Marina Longo

Polymerase eta mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy.

Purpose: The effect of translesion DNA synthesis system in conferring cellular tolerance to DNA-damaging agents has been recently described. DNA polymerase η (Pol η) is part of this machinery and in vitro models showed that it can overcome DNA damages caused by cisplatin and UV rays. The aim of the present study was to investigate the role of Pol η mRNA expression levels in non–small cell lung cancer (NSCLC). Experimental Design: Pol η mRNA expression levels were evaluated by real-time PCR in (a) formalin-fixed paraffin-embedded biopsies of 72 NSCLC patients treated with platinum-based chemotherapy, (b) fresh snap-frozen surgical specimens of tumor and corresponding normal lung tissue from 50 consecutive patients not treated with perioperative or postoperative chemotherapy, and (c) five NSCLC cell lines. Results: High Pol η expression levels were strongly associated with shorter survival at both univariate (6.9 versus 21.1 months; P = 0.003) and multivariate (hazard ratio, 3.18; 95% confidence interval, 1.73-5.84; P = 0.008) analysis in the group of platinum-treated patients. By contrast, Pol η expression was not significantly correlated with the prognosis in surgically resected patients (P = 0.54) and mRNA levels did not significantly differ in tumor versus normal lung (P = 0.82). Moreover, endogenous Pol η mRNA expression was found to be inducible by cisplatin in three of five cell lines and significantly associated with in vitro sensitivity (P = 0.01). Conclusions: Taken together, these data indicate Pol η as a predictive rather than prognostic marker worth of further investigation in NSCLC patients candidate to platinum-based chemotherapy.

Nonsmall cell lung cancer in never smokers.

Purpose of review To summarize the available knowledge about nonsmall cell lung cancer (NSCLC) in never smokers in terms of biological and clinical–pathological findings. Recent findings Overall in newly diagnosed NSCLC, 10% of men and 20% of women, with a much higher proportion among Asiatic women, are never smokers and among them an overwhelming proportion have adenocarcinoma. Several environmental, genetic, hormonal and viral factors have been associated with an increased risk of NSCLC in never smokers, but for none of them there is definitive evidence. The incidence of epidermal growth factor receptor mutations is higher in never smokers, whereas K-ras mutations are rarely detected in this group of never smoking patients. The role of never smoking status in NSCLC as a positive prognostic factor or predictive of a better chemosensitivity to systemic treatments is still undefined. Summary Epidemiological, molecular and clinical–pathological features indicate NSCLC in never smokers as a distinct entity. Future preclinical studies should address more deeply the biological differences between NSCLC in smokers and never smokers and, to avoid biased results due to differences in survival outcomes, smoking status should be considered among stratification factors in future clinical studies.

Excision Repair Cross Complementing-1 and Topoisomerase IIα Gene Expression in Small-Cell Lung Cancer Patients Treated with Platinum and Etoposide: A Retrospective Study

Hypothesis: Aim of the study was to quantify ERCC1, RRM1, and TopoII&agr; mRNA expression profile as predictive factors for response and survival in SCLC patients treated with platinum/etoposide. Methods: Total RNA was extracted from microdissected sections of 103 formalin-fixed, paraffin embedded biopsies. Relative quantification was performed by real-time polymerase chain reaction (PCR) using intron-spanning probes. Results: Eighty-five samples (83%) were successfully amplified. Median overall survival (OS) was 9.9 months; 45 patients had limited disease (LD) (OS = 13.1) and 40 had extensive disease (ED) (OS = 7.1). Fifty-six (65%) patients had an objective response to treatment. A gene expression was detectable in all samples and a correlation between ERCC1 and RRM1 (Rs = 0.34, p = 0.0011) was found. According to response to treatment, it was found that lower TopoII&agr; expression was associated to a better response in LD patients (p = 0.025) and, more interestingly, those who had a complete response had lower TopoII&agr; than both partial and nonresponsive patients (p = 0.015). At univariate analysis LD patients with low ERCC1 had significantly longer survival (median survival 14.9 versus 9.9, p = 0.012), whereas RRM1 and TopoII&agr; levels showed no influence on outcome. At the multivariate analysis, ERCC1 was confirmed to be an independent prognostic factor for survival in LD patients. No significant role was found for ERCC1, RRM1 and TopoII&agr; in ED patients. Conclusions: ERCC1 and TopoII&agr; are candidate markers in predicting clinical outcome and response to treatment in LD SCLC patients and are worth of further investigation in a prospective study.

Co-expression of EGF receptor, TGFα and S6 kinase is significantly associated with colorectal carcinomas with distant metastases at diagnosis

Autocrine tumour growth factor alpha (TGFα)/epidermal growth factor receptor (EGFR) stimulation in colorectal carcinoma (CRC) cells regulates cell adhesion and invasiveness via ribosomal protein S6 kinase (S6K) phosphorylation in pre-clinical studies. The aim of this study was to evaluate whether TGFα and EGFR expression might be correlated with a higher metastatic behaviour in human tumours. Paraffin-embedded material was retrospectively collected from 101 primitive CRCs including all stage IV patients at diagnosis treated at our Institution from 1999 to 2004 (50 cases, Group B) and 51 stage II–III control cases (Group A). EGFR and TGFα expression, together with signalling molecules (including signal transducer and activator of transcription [STAT3], serine–treonine kinase [Akt], mitogen-activated protein kinase [MAPK], mammalian target of rapamycin [mTOR] and S6K) in selected samples, was evaluated by immunohistochemistry using the EGFR Dako antibody. A total of 68/101 (67.3%) cases were EGFR positive and 79/101 (78.2%) cases were TGFα positive. EGFR/TGFα co-expression differed significantly (p = 0.02) between Group A and Group B tumours (23/51, 45.1% vs 34/50, 68.0%, respectively), whereas no differences in STAT, Akt, mTOR expression was evident between the two groups. Conversely, there was a significantly higher expression of phosphorylated S6K in stage IV cases (Group B) than in the controls (Group A; 70.4% vs 38.7%; p = 0.02). In agreement with in vitro data, EGFR, TGFα and S6K co-expression in human CRC was significantly higher in patients with advanced stage at diagnosis.

Role of Hormone Receptor Expression in Patients With Advanced-Stage Lung Cancer Treated With Chemotherapy.

BACKGROUND Evidence that supports a role for hormonal status in lung cancer has been inconsistently reported and is still unclear. We retrospectively assessed the potential correlation between sex-linked hormone receptor expression and the clinical outcome of patients with advanced-stage lung cancer treated with chemotherapy. PATIENTS AND METHODS Based on tissue availability, 130 consecutive patients diagnosed at San Luigi Hospital from January 2008 to June 2010 were collected, including 24 small-cell lung cancer, 57 adenocarcinomas, 34 squamous cell carcinomas, 5 large-cell carcinomas, and 10 non-small-cell lung cancer-not otherwise specified. The immunohistochemical expression of estrogen receptors (ER-α and ER-β) and progesterone receptor, aromatase, epidermal growth factor receptor (EGFR), and excision repair cross-complementing 1 (ERCC1) was assessed. RESULTS ER-β nuclear expression was higher than ER-α and progesterone receptor, whose expression was null or weak (mainly in women). ER-β expression was significantly higher in patients with metastatic disease compared with all other disease stages (P = .02). EGFR expression was strongly correlated with non-small-cell lung cancer histology, being higher in squamous types and stage related. In men, aromatase positive cases had a worse outcome (P = .03) as well as in men with non-small-cell lung cancer and high ER-β expression. In the latter group, the combined aromatase negative and/or low ER-β expression and low ERCC1 and/or low ER-β expression showed a better outcome (P = .026; P = .03, respectively). CONCLUSION In patients with advanced-stage lung cancer treated with chemotherapy, the prognostic and predictive role of sex-linked hormone receptor expression, if any, is of borderline significance and is restricted to selected subgroups of patients.

Toward therapies tailored to patient characteristics.

Although considerable progress has been made in the diagnosis and treatment of non-small cell lung cancer (NSCLC) in recent years, this disease is still associated with a dismal prognosis. Some improvements have been reported recently after the implementation of third-generation drugs into the clinic. Realistically, we have probably reached a plateau in terms of clinical outcomes with the ways in which we are currently administering cytotoxic chemotherapy. Further steps could be the implementation of molecularly targeted therapies and pharmacogenomics into the therapeutic armamentarium. Pharmacogenomics is the branch of pharmaceutics that deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug’s efficacy or toxicity. In this way, pharmacogenomics aims to develop rational means of optimizing drug therapy with respect to the patient’s genotype, to ensure maximal efficacy with minimal adverse effects. Such approaches suggest the advent of “personalized medicine,” in which drugs and drug combinations are optimized for each individual’s unique genetic makeup. Pharmacogenomics, the whole genome application of pharmacogenetics that examines the single gene interactions with drugs, holds the promise that drugs might one day be tailored to the individual and adapted to each person’s genetic makeup. Environment, diet, age, lifestyle, and state of health can all influence a person’s response to medicines, but understanding an individual’s genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety. What Are the Anticipated Benefits of Pharmacogenomics? Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. This will facilitate drug discovery and allow drug makers to produce a therapy more targeted to specific diseases. This accuracy will not only maximize therapeutic effects, but also decrease damage to nearby healthy cells. Instead of the standard trial-and-error method of matching patients with the right drugs, physicians will be able to analyze a patient’s genetic profile and prescribe the best available drug therapy from the very beginning. This will not only take the guesswork out of finding the right drug, but also speed up recovery time and increase safety as the likelihood of adverse reactions is eliminated. Pharmacogenomics has the potential to dramatically reduce the estimated 100,000 deaths and 2 million hospitalizations that occur each year in the United States as the result of adverse drug response. Current methods of dosing based on weight and age will be replaced with dosages based on a person’s genetics, which will maximize the value of the therapy and decrease the chance of overdose. The decrease in the number of adverse drug reactions, the number of failed drug trials, the time it takes to get a drug approved, the length of time patients receive medication, the number of medications patients must take to find an effective therapy, the effects of a disease on the body (through early detection), and an increase in the range of possible drug targets will promote a net decrease in the cost of health care.

Fetal Adenocarcinoma of the Lung in a 25-Year-Old Woman

We report the case of a 25-year-old woman with a chance detection at x-ray of a well-defined mass in the right upper lobe during a medical examination. The patient suffered from a modest flu syndrome, with cough and fever. She was a current smoker. CT scan showed a homogeneous well-defined perihilar mass without calcifications, located in the right upper lobe and fully surrounded by aerated parenchyma. A right upper lobectomy with mediastinal lymph node sampling was performed. A pathologic diagnosis of well-differentiated fetal adenocarcinoma of the lung was made and staged as T2N0. Few cases of this type of malignancy have been reported in literature.

C2-02: Factors effecting risk of pneumothorax (PNX) in CT-guided transthoracic needle biopsy of lung lesions: results of 708 consecutive procedures

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Differential expression of DNA repair machinery genes in normal bronchial tissue and non-small cell lung cancer (NSCLC)

22017 Background: Genes involved in DNA repair and/or replication have been recently investigated as predictive markers of response to chemotherapy in NSCLC. However, few data on the expression of these genes in NSCLC tumor samples versus corresponding normal lung are currently available. Aim of this study was to evaluate differential mRNA levels of 22 DNA repair genes belonging to 5 different DNA repair pathways: direct (DR), base excision (BER), nucleotide excision (NER), double strand break (DSBR) and post-replicative (PRR) repair. In addition, 6 genes involved in DNA replication (REP) and 2 telomere maintenance (TM) genes were also investigated. Methods: Total RNA was extracted from fresh snap-frozen tumors and corresponding normal tissues from 50 consecutive chemo-naive resected NSCLC patients. Transcript levels were quantified by Real-Time PCR (TaqMan), fold changes were calculated with the 2-ΔΔCt method and statistical significance assessed by Wilcoxons test. POLR2A and 18SrRNA were used as refere...