Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus. METHODS: LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing. FINDINGS: Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related. INTERPRETATION: The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids. FUNDING: Novartis Pharma AG.

Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models.

INTRODUCTION: Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib. METHODS: To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration, and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses. RESULTS: Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration, and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinib-resistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration, and invasion of resistant cells, thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling. CONCLUSIONS: Complete pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.

Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial.

BACKGROUND: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). PATIENTS & METHODS: Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1-14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). RESULTS: Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48-61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3-4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5-16.5). CONCLUSION: Capecitabine and gemcitabine is highly active in TETs.

Clinical Characteristics of Malignant Phosphaturic Mesenchymal Tumor Causing Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). PMTs are usually benign neoplasms but some of them show malignant characteristics. OBJECTIVE: The aim of this study was to compare the clinical characteristics of benign and malignant PMTs inducing TIO. METHODS: On March 31, 2023, we performed a systematic review of individual patient data analysis in Medline, Google Scholar, Google book, and Cochrane Library using the terms "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia," with no language restrictions and according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. RESULTS: Overall, we collected data from 837 patients with TIO in which the diagnosis of benign and malignant PMT was specified. Of them, 89 were affected by malignant PMT and 748 by benign PMT. Patients with malignant PMTs were younger and presented bone pain, functional impairment, and bone deformities more frequently. Malignant PMTs showed higher values of intact FGF23 and a higher mortality rate. CONCLUSION: The study results identify the clinical characteristics of patients with malignant TIO, permitting the early identification of patients with PMT at increased risk of malignancy. This may significantly improve the diagnostic approach to disease. Further experimental studies are mandatory to clarify the role of FGF23 in the pathogenesis of malignancy in PMTs.

Improving single nucleotide polymorphisms genotyping accuracy for dihydropyrimidine dehydrogenase testing in pharmacogenetics.

Fluoropyrimidines, crucial in cancer treatment, often cause toxicity concerns even at standard doses. Toxic accumulation of fluoropyrimidine metabolites, culminating in adverse effects, can stem from impaired dihydropyrimidine dehydrogenase (DPYD) enzymatic function. Emerging evidence underscores the role of single nucleotide polymorphisms (SNPs) in DPYD gene, capable of inducing DPYD activity deficiency. Consequently, DPYD genotyping's importance is on the rise in clinical practice before initiating fluoropyrimidine treatment. Although polymerase chain reaction (PCR) followed by Sanger sequencing (SS; PCR-SS) is a prevalent method for DPYD genotyping, it may encounter limitations. In this context, there is reported a case in which a routine PCR-SS approach for genotyping DPYD SNP rs55886062 failed in a proband of African descent. The Clinical Pharmacogenetics Implementation Consortium (CPIC) categorizes the guanine (G) allele of this SNP as non-functional. The enforcement of whole genome sequencing (WGS) approach led to the identification of two adenine (A) insertions near the PCR primers annealing regions in the proband, responsible for a sequence frameshift and a genotyping error for rs55886062. These SNPs (rs145228578, 1-97981199-T-TA and rs141050810, 1-97981622-G-GA) were extremely rare in non-Finnish Europeans (0.05%) but prevalent in African populations (16%). Although limited evidence was available for these SNPs, they were catalogued as benign variants in public databases. Notably, these two SNPs exhibited a high linkage disequilibrium [LD; squared correlation coefficient (R2) = 0.98]. These findings highlighted the importance to consider the prevalence of genetic variants within diverse ethnic populations when designing primers and probes for SNP genotyping in pharmacogenetic testing. This preventive measure is essential to avoid sequence frameshifts or primer misalignments arising from SNP occurrences in the genome, which can compromise PCR-SS and lead to genotyping failures. Furthermore, this case highlights the significance of exploring alternative genotyping approaches, like WGS, when confronted with challenges associated with conventional techniques.

Tumor-to-tumor metastasis: breast cancer metastatic to thymic epithelial tumor.

Tumor-to-tumor metastasis is a rare phenomenon, with around 150 cases being reported in the literature. Breast cancer is the second most commonly reported donor tumor after lung cancer, but thymic epithelial tumors have never been reported as recipient tumors. Furthermore, the thymus is rarely affected by metastases. To our knowledge, the present report is the first case of breast cancer metastatic to thymic epithelial tumor.

Heterogeneity of Glycolytic Phenotype Determined by 18F-FDG PET/CT Using Coefficient of Variation in Patients with Advanced Non-Small Cell Lung Cancer.

We investigated the role of Coefficient of Variation (CoV), a first-order texture parameter derived from 18F-FDG PET/CT, in the prognosis of Non-Small Cell Lung Cancer (NSCLC) patients. Eighty-four patients with advanced NSCLC who underwent 18F-FDG PET/CT before therapy were retrospectively studied. SUVmax, SUVmean, CoV, total Metabolic Tumor Volume (MTVTOT) and whole-body Total Lesion Glycolysis (TLGWB) were determined by an automated contouring program (SUV threshold at 2.5). We analyzed 194 lesions: primary tumors (n = 84), regional (n = 48) and non-regional (n = 17) lymph nodes and metastases in liver (n = 9), bone (n = 23) and other sites (n = 13); average CoVs were 0.36 ± 0.13, 0.36 ± 0.14, 0.42 ± 0.18, 0.30 ± 0.14, 0.37 ± 0.17, 0.34 ± 0.13, respectively. No significant differences were found between the CoV values among the different lesion categories. Survival analysis included age, gender, histology, stage, MTVTOT, TLGWB and imaging parameters derived from primary tumors. At univariate analysis, CoV (p = 0.0184), MTVTOT (p = 0.0050), TLGWB (p = 0.0108) and stage (p = 0.0041) predicted Overall Survival (OS). At multivariate analysis, age, CoV, MTVTOT and stage were retained in the model (p = 0.0001). Patients with CoV > 0.38 had significantly better OS than those with CoV ≤ 0.38 (p = 0.0143). Patients with MTVTOT ≤ 89.5 mL had higher OS than those with MTVTOT > 89.5 mL (p = 0.0063). Combining CoV and MTVTOT, patients with CoV ≤ 0.38 and MTVTOT > 89.5 mL had the worst prognosis. CoV, by reflecting the heterogeneity of glycolytic phenotype, can predict clinical outcomes in NSCLC patients.

Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone.

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15-30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = -0.45, p = 0.0002, 95% confidence interval [CI] -0.63 to -0.23; Ala/Thr r = -0.39, p = 0.0012, CI -0.60 to -0.67; and Ala/Ala r = -0.30, p = 0.2347; CI -0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients (p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).

Neutrophil-to-Lymphocyte Ratio Is a Major Prognostic Factor in Non-small Cell Lung Carcinoma Patients Undergoing First Line Immunotherapy With Pembrolizumab.

BACKGROUND/AIM: Lung cancer is one of the most common malignant neoplastic diseases and by far the leading cause of cancer death worldwide. Recently, immune checkpoint inhibitors (ICIs) have received increasing attention for playing a crucial role in non-small cell lung cancer (NSCLC). Biomarkers, such as programmed cell death-ligand 1 (PD-L1) and tumor mutational burden (TMB), seemed to be helpful in selecting patients who are more likely to benefit from ICI treatment: however, their role has not yet been fully clarified. PATIENTS AND METHODS: In this retrospective study, we evaluated the relationship between pre-treatment peripheral blood neutrophil-to-lymphocyte ratio (NLR) and survival in 252 patients suffering from advanced NSCLC who had received pembrolizumab as their first-line immunotherapy. RESULTS: Compared to their NLR low counterparts who had a median overall survival (OS) of 34.8 months, patients with NLRs above 4.8 had a median OS of 7.6 months (HR=3.26, 95%Cl=2.3-4.6, p-value<0.0000001). In multivariate Cox regression analysis, alongside other variables, such as metastatic sites, age, and sex, NLR and PD-L1 predicted progression-free survival and OS; furthermore, a very high NLR - over 10 - seemed to forecast a very dismal prognosis in patients undergoing immunotherapy, with sudden deaths in the days immediately following therapy (median OS=3.8 months). CONCLUSION: NLR acts as a valuable and reliable prognostic factor in non-small cell lung carcinoma patients undergoing first line immunotherapy with pembrolizumab. Additional investigation is necessary to fully elucidate the underlying biological rationale, which can be found in myeloid derived suppressor cells, a heterogeneous population of cells with neutrophil-like immunophenotypic features.

Combination of docetaxel and cetuximab for penile cancer: a case report and literature review.

Guidelines on the treatment of metastatic squamous cell carcinoma of the penis are limited to a few prospective trials. Cisplatin-based regimens represent the standard of treatment with promising activity of taxanes. Recently, epidermal growth factor receptor overexpression has been shown in these patients. We treated an elderly man with a docetaxel-cetuximab combination after failure of the cisplatin regimen. We observed a necrosis of the inguinal lymph nodes and a reduction of (18)F-fluorodeoxyglucose uptake at PET/CT scan. Only mild mucositis and skin toxicity had been detected. Our case report, the first in the literature, shows that this combination is active and well tolerated in penile squamous cell carcinoma.

The unusual first sign of presentation of renal cell carcinoma: a rare case report.

Background: Renal cell carcinoma (RCC) usually is characterized by a slow pattern of growth, although with an unpredictable evolution and metastatic potential, favored by its extensive vascularity and related high angioinvasive profile. The most common sites of metastases from kidney cancer are lung, lymph nodes, bone and liver; whereas orbital metastases are very uncommon. In more than 25% of cases, orbital metastases are the first manifestation of a primary tumor of unknown origin. The clinical features of orbital metastases from kidney cancer are non-specific and could divert attention from the real problem. Case Description: In this article, we describe the case of a 72-year-old male patient reporting a painful mass on the right orbit, with exophthalmos and ptosis, as the first and unique signs of a previously undetected advanced RCC. Due to the clinical conditions, the patient underwent palliative radiation therapy delivered to the orbital lesion with the scope to relieve pain; subsequently started systemic therapy with pazopanib at the dose of 800 mg daily. Unfortunately, he did not achieve any benefit from systemic therapy, his conditions progressively worsened, and he finally passed away after four months of treatment due to rapid disease progression. Conclusions: Despite its rarity, differential diagnosis of an orbital lesion should always consider the possibility of metastasis from RCC, performing an appropriate radiological evaluation.

Combination of Lenvatinib and Pembrolizumab as Salvage Treatment for Paucicellular Variant of Anaplastic Thyroid Cancer: A Case Report.

Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time.

Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells.

PURPOSE: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor-resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies. EXPERIMENTAL DESIGN: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways. RESULTS: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor-resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents. CONCLUSIONS: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.

Total metabolic tumor volume by 18F-FDG PET/CT for the prediction of outcome in patients with non-small cell lung cancer.

OBJECTIVE: Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are imaging parameters derived from 18F-FDG PET/CT that have been proposed for risk stratification of cancer patients. The aim of our study was to test whether these whole-body volumetric imaging parameters may predict outcome in patients with non-small cell lung cancer (NSCLC). METHODS: Sixty-five patients (45 men, 20 women; mean age ± SD, 65 ± 12 years), with histologically proven NSCLC who had undergone 18F-FDG PET/CT scan before any therapy, were included in the study. Imaging parameters including SUVmax, SUVmean, total MTV (MTVTOT) and whole-body TLG (TLGWB) were determined. Univariate and multivariate analyses of clinical and imaging variables were performed using Cox proportional hazards regression. Survival analysis was performed using Kaplan-Meier method and log-rank tests. RESULTS: A total of 298 lesions were analyzed including 65 primary tumors, 114 metastatic lymph nodes and 119 distant metastases. MTVTOT and TLGWB could be determined in 276 lesions. Mean value of MTVTOT was 81.83 ml ± 14.63 ml (SE) whereas mean value of TLGWB was 459.88 g ± 77.02 g (SE). Univariate analysis showed that, among the variables tested, primary tumor diameter (p = 0.0470), MTV of primary tumor (p = 0.0299), stage (p < 0.0001), treatment (p < 0.0001), MTVTOT (p = 0.0003) and TLGWB (p = 0.0002) predicted progression-free survival in NSCLC patients, while age (p = 0.0550), MTV of primary tumor (p = 0.0375), stage (p < 0.0001), treatment (p < 0.0001), MTVTOT (p = 0.0001) and TLGWB (p = 0.0008) predicted overall survival. At multivariate analysis age, TLGWB and stage were retained in the model for prediction of progression-free survival (p < 0.0001), while age, MTVTOT and stage were retained in the model for prediction of overall survival (p < 0.0001). Survival analysis showed that patients with TLGWB ≤ 54.7 g had a significantly prolonged progression-free survival as compared to patients with TLGWB > 54.7 g (p < 0.0001). Moreover, overall survival was significantly better in patients showing a MTVTOT ≤ 9.5 ml as compared to those having MTVTOT > 9.5 ml (p < 0.0001). Similar results were obtained in a subgroup of 43 patients with advanced disease (stages III and IV). CONCLUSIONS: Whole-body PET-based volumetric imaging parameters are able to predict outcome in NSCLC patients.

Long term deficiency of vitamin D in germ cell testicular cancer survivors.

BACKGROUND: Cisplatin-based chemotherapy significantly improved the survival of patients with germ cell testicular cancer. However, long term side effects of chemotherapy have non-negligible impact on the quality of life of these young patients, who have a long life expectancy after being successfully treated. MATERIALS AND METHODS: 25-OH vitamin D, testosterone, FSH and LH of patients with testicular cancer were retrospectively evaluated and for each patient clinical information were collected. The tissue of 52 patients with germ cell tumors was analyzed for VDR expression by immunohistochemistry. The serum 25-OH vitamin D and VDR expression were correlated to the patients 'clinical characteristics. RESULTS: 25-OH vitamin D was analyzed in 82 patients. Insufficient (< 30 ng/ml) levels were detected in 65%-85%, mild deficient (< 20 ng/ml) in 25%-36% and severe deficient (< 10 ng/ml) in 6%-18% of the patients over a median follow-up of 48 months. No difference in serum 25-OH vitamin D was detected over the follow-up time points. No correlation with histology, stage and type of treatment was found. The 25-OH vitamin D levels were not correlated to testosterone, FSH and LH levels. Interestingly, the expression of VDR was much higher in non seminoma than in seminoma tissue. CONCLUSIONS: Patients with testicular cancer have reduced vitamin D levels after the treatment of the primary cancer. Since long term hypovitaminosis D leads to high risk of fractures, infertility and cardiovascular diseases, we envision that vitamin D should be regularly checked in patients with testicular cancer and replaced if needed.

Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = ß = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.

Rational bases for the development of EGFR inhibitors for cancer treatment.

Growth factor receptors and their ligands not only regulate normal cell processes but have been also identified as key regulators of human cancer formation. The epidermal growth factor receptor (EGFR/ErbB1/HER1) belongs to the ErbB/HER-family of tyrosine kinase receptors (RTKs). These trans-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Several evidences suggest that cooperation of multiple ErbB receptors and ligands is required for the induction of cell transformation. In this respect, EGFR, upon activation, sustains a complex and redundant network of signal transduction pathways with the contribution of other trans-membrane receptors. EGFR has been found to be expressed and altered in a variety of malignancies and clearly it plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Moreover, amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain have been recently reported in human carcinomas. As a result, investigators have developed approaches to inhibit the effects of EGFR activation, with the aim of blocking tumor growth and invasion. A number of agents targeting EGFR, including specific antibodies directed against its ligand-binding domain and small molecules inhibiting its tyrosine kinase activity are either in clinical trials or are already approved for clinical treatment. This article reviews the EGFR role in carcinogenesis and tumor progression as rational bases for the development of specific therapeutic inhibitors.

Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors.

PURPOSE: Immunostimulating Toll-like receptor 9 (TLR9) agonists cause antitumor activity interfering also with cancer proliferation and angiogenesis by mechanisms still incompletely understood. We hypothesized that modified TLR9 agonists could impair epidermal growth factor receptor (EGFR) signaling and, by this means, greatly enhance EGFR inhibitors effect, acting on both the receptor targeting and the immunologic arm. EXPERIMENTAL DESIGN: We used a novel second-generation, modified, immunomodulatory TLR9 agonist (IMO), alone and in combination with the anti-EGFR monoclonal antibody cetuximab or tyrosine kinase inhibitor gefitinib, on the growth of GEO and cetuximab-resistant derivatives GEO-CR colon cancer xenografts. We have also evaluated the expression of several proteins critical for cell proliferation, apoptosis, and angiogenesis, including EGFR, mitogen-activated protein kinase, Akt, bcl-2, cyclooxygenase-2, vascular endothelial growth factor, and nuclear factor-kappaB. RESULTS: IMO inhibited GEO growth and signaling by EGFR and the other proteins critical for cell proliferation and angiogenesis. IMO plus the anti-EGFR antibody cetuximab synergistically inhibited tumor growth, signaling proteins, and microvessel formation. EGFR signaling inhibition by IMO is relevant because IMO cooperated also with EGFR tyrosine kinase inhibitor gefitinib in GEO tumors, while it was inactive against GEO-CR xenografts. On the other hand, IMO boosted the non-EGFR-dependent cetuximab activity, causing a cooperative antitumor effect in GEO-CR cells. Finally, combination of IMO, cetuximab and chemotherapeutic irinotecan eradicated the tumors in 90% of mice. CONCLUSION: IMO interferes with EGFR-related signaling and angiogenesis and has a synergistic antitumor effect with EGFR inhibitors, especially with cetuximab, boosting both the EGFR dependent and independent activity of this agent. Moreover, this therapeutic strategy could be translated in patients affected by colorectal cancer.

Evaluation of metabolic response with 18F-FDG PET-CT in patients with advanced or recurrent thymic epithelial tumors.

BACKGROUND: Patients with advanced or recurrent thymic epithelial tumors (TETs) often need several consecutive lines of chemotherapy. The aim of this retrospective monocentric study was to test whether 18F-Fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) is able to monitor standard chemotherapy efficacy in those patients and whether metabolic response correlates with morphovolumetric response as assessed by Response Evaluation Criteria in Solid Tumor (RECIST). METHODS: We evaluated 27 consecutive patients with advanced (16 patients) or recurrent (11 patients) TETs. All patients underwent 18F-FDG PET-CT before and after at least 3 cycles of chemotherapy. Maximum standardized uptake value (SUVmax) of all detected lesions was recorded and the most 18F-FDG avid lesion in each patient was selected for determination of percentage change of SUVmax (ΔSUVmax) in pre- and post-treatment scans. Tumor response was assessed by contrast-enhanced computed tomography (CE-CT) using RECIST criteria. Receiver operating characteristic (ROC) curve analysis was performed to define the optimal threshold of ΔSUVmax discriminating responders from non-responders. RESULTS: Metabolic response expressed as ΔSUVmax was significantly correlated with morphovolumetric response (Spearman's rank correlation, r = 0.64, p = 0.001). ROC curve analysis showed that a ΔSUVmax value of -25% could discriminate responders from non-responders with a sensitivity of 88% and a specificity of 80%. Conversely, basal SUVmax values were not predictive of morphovolumetric tumor response. CONCLUSIONS: Our findings indicate that metabolic response assessed by 18F-FDG PET-CT, through evaluation of ΔSUVmax, may allow identification of responders and non-responders thus guiding adaptation of therapy in patients with advanced or recurrent TETs.