The IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases donated from 35 sources in 16 countries around the globe. This has now been analysed by our statistical partners at Cancer Research And Biostatistics and, in close collaboration with the members of the committee proposals have been developed for the T, N, and M categories of the 8th edition of the TNM Classification for lung cancer due to be published late 2016. In this publication we describe the methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition.

In this work, we have investigated a new and general method for the reconstitution of membrane proteins into giant unilamellar vesicles (GUVs). We have analyzed systematically the reconstitution of two radically different membrane proteins, the sarcoplasmic reticulum Ca(2+)-ATPase and the H(+) pump bacteriorhodopsin. In a first step, our method involved a detergent-mediated reconstitution of solubilized membrane proteins into proteoliposomes of 0.1-0.2 microm in size. In a second step, these preformed proteoliposomes were partially dried under controlled humidity followed, in a third step, by electroswelling of the partially dried film to give GUVs. The physical characteristics of GUVs were analyzed in terms of morphology, size, and lamellarity using phase-contrast and differential interference contrast microscopy. The reconstitution process was further characterized by analyzing protein incorporation and biological activity. Both membrane proteins could be homogeneously incorporated into GUVs at lipid/protein ratios ranging from 5 to 40 (w/w). After reconstitution, both proteins retained their biological activity as demonstrated by H(+) or Ca(2+) pumping driven by bacteriorhodopsin or Ca(2+)-ATPase, respectively. This constitutes an efficient new method of reconstitution, leading to the production of large unilamellar membrane protein-containing vesicles of more than 20 microm in diameter, which should prove useful for functional and structural studies through the use of optical microscopy, optical tweezers, microelectrodes, or atomic force microscopy.

An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.

We have experimentally investigated the effect of a transmembrane protein, the Ca2+-ATPase, on shape fluctuations of giant vesicles. By using the micropipette method, we have measured a substantial renormalization of the bending modulus due to the presence of proteins in the membrane. Moreover, we have produced the first quantitative measurement of the active force dipole associated with the amplification of the fluctuations when the proteins are activated by adenosine 5'-triphosphate (ATP).

Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR high ) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7);

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.

BACKGROUND Isolated lung metastases have been reported to occur in 10–20% of all women with breast carcinoma. The authors described a series of patients who underwent surgery for lung metastases from breast carcinoma. METHODS They reviewed the files of 125 consecutive patients who underwent surgery with a curative intent for lung metastases from breast carcinoma between 1972 an 1998 at a single institution. Survival curves were plotted by the Kaplan–Meier method. Prognostic factors were identified using the log‐rank test and a Cox proportional hazards model for univariate and multivariate analyses, respectively. RESULTS The median age at surgery was 53 years. There was a median of 1 resected metastasis (range, 1–16 resected metastases). The median size of the largest metastasis was 19 mm (range, 5–70 mm). The median disease‐free interval (DFI) was 3 years. The median follow‐up time after surgery was 8.5 years (range, 25 days to 22 years). The 3‐year, 5‐year, and 10‐year probabilities of survival were 58% (95% confidence interval [95% CI], 49–67%), 45% (95% CI, 36–55%), and 30% (95% CI, 21–41%), respectively. The median survival time after surgery was 4.2 years. Complete resection was achieved in 96 patients. The quality of the resection (complete vs. incomplete) was not a statistically significant prognostic factor by univariate analysis and there was no significant difference between these two groups in terms of adjuvant postoperative therapy. The characteristics of the primary tumor and the number of metastases (one vs. two or more) had no detectable influence on survival. The size of the largest metastasis (> 20 mm or ≤ 20 mm) and the DFI (≤ 3 years vs. > 3 years) were highly significant prognostic factors (P = 0.006 and P = 0.003, respectively). This was confirmed by multivariate analysis. Patients with a DFI ≤ 3 years and/or the largest metastasis > 20 mm reportedly had a poor outcome (median survival, 2.6 years vs. 8.5 years for patients with none of these poor prognostic factors). CONCLUSIONS Resection of lung metastases from breast carcinoma was associated with a significant 5‐year survival rate of 45%. Whether these encouraging findings resulted from the surgical procedure itself or the preoperative selection of patients remained uncertain. When surgery is considered in this setting, the size of the largest metastasis and the DFI should be taken into account. Cancer 2004;100:28–35.© 2003 American Cancer Society.

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