Università degli studi di Modena e Reggio Emilia

OBJECTIVES: Optimal procedures for adjuvant treatment and post-surgical surveillance of resected non-small-cell lung cancer remain under discussion. Pathological features are the main determinant of follow-up therapy but have limited ability to identify patients at risk of recurrence. Increasingly, molecular markers are incorporated into clinical decision-making, including measures of tumor growth. The CCP score is a quantitative, molecular measure of proliferation derived from the RNA expression of 31 cell cycle genes and a component of the molecular prognostic score (mPS). The mPS score is a linear combination of CCP score and pathological stage. CCP score and mPS are independent predictors of survival in resected lung adenocarcinoma. MATERIALS AND METHODS: CCP scores were determined by RT-qPCR for 318 patients diagnosed with stage I-II lung adenocarcinoma. Association of mPS and CCP score with distant recurrence and lung-cancer specific survival was assessed in Cox proportional hazards regression models adjusted for age, gender, tumor size, pathological stage and pleural invasion. Distant recurrence-free survival and lung-cancer specific survival by mPS risk group were calculated by Kaplan-Meier survival analysis. RESULTS: CCP scores were obtained for 205 stage I and 84 stage II patients. CCP score and mPS were independent markers of distant recurrence (CCP: HR 1.62, 95%CI 1.15-2.29, p=0.0055; mPS: HR 2.22, 95%CI 1.11-4.44, p=0.023). Patients with low mPS tumors were at significantly reduced risk of distant recurrence (log-rank p=4.2×10-5). Among stage I patients, stratification by mPS identified a patient group with increased risk of distant recurrence (36%, 95%CI 28-46%, log-rank p=0.0011) CONCLUSIONS: The molecular prognostic score stratifies early-stage, resected lung cancer patients for risk of distant recurrence and could be useful to inform treatment and surveillance decisions.

Objectives Optimal procedures for adjuvant treatment and post-surgical surveillance of resected non-small-cell lung cancer remain under discussion. Pathological features are the main determinant of follow-up therapy but have limited ability to identify patients at risk of recurrence. Increasingly, molecular markers are incorporated into clinical decision-making, including measures of tumor growth. The CCP score is a quantitative, molecular measure of proliferation derived from the RNA expression of 31 cell cycle genes and a component of the molecular prognostic score (mPS). The mPS score is a linear combination of CCP score and pathological stage. CCP score and mPS are independent predictors of survival in resected lung adenocarcinoma. Materials and methods CCP scores were determined by RT-qPCR for 318 patients diagnosed with stage I–II lung adenocarcinoma. Association of mPS and CCP score with distant recurrence and lung-cancer specific survival was assessed in Cox proportional hazards regression models adjusted for age, gender, tumor size, pathological stage and pleural invasion. Distant recurrence-free survival and lung-cancer specific survival by mPS risk group were calculated by Kaplan-Meier survival analysis. Results CCP scores were obtained for 205 stage I and 84 stage II patients. CCP score and mPS were independent markers of distant recurrence (CCP: HR 1.62, 95%CI 1.15-2.29, p = 0.0055; mPS: HR 2.22, 95%CI 1.11-4.44, p = 0.023). Patients with low mPS tumors were at significantly reduced risk of distant recurrence (log-rank p = 4.2 × 10−5). Among stage I patients, stratification by mPS identified a patient group with increased risk of distant recurrence (36%, 95%CI 28–46%, log-rank p = 0.0011) Conclusions The molecular prognostic score stratifies early-stage, resected lung cancer patients for risk of distant recurrence and could be useful to inform treatment and surveillance decisions.

Scopo del lavoro I carcinoidi polmonari entrano nella diagnosi differenziale dei noduli polmonari solitari (NPS). I carcinoidi sono tradizionalmente considerati come tumori PET negativi, anche se studi più recenti hanno evidenziato una certa sensibilità della FDG-PET/TC per la diagnosi di queste neoplasie. Lo scopo di questo studio è di determinare l’utilità della PET/TC nella valutazione dei NPS sospetti per carcinoide. Materiali e metodi Si tratta di uno studio retrospettivo eseguito su tutti i pazienti sottoposti ad exeresi chirurgica di carcinoide e precedente FDG-PET/TC dal 2006 al 2012. L’esame PET/TC è stato eseguito con la stessa macchina e la stessa tecnica in tutti i casi. Sono state analizzate le seguenti variabili: età, sesso, aspetti TC (lato, sede, dimensioni, forma, margini), SUVmax, tipo di intervento, aspetti patologici (dimensioni, numero di mitosi). Riguardo alla valutazione PET, è stato considerato soltanto il SUVmax e non la valutazione qualitativa. I carcinoidi sono stati classificati come tipici o atipici e periferici o centrali. E’ stato registrato anche il follow-up a distanza. Il SUVmax è stato confrontato con tutte le altre variabili cliniche, radiologiche e patologiche, al fine di evidenziare eventuali associazioni o differenze. Risultati Sono stati recuperati 25 pazienti. Si è trattato di 24 forme tipiche e un carcinoide atipico, 21 periferici e 4 centrali. Il diametro medio alla TC è stato di 25.3mm e il dato correlava con le dimensioni patologiche. 60% dei tumori avevano forma ovalare e il 68% margini lisci. Il SUVmax medio è stato 3.6 (range 1.4-12.9). Tutte le lesioni sono state asportate in modo radicale. L’analisi di regressione lineare ha evidenziato una associazione diretta tra il SUVmax e le dimensioni (p=0.004), mentre nessun’altra correlazione è stata ritrovata tra il SUVmax e le altre variabili. Nessun paziente ha presentato recidiva o è morto durante il follow-up. Conclusioni Questo studio dimostra che la FDG-PET/TC è utile nella valutazione del NPS sospetto per carcinoide. E’ necessario utilizzare il SUVmax e non la valutazione qualitativa e il confronto deve essere eseguito con il resto del polmone e non con la captazione mediastinica, come usualmente nell’interpretazione della captazione FDG. Quando un NPS si presenta con forma ovoidale/rotonda e margini lisci alla TC e mostra una captazione alla FDG-PET superiore a quella del polmone circostante, con un SUVmax>1-1.5, in questo caso è elevato il sospetto di carcinoide. Pertanto, se si può ragionevolmente escludere una lesione benigna, si raccomanda la resezione chirurgica o almeno una biopsia della lesione.

BackgroundNon Small Cell Lung Cancer (NSCLC) is the major cause of cancer related-death. Many patients receive diagnosis at advanced stage leading to a poor prognosis. At present, no satisfactory screening tests are available in clinical practice and the discovery and validation of new biomarkers is mandatory. Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-ToF-MS) is a recent high-throughput technique used to detect new tumour markers. In this study we performed SELDI-ToF-MS analysis on serum samples treated with the ProteoMinerTM kit, a combinatorial library of hexapeptide ligands coupled to beads, to reduce the wide dynamic range of protein concentration in the sample. Serum from 44 NSCLC patients and 19 healthy controls were analyzed with IMAC30-Cu and H50 ProteinChip Arrays.ResultsComparing SELDI-ToF-MS protein profiles of NSCLC patients and healthy controls, 28 protein peaks were found significantly different (p<0.05), and were used as predictors to build decision classification trees. This statistical analysis selected 10 protein peaks in the low-mass range (2-24 kDa) and 6 in the high-mass range (40-80 kDa). The classification models for the low-mass range had a sensitivity and specificity of 70.45% (31/44) and 68.42% (13/19) for IMAC30-Cu, and 72.73% (32/44) and 73.68% (14/19) for H50 ProteinChip Arrays.ConclusionsThese preliminary results suggest that SELDI-ToF-MS protein profiling of serum samples pretreated with ProteoMinerTM can improve the discovery of protein peaks differentially expressed from NSCLC patients and healthy subjects, useful to build classification algorithms with high sensitivity and specificity. However, identification of the significantly different protein peaks needs further study in order to provide a better understanding of the biological nature of these potential biomarkers and their role in the underlying disease process.

Lung is one of the main sites of metastatic tumors, but collision neoplasms consisting of a primary lung cancer and metastatic breast carcinoma have never been so far reported. We describe here 2 cases of primary non-small cell lung cancers (squamous cell and adenocarcinoma, respectively) colliding with metastatic breast carcinomas (ductal and lobular carcinomas, respectively). Clinico-pathologic features characterizing this challenging diagnosis and the important therapeutic implications are discussed.

Adipose-derived mesenchymal stromal/stem cells (AD-MSC) may offer efficient tools for cell-based gene therapy approaches. In this study, we evaluated whether AD-MSC could deliver proapoptotic molecules for cancer treatment. Human AD-MSCs were isolated and transduced with a retroviral vector encoding full-length human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a proapoptotic ligand that induces apoptosis in a variety of human cancers but not normal tissues. Although several studies have documented the antitumor activity of recombinant human TRAIL, its use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney. We found that these limitations can be overcome using stably transduced AD-MSC, which could serve as a constant source of TRAIL production. AD-MSC armed with TRAIL targeted a variety of tumor cell lines in vitro, including human cervical carcinoma, pancreatic cancer, colon cancer, and, in combination with bortezomib, TRAIL-resistant breast cancer cells. Killing activity was associated with activation of caspase-8 as expected. When injected i.v. or s.c. into mice, AD-MSC armed with TRAIL localized into tumors and mediated apoptosis without significant apparent toxicities to normal tissues. Collectively, our results provide preclinical support for a model of TRAIL-based cancer therapy relying on the use of adipose-derived mesenchymal progenitors as cellular vectors.