stage III NSCLC. 65 patients received 3 cycles of cisplatin 60 mg/m2 and mitomycin C 8 mg/m2 on day 1, and vindesin 3 mg/m2 on days 1 and 8 in weeks 1-2, 5-6 and 9-10, alternating with AHRT, 2 daily 1.5 Gy fractions, 5 days/week, in weeks 2-3 (30 Gy) and weeks 6-7 (33 Gy). The dose actually delivered was > 98% for RT, and 85-100% for CT. Mean duration before last CT cycle was 9.5 weeks. Toxic effects were leucopenia, nausea and vomiting, mucositis, diarrhoea, alopecia and peripheral neuropathy. 1 patient died of bronchial haemorrhage at the end of RT. 1 of 5 patients, who underwent secondary pulmonary resections, died of acute respiratory distress syndrome. Evaluation of tumour response was hampered by lung condensations in radiation fields. Some long-term survivors had an initial tumour response assessed as partial response or no change. First failures were more frequent outside (34) than within (21) radiation fields. The median survival was 15.7 months and the 5 year survival rate was 15% (95% CI = 6-26%). 1 patient died of bladder cancer and another of myocardial infarction. Alternating CT and AHRT, as used in this study, were well tolerated and allowed full dose delivery within less than 12 weeks. Initial response was not predictive of survival. The survival curve is encouraging and the 5 year survival is superior to the 5% generally observed with conventionally fractionated radiotherapy.

Thirty six SLC patients have been treated with a combination therapy of ifosfamide 2 g/m2, D1 and D2, carboplatin 300 mg/m2 D1 and teniposide 100 mg/m2 D1 to D3. All patients were younger than 70 years, 31 males, five females, ten limited diseases, 26 extended diseases (without brain metastasis) Performance status 0, 1 or 2, mean weight loss 3.7 kg. Thirty six patients were evaluable for response. We have noted three complete response and 28 partial response (objective response rate 86%). The main toxicity of this combination therapy was myelo-suppression (86% of grade 3 and 4). Twenty seven patients have relapsed, the median relapse free survival time is 310 days. The median survival of the 36 patients is 340 days, one patient is alive more than 30 months after the diagnosis. The ifosfamide-carboplatin-teniposide combination is an effective treatment in small cell lung cancer, its toxicity remains tolerable.

Forty-seven patients with unresectable non small cell lung carcinoma, 15 stage IIIA, 31 stage IIIB, 1 stage IV (cervical lymphadenopathy) were treated with a combination of three courses of chemotherapy and hypofractionated irradiation followed after 3 weeks by split course radiotherapy. Each course was repeated every 3 weeks with the following sequence: Cisplatinum (CDDP) (20 mg/m2) was given in a 20-min infusion, followed by a 2-h infusion of 5-fluorouracil (5-FU) (400 mg/m2) on days 1, 2, 5 and 6. Radiation with a dose of 3 Gy on the target volume was given on days 3 and 4--in one fraction for the former 27 patients, in 2 fractions of 1.5 Gy for the latter 20 patients with a 6-h interval--after a 2-h infusion of 5-FU (400 mg/m2). The results remain disappointing: the objective response rate was 53%, the median survival was 10 months for the series, and the one-year survival 47%. The median survival was 14 months for IIIA, 10 months for IIIB and IV. Regarding the therapeutic regimen there seems to be less morbidity with 2 fractions per day for which the median survival is nearly the same at 10 months (1 fraction/day) versus 12 months (2 fractions/day).

Despite the high response rates resulting from chemotherapy, the majority of small-cell lung cancer (SCLC) patients relapse with chemoresistant tumors. To analyze the phenotypic changes that are precursors of chemoresistant status, and to investigate the role of chemotherapy in these changes, tumor samples from 20 patients, taken before chemotherapy (etoposide, doxorubicin, and cyclophosphamide) and again at the onset of chemoresistance (after at least three courses of chemotherapy), were compared. The histologic changes were minor in 10 of 20 patients, as shown by an increase in cell size; they were major in 10 of 20 patients, with the appearance of mixed composite tumors in which neuroendocrine (NE), epidermoid, and glandular components were mixed. Major changes correlated with a good response to chemotherapy (P = .001). Ultrastructural studies showed an increase in neurosecretory granules and desmosomes, and a high frequency of multidirectional differentiation (45%) when comparison was made with pretherapy samples (10%) (P less than .01). Immunohistochemical (IH) analysis showed an increase in cytokeratin (CK) expression in treated patients, with a different labeling pattern and the expression of higher molecular weight CK. The expression of NE lineage markers (Leu 19, Sy 38, SL 11-14) remained stable, while that of NE differentiation markers (Leu 7, chromogranin) increased in the treated patients. The neuron-specific enolase (NSE) activity remained stable in treated SCLC. Large cells with a more differentiated phenotype and proliferative capacity (as shown by Ki 67 labeling), appeared to be characteristic of treated and secondary chemoresistant SCLC. The acquisition of a more complex phenotype, which correlates with primary response to therapy, implies a drug-induced differentiation in SCLC.

Progress in genetics now enables the synthesis of molecules acting on the regulation of the immune system which are called cytokines. Currently there are several cytokines, Interferon (IFN), Interleukin 2 (IL2), tumour necrosis factor (TNF) as well as haematopoietic growth factors and these are the object of study in clinical trials. Interferon has already been used in the therapy of hairy cell leukaemia, Kaposi sarcoma associated with AIDS(SIDA) and metastasis of malignant melanoma. Interleukin 2 allows for an increase in the cytotoxic activity of NK cells in producing LAK cells, the lymphocyte infiltrating the tumour (TIL). Therapeutic combinations combining IL2 associated with LAK or of TIL have been evaluated in some private studies. These treatments have shown some interesting response levels on those tumours which are usually resistant, such as malignant melanoma or carcinoma of the kidney. TNF is active in vitro on human tumours; its potential toxicity is important; it is the object of a phase 1 clinical trial. Haematopoietic growth factors, G-CSF and GM-CSF, stimulate the production of leucocytes which will be valuable to correct toxic affects on the marrow during chemotherapy. This will enable chemotherapy to be given at a high dose.

Twenty patients with unresectable non-small cell lung carcinoma, 15 stage III and 5 stage IV (supraclavicular lymphadenopathy) were treated with a combination of three courses of chemotherapy and hypofractionated irradiation followed after 3 weeks by split-course radiotherapy. Each course was repeated every 3 weeks with the following sequence. Cis-platin (CDDP) (20 mg/m2) was given in a 20-min infusion, followed by a 2-h infusion of 5-fluorouracil (5-FU) (400 mg/m2) on days 1, 2, 5 and 6. Radiation with a dose of 3 Gy on the target volume was given on days 3 and 4, after a 2-h infusion of 5-FU (400 mg/m2). Split course of irradiation consisted of 16 Gy in 5 fractions repeated after 3 weeks interval. The objective response rate was 75%. Median follow-up was 24 months, the median survival was 14 months. The 1-year survival was 53% and the 2-year survival was 16%.

Neurone specific enolase (NSE); alpha gamma and gamma gamma isoenzymes of the glycolytic enzyme enolase, is found in considerable quantity in serum of patients with small cell lung cancer (SCLC). The spectrophotometric measurement of serum enolase activity, plus the electrophoretic separation of isoenzymes (alpha alpha, alpha gamma and gamma gamma) using an amplification reaction constitute a simple method, the application of which has not yet been demonstrated. In patients, serum values of higher than 25 U/l of total enolase activity, with more than 10% NSE, were considered to be positive. Seventy patients diagnosed as SCLC were classified before treatment as having either limited (LD) or extensive (ED) disease, and after chemotherapy as being in complete (CR) or partial remission (PR), stable state (SS) or in relapse (R). The levels of enolase activity and NSE (M +/- SE) in these patients (enolase: 67 +/- 7 U/l, NSE 27 +/- 2%) were different from those in a control group of 19 patients with non-small cell lung cancer (enolase: 29 +/- 2 U/l, NSE: 7 +/- 1%) (p less than 0.001) at the time of diagnosis. Mean enolase and NSE levels in patients with SCLC were seen to differ significantly according to the clinical stage. The results of those patients with ED differed from those of patients with LD (p less than 0.001). The results of the group of patients that achieved remission differed from that of patients during relapse (p less than 0.0001). Serial measurements demonstrated a good correlation between enolase and NSE serum levels and the progression of the disease. The usefulness of this method in the early assessment of treatment was also demonstrated. The clinical usefulness of the dosage of NSE with that of two other tumour markers CKBB and mitochondrial CK was compared.

In order to validate xenografted small cell lung carcinomas (SCLC) for biological studies, the authors established 12 lung neuroendocrine (NE) tumors (eight typical SCLC and four atypical NE tumors [ANE]) by heterotransplantation onto nude mice. Their characterization was performed using serial ultrastructural, enzymatic, and immunohistochemical methods on primary tumors and after xenografts. These were subclassified into epithelial (one), neuroendocrine (three), and multidifferenciated (eight) types. The phenotypic characters (cytokeratins, neurofilaments, neurone-specific enolase) and the proliferative rate (Ki 67 labelling) of original tumor were maintained until the last passage studied. Although further acquisition of subsets of cytokeratin or neurofilaments was observed in some cases, the authors could not detect any morphologic and/or biological spontaneous change comparable to those described in in vitro cell lines. In addition, ANE are not quite identical to variant subclasses described in vitro. The authors conclude that the stability of heterotransplanted SCLC is an advantage in further biological studies.