Analysis of CT features and quantitative texture analysis in patients with thymic tumors: correlation with grading and staging.

OBJECTIVES: To evaluate potential relationship between qualitative CT features, quantitative texture analysis (QTA), histology, WHO staging, Masaoka classification and myasthenic syndrome in patients with thymic tumors. MATERIALS AND METHODS: Sixteen patients affected by histologically proven thymic tumors were retrospectively included in the study population. Clinical information, with special regard to myasthenic syndrome and serological positivity of anti-AchR antibodies, were recorded. Qualitative CT evaluation included the following parameters: (a) location; (b) tumor edges; (c) necrosis; (d) pleural effusion; (e) metastases; (f) chest wall infiltration; (g) tumor margins. QTA included evaluation of "Mean" (M), "Standard Deviation" (SD), "Kurtosis" (K), "Skewness" (S), "Entropy" (E), "Shape from Texture" (TX_sigma) and "average of positive pixels" (MPP). Pearson-Rho test was used to evaluate the relationship of continuous non-dichotomic parameters, whereas Mann-Whitney test was used for dichotomic parameters. RESULTS: Histological evaluation demonstrated thymoma in 12 cases and thymic carcinoma in 4 cases. Tumor necrosis was significantly correlated with QTA Mean (p = 0.0253), MPP (p = 0.0417), S (p = 0.0488) and K (p = 0.0178). WHO staging was correlated with Mean (p = 0.0193), SD (p = 0.0191) and MPP (p = 0.0195). Masaoka classification was correlated with Mean (p = 0.0322), MPP (p = 0.0315), skewness (p = 0.0433) and Kurtosis (p = 0.0083). Myasthenic syndrome was significantly associated with Mean (p = 0.0211) and MPP (p = 0.0261), whereas tumor size was correlated with Mean (p = 0.0241), entropy (p = 0.0177), MPP (p = 0.0468), skewness (p = 0.009) and Kurtosis (p = 0.006). CONCLUSION: Our study demonstrates significant relationship between radiomics parameters, histology, grading and clinical manifestations of thymic tumors.

Preliminary clinical experience with a dedicated interventional robotic system for CT-guided biopsies of lung lesions: a comparison with the conventional manual technique.

OBJECTIVE: Evaluate the performance of a robotic system for CT-guided lung biopsy in comparison to the conventional manual technique. MATERIALS AND METHODS: One hundred patients referred for CT-guided lung biopsy were randomly assigned to group A (robot-assisted procedure) or group B (conventional procedure). Size, distance from entry point and position in lung of target lesions were evaluated to assess homogeneity differences between the two groups. Procedure duration, dose length product (DLP), precision of needle positioning, diagnostic performance of the biopsy and rate of complications were evaluated to assess the clinical performance of the robotic system as compared to the conventional technique. RESULTS: All biopsies were successfully performed. The size (p = 0.41), distance from entry point (p = 0.86) and position in lung (p = 0.32) of target lesions were similar in both groups (p = 0.05). Procedure duration and radiation dose were significantly reduced in group A as compared to group B (p = 0.001). Precision of needle positioning, diagnostic performance of the biopsy and rate of complications were similar in both groups (p = 0.05). CONCLUSION: Robot-assisted CT-guided lung biopsy can be performed safely and with high diagnostic accuracy, reducing procedure duration and radiation dose in comparison to the conventional manual technique. KEY POINTS: • CT-guided biopsy is the main procedure to obtain diagnosis in lung tumours. • The robotic device facilitates percutaneous needle placement under CT guidance. • Robot-assisted CT-guided lung biopsy reduces procedure duration and radiation dose.

Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.

BACKGROUND: Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR wild-type-which includes most patients-is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. METHODS: We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m(2) every 21 days or 35 mg/m(2) on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT00637910. FINDINGS: We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8-10·9) with docetaxel versus 5·4 months (4·5-6·8) with erlotinib (adjusted hazard ratio [HR] 0·73, 95% CI 0·53-1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4-3·8) with docetaxel versus 2·4 months (2·1-2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53-0·95; p=0·02). The most common grade 3-4 toxic effects were: low absolute neutrophil count (21 [20%] of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 [14%]), and asthenia (ten [10%] vs six [6%]). INTERPRETATION: Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours.

Evaluation of a CLEIA automated assay system for the detection of a panel of tumor markers.

Tumor markers are commonly used to detect a relapse of disease in oncologic patients during follow-up. It is important to evaluate new assay systems for a better and more precise assessment, as a standardized method is currently lacking. The aim of this study was to assess the concordance between an automated chemiluminescent enzyme immunoassay system (LUMIPULSE® G1200) and our reference methods using seven tumor markers. Serum samples from 787 subjects representing a variety of diagnoses, including oncologic, were analyzed using LUMIPULSE® G1200 and our reference methods. Serum values were measured for the following analytes: prostate-specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), carbohydrate antigen 15-3 (CA15-3), carbohydrate antigen 19-9 (CA19-9), and cytokeratin 19 fragment (CYFRA 21-1). For the determination of CEA, AFP, and PSA, an automatic analyzer based on chemiluminescence was applied as reference method. To assess CYFRA 21-1, CA125, CA19-9, and CA15-3, an immunoradiometric manual system was employed. Method comparison by Passing-Bablok analysis resulted in slopes ranging from 0.9728 to 1.9089 and correlation coefficients from 0.9977 to 0.9335. The precision of each assay was assessed by testing six serum samples. Each sample was analyzed for all tumor biomarkers in duplicate and in three different runs. The coefficients of variation were less than 6.3 and 6.2 % for within-run and between-run variation, respectively. Our data suggest an overall good interassay agreement for all markers. The comparison with our reference methods showed good precision and reliability, highlighting its usefulness in clinical laboratory's routine.

Circulating tumor cells in high-risk nonmetastatic colorectal cancer.

The identification of patients at higher risk of recurrence after primary colorectal cancer resection is currently one of the challenges facing medical oncologists. Circulating tumor cell (CTC) may represent a surrogate marker of an early spread of disease in patients without overt metastases. Thirty-seven high-risk stages II-III colorectal cancer patients were evaluated for the presence of CTC. Enumeration of CTCs in 7.5 ml of blood was carried out with the FDA-cleared CellSearch system. CTC count was performed after primary tumor resection and before the start of adjuvant therapy. CTC was detected in 22 % of patients with a significant correlation with regional lymph nodes involvement and stage of disease. No significant correlation was found among the presence of CTC and other clinicopathological parameters. These data suggest that CTCs detection might help in the selection of high-risk stage II colorectal cancer patient candidates for adjuvant chemotherapy.

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma.

The purpose of the study was to evaluate the expression of the biomarkers CA125 and HE4 combined with imaging, in patients with advanced epithelial ovarian cancer (EOC). Forty-six women with EOC were included in the study all affected with peritoneal carcinomatosis. Twenty-two of 46 patients (group I) had peritoneal carcinomatosis with small implants in single or in multiple sites (score 1); 24/46 patients (group II) had macro-nodular implants and omental thickening (score 2). High levels of CA125 (350 ± 11, mean ± SEM) have been observed in 21/22 patients of group I, and a similar value (370 ± 13) has been observed in all patients belonging to group II. HE4 positivity values (350 ± 9) have been observed in all group I patients, whereas all patients belonging to group II showed a higher value of HE4 (600 ± 12). Statistically significant differences were observed between the HE4 levels observed in group I patients in comparison with group II patients (p < 0.0001). In addition, we expressed the extension of lymph nodal disease in three scores: L1-L2-L3, and a statistically significant correlation was observed between high HE4 levels and severity of lymph nodal disease L3 (p < 0.0001). The availability of biomarkers, particularly HE4, together with sophisticated imaging techniques, strengthens the clinical relevance of this study, for the follow-up of patients with peritoneal carcinomatosis.

Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer.

The aim of this study was to investigate the role of biomarkers CA125, HE4, and CA72.4 at diagnosis and throughout the follow-up in patients with epithelial ovarian cancer (EOC). Thirty-nine patients with EOC were deemed eligible, and 20 were followed up. CA125, HE4, and CA72.4 serum levels were determined for all patients at initial diagnosis of EOC. Among these patients, the number of cases with an elevated level of each individual marker was CA125 77 %, HE4 85 %, and CA72.4 72 %. A statistically significant difference was observed between the level of HE4 when compared to CA72.4 (p < 0.02). In the follow-up phase, we observed tumor marker levels fluctuating according to response to chemotherapy. When combining two out of the three biomarkers together, we observed increased values of CA125 and CA72.4 in 55 % of the patients, increased values of CA125 and HE4 in 65 % of the patients, and finally increased HE4 and CA72.4 in 75 % of the patients. A statistically significant difference was observed when combining HE4 and CA72.4, but not CA125 and CA 72.4 (p < 0.002). In conclusion, our study demonstrates that the association of three biomarkers CA125, HE4, and CA72.4 provides a valuable contribution in the follow-up of EOC patients.

Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice.

AIM: The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. PATIENTS & METHODS: This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. RESULTS: Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. CONCLUSION: Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.

Whole-tumor perfusion CT in patients with advanced lung adenocarcinoma treated with conventional and antiangiogenetic chemotherapy: initial experience.

PURPOSE: To determine whether wide-volume perfusion computed tomography (CT) performed with a new generation scanner can allow evaluation of the effects of chemotherapy combined with antiangiogenetic treatment on the whole tumor mass in patients with locally advanced lung adenocarcinoma and to determine if changes in CT numbers correlate with the response to therapy as assessed by conventional response evaluation criteria in solid tumors (RECIST). MATERIALS AND METHODS: Forty-five patients with unresectable lung adenocarcinoma underwent perfusion CT before and 40 and 90 days after chemotherapy and antiangiogenetic treatment. RECIST measurements and calculations of blood flow, blood volume, time to peak, and permeability were performed by two independent blinded radiologists. Pearson correlation coefficient was used to assess the correlation between baseline CT numbers. Baseline and follow-up perfusion parameters of the neoplastic lesions were tested overall for statistically significant differences by using the repeated-measures analysis of variance and then were also compared on the basis of the therapy response assessed according to the RECIST criteria. RESULTS: Pearson correlation coefficient showed a significant correlation between baseline values of blood flow and blood volume (ρ = 0.48; P = .001), time to peak and permeability (ρ = 0.31; P = .04), time to peak and blood flow (ρ = -0.66; P < .001), and time to peak and blood volume (ρ = -0.39; P = .007). Blood flow, blood volume, and permeability values were higher in responding patients than in the other patients, with a significant difference at second follow-up for blood flow (P = .0001), blood volume (P = .02), and permeability (P = .0001); time to peak was higher in nonresponding patients (P = .012). CONCLUSION: Perfusion CT imaging may allow evaluation of lung cancer angiogenesis demonstrating alterations in vascularity following treatment.

Palonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapy.

BACKGROUND: The combination of a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT(3) receptor antagonist is currently the standard antiemetic treatment in patients receiving cisplatin-based high emetogenic chemotherapy (HEC). The aim of this study was to evaluate the efficacy of a combination of palonosetron, a unique second-generation 5-HT(3) receptor antagonist, aprepitant, the only approved neurokinin-1 receptor antagonist, and dexamethasone as antiemetic prophylaxis in patients receiving HEC (cisplatin ≥50 mg/mq). METHODS: Chemotherapy-naïve adult patients, receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v., and aprepitant 125 mg/p.o., 1-h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg p.o. were administered on days 2-3. Primary end point was complete response (CR; no vomiting and no use of rescue medication), during the overall study period (0-120 h). Secondary end points were complete control (CR and no more than mild nausea), emesis-free rate, and nausea-free rate during the acute (0-24 h), delayed (24-120 h), and overall (0-120 h) periods. Safety was also evaluated. RESULTS: A total of 222 patients were included in the study. Median age was 62 years, 76.6% were male and 23.4% female, and most common tumors were lung (66.7%) and head and neck (15.8%); 70.3% of patients achieved CR during the overall study period. Complete control, emesis-free rate, and nausea-free rate were 70.3%, 92.8%, and 59.9%, respectively, during the overall phase. The most commonly reported side effects were constipation (39% of patients) and headache (5%). CONCLUSIONS: This study shows that palonosetron in combination with aprepitant and dexamethasone is effective to prevent chemotherapy-induced nausea and vomiting in patients treated with cisplatin-based HEC.

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens.

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4+ and CD8+ T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients' survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients.

A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer.

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy.

Capecitabine versus bolus fluorouracil plus leucovorin (folinic acid) as adjuvant chemotherapy for patients with Dukes' C colon cancer : economic evaluation in an Italian NHS setting.

BACKGROUND AND OBJECTIVE: In the recent X-ACT (Xeloda in Adjuvant Colon cancer Therapy) trial, oral capecitabine (Xeloda) demonstrated superior efficacy and an improved safety profile compared with infused fluorouracil + leucovorin (folinic acid) [FU+LV] in patients with Dukes' C colorectal cancer. We used the X-ACT results to determine the cost effectiveness of capecitabine compared with FU+LV from the perspective of the Italian National Health Service (NHS). METHODS: Medical resource use data were collected throughout the treatment period. Unit costs for drug administration, hospitalization, emergency room visits and concomitant medications were obtained using Italian published sources. A health-state transition model was used to estimate the incremental cost-effectiveness ratio per quality-adjusted life-month (QALM) gains in the intent-to-treat population (1004 and 983 patients in the capecitabine and FU+LV arms, respectively). Costs and effectiveness were discounted at 3.5%. Costs were calculated in euros (2005 values). RESULTS: Administration of capecitabine required fewer clinic visits per patient than FU+LV (7.35 vs 28.0, respectively). Mean acquisition costs per patient for capecitabine were higher than for FU+LV (euro 2533 vs euro 231, respectively), but this difference was offset by the difference in mean chemotherapy administration costs per patient for FU+LV (euro 4338, compared with euro 152 for capecitabine). Mean total hospital days and medication costs for treatment-related adverse events were higher for FU+LV than for capecitabine (euro 352 vs euro 78, respectively). The cost of emergency room visits for the treatment of adverse events did not differ between the treatment groups. With respect to the lifetime horizon, compared with FU+LV, capecitabine is projected to increase QALMs by a mean 6.5 months, with overall cost savings of euro 2234 over the treatment period. These findings show that capecitabine is an economically dominant treatment in this setting. CONCLUSIONS: Adjuvant capecitabine for patients with Dukes' C colon cancer has the same activity in terms of outcome when compared with FU+LV but is a lower cost option from the economic perspective of the Italian NHS.

Vascular Endothelial Growth Factor Inhibitor Therapy and Cardiovascular and Renal Damage in Renal Cell Carcinoma.

BACKGROUND: Sunitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF), is approved for first and second line treatment of advanced renal cell carcinoma (RCC). Knowledge on the effects of sunitinib on cardiovascular (CV) risk and renal damage is limited. AIM: To evaluate possible renal and CV damage in patients with RCC treated with sunitinib. MATERIALS AND METHODS: Patients with metastatic RCC treated with sunitinib were enrolled. This population was evaluated before starting treatment (T0) and after 3 months (T1). Laboratory and instrumental parameters, including interventricular septum (IVS) and left ventricular mass index (LVMI) were recorded before and after treatment. RESULTS: Thirty-two patients (13 female, 19 male, mean age 62.7±9.9 years) were enrolled. We observed overtime, a significant reduction in estimated glomerular filtration rate (eGFR) (p=0.01), hemoglobin (Hb) (p=0.04) and 25-hydroxyvitamin D (25-OH-VitD) (p=0.002), in association with a significant increase in serum phosphorus (p<0.001), systolic blood pressure (SBP) (p<0.001), diastolic blood pressure (DBP) (p<0.001), IVS (p=0.03) and proteinuria (p<0.001), while we showed no significant differences in glycosuria, phosphaturia, serum uric acid, intact parathormone, and LVMI. CONCLUSION: We observed the development of renal damage and worsening of CV indices in patients treated with sunitinib. We suggest to consider a careful assessment of renal function and CV risk factors, before initiation and during administration of this drug.

Mineral metabolism abnormalities in patients with prostate cancer: a systematic case controlled study.

PURPOSE: Prostate cancer is the most common tumor in men. To the best of our knowledge a systematic assessment of bone and mineral abnormalities has not been performed in prostatic cancer patients consecutively enrolled. METHODS: This study was therefore carried out to investigate changes of skeletal and mineral metabolism in patients with prostate cancer (n = 69). A population of patients with cancer of various origin was also investigated as a control group (n = 53), since a comparison with non-prostate cancer patients has not been previously reported. RESULTS: In the prostatic cancer group, one patient had extremely high values of C-terminal Fibroblast Growth Factor 23, low values of tubular reabsorption of phosphate and very high values of bone alkaline phosphatase, suggesting the diagnosis of oncogenic osteomalacia. We found nine patients with primary hyperparathyroidism in the group of prostate cancer vs. only one in cancer patients group (p < 0.026). We stratified the population on the basis of Gleason score, prostate specific antigen and hormonal therapy. Using a generalized linear model with a logit link to predict the probability of developing primary hyperparathyroidism, only Gleason score, C-terminal fibroblast growth factor 23 and hormonal therapy had a significant effect (p < 0.05). Controlling for other covariates, a rise in fibroblast growth factor 23 increases the odds of developing primary hyperparathyroidism by 2% (p = 0.017), while patients with higher values of Gleason score have a much greater probability of developing primary hyperparathyroidism (log-odds = 3.6, p < 0.01). The probability decreases with higher values of Gleason score while on hormonal therapy; a further decrease was observed in patients on hormonal treatment and lower values of GS. Finally, lower grade of Gleason score without hormonal therapy have a significant protective factor (p < 0.01) decreasing the odds of developing primary hyperparathyroidism by 8%. CONCLUSION: We showed a remarkable prevalence of primary hyperparathyroidism in men with prostate cancer; the multivariate analysis demonstrates that higher aggressiveness of prostate cancer, as determined by Gleason score, is a significant predictor of increased risk of developing primary hyperparathyroidism.

IL-18 receptor marks functional CD8+ T cells in non-small cell lung cancer.

IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8+ T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet+Eomes+), than by the majority of those with the dysfunctional phenotype T-bet-Eomes+ generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFNγ production ex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8+ T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches.

Multimodality treatment of stage II thymic tumours.

BACKGROUND: Complete resection for stage II thymic tumors can be easily accomplished even if the capsula and adjacent mediastinal tissue are macroscopically involved; however, also at this stage, recurrence may occur, particularly for B2, B3 and thymic carcinoma. The criteria for the administration of adjuvant therapy remain controversial and it is unclear whether patients at this stage may benefit from it. We reviewed a series of patients at this stage receiving adjuvant chemo-radiotherapy (chemo-RT) based on histology. METHODS: Eighty-eight consecutive patients with stage II thymic tumors were reviewed; 59 patients (67%) with B thymoma or thymic carcinoma received adjuvant treatment with mediastinal irradiation (40-55 Gy), chemotherapy (CH) (PAC regimen) or a combination of both. RESULTS: Complete resection was achieved in all patients. Fifty-four patients (61%) received post-operative chemo-RT, 2 (2%) patients received adjuvant CH only and 3 (3%) post-operative RT only; they all had B2, B3 histology or thymic carcinoma. The median follow up was 107±83 months. 5-year and 10-year survival were 96%±2% and 83.4%±5%. Recurrence was observed in 5 patients (5.7%). Disease-free 5 and 10-year survival was 94%±2% and 92%±3% respectively. Five patients (5.7%) had recurrence. CONCLUSIONS: The administration of adjuvant chemo-RT to patients with stage II type B thymoma and thymic carcinoma contributes to reduce the recurrence rate and to increase long-term survival.

Anaplastic thyroid carcinoma and foscarnet use in a multitarget treatment documented by 18F-FDG PET/CT: A case report.

RATIONALE: The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low molecular weight heparin and sunitinib for the first time in a patient with an anaplastic thyroid cancer (ATC). PATIENT CONCERNS: A 65-year-old woman with a multinodular goiter referred for a rapid enlargement of a nodule. Histological examination revealed an ATC with a little area of papillary thyroid cancer (PTC). The patient was resistant to selective single-target treatment. DIAGNOSES: Immunophenotyping and gene analyses found a significant increase in FGF2 and FGFR1 expression in the primary ATC area (FGF2 = 38.2 ±â€Š6.2% in ATC vs 34.6 ±â€Š6.0% in the differentiated area of PTC, P < 0.05; FGFR1: 41.7 ±â€Š6.0% in ATC vs 34.4 ±â€Š4.2% in PTC, P < 0.001) and in metastatic neck lymph nodes (P < 0.001 vs normal control tissues). Unlike conventional imaging, F-FDG PET/CT with PERCIST 1.0 criteria promptly and quantitatively detected disease recurrence and remission before and after multitarget therapy, combining anatomic, metabolic, and functional data. INTERVENTIONS: Foscarnet was administered given the positivity for FGF2, FGFR1 and FGFR4 in ATC. Low molecular wight heparin and Sunitinib were coadministere to limiti metastatic progression and on neck tumor masse, respectively. OUTCOMES: The rationale for the clinical response to this innovative multitarget association with foscarnet is based on the histological and genetic finding that fibroblast growth factors and their receptor super-family are up-regulated in the primary anaplastic thyroid tumor and in the metastatic lymph node of our patient. LESSONS: We propose that fibroblast growth factors and their receptor super-family play a key role as potential therapeutic targets in anaplastic thyroid cancer and the positive relevance of this suggestion for patient care, especially for an individualized management.

Evaluation of the efficacy of cisplatin-etoposide and the role of thoracic radiotherapy and prophylactic cranial irradiation in LCNEC.

In small-cell lung cancer (SCLC), the role of chemotherapy and radiotherapy is well established. Large-cell neuroendocrine carcinoma (LCNEC) shares several clinicopathological features with SCLC, but its optimal therapy is not defined. We evaluated clinical response and survival outcomes of advanced LCNEC treated in first-line therapy compared with SCLC. 72 patients with stage III-IV LCNEC (n=28) and extensive-stage SCLC (ES-SCLC) (n=44) received cisplatin-etoposide with/without thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). Comparing LCNEC with SCLC, we observed similar response rates (64.2% versus 59.1%), disease control rates (82.1% versus 88.6%), progression-free survival (mPFS) (7.4 versus 6.1 months) and overall survival (mOS) (10.4 versus 10.9 months). TRT and PCI in both histologies showed a benefit in mOS (34 versus 7.8 months and 34 versus 8.6 months, both p=0.0001). LCNEC patients receiving TRT showed an improvement in mPFS and mOS (12.5 versus 5 months, p=0.02 and 28.3 versus 5 months, p=0.004), similarly to ES-SCLC. PCI in LCNEC showed an increase in mPFS (20.5 versus 6.4 months, p=0.09) and mOS (33.4 versus 8.6 months, p=0.05), as in ES-SCLC. Advanced LCNEC treated with SCLC first-line therapy has a similar clinical response and survival outcomes to ES-SCLC.