Combi-TED: a new trial testing Tedopi® with docetaxel or nivolumab in metastatic non-small-cell lung cancer progressing after first line.

Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi®, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers. The results will hopefully provide more information on Tedopi combinational treatment compared with current standard of care in NSCLC patients who fail first-line chemoimmunotherapy. Clinical Trial Registration: NCT04884282 (ClinicalTrials.gov).

Patients with lung cancer that has spread to other parts of the body are usually treated with a combination of chemotherapy and drugs that stimulate the immune system to kill cancer cells, which is referred to as immunotherapy. If after receiving these drugs the cancer still gets worse, patients have only a few treatment options left and are usually treated with chemotherapy only. Researchers will study if a new medicine called Tedopi^®, a vaccine that specifically attacks cancer cells, used together with chemotherapy or immunotherapy, will work better then chemotherapy alone for these patients. The study will monitor how long patients will live after treatment, for how long they will live without their disease getting worse and how many patients will improve after treatment. Moreover, researchers will study if patients present specific features, such as certain molecules in their tumor cells or blood cells, that may indicate that they respond better to certain treatments.

Enzalutamide in patients with castration-resistant prostate cancer: retrospective, multicenter, real life study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is the final stage of pCa history and represents a clinically relevant phenotype with an elevated burden of mortality. The aim of the present study was to evaluate the efficacy and safety of enzalutamide in a "real-life" setting in mCRPC patients. METHODS: Data about all mCRPC patients treated with enzalutamide from September 2017 to September 2018 were collected. Demographics, comorbidities, clinical parameters, outcomes, toxicity, overall survival and progression free survival were analyzed. RESULTS: Overall, 158 patients were enrolled. Mean age was 75.8 (±8.7) years with a baseline median PSA of 16.5 (IQR 7.4-47.8) ng/mL. The median follow-up lasted 7.7 (IQR 4-14.1) months. Of all the 10.1% of patients reported grade 3-4 adverse events. 43.7% of patients experienced a progression. Overall, the 6 and 12 months PFS rates were 69.5% (95% CI: 61.7-78.3%) and the 45.6% (95% CI: 36.5-57.1%); a median baseline PSA>16 ng/mL (HR:2.0, 95% CI: 1.2-3.3, P<0.005), the use of opioid (HR: 3.1, 95% CI: 1.9-5.0, P<0.001), a previous treatment (abiraterone, docetaxel or abiraterone + docetaxel) were significantly associated with higher rates of cancer progression. Conversely, a brief pain questionnaire of 0-1 (HR: 0.4, 95% CI: 0.2-0.7, P<0.001), a 12 weeks 50% PSA reduction (HR: 0.4, 95% CI: 0.2-0.8, P<0.006) and a longer time to mCRPC (HR: 0.4, 95% CI: 0.3-0.7, P<0.002) were related to lower cancer progression rates. CONCLUSIONS: Our data shows an effective and safe profile of enzalutamide in a "real world" perspective in patients with mcRPC.

Prognostic Significance of Neutrophil-to-lymphocyte Ratio in the Framework of the 8th TNM Edition for Breast Cancer.

BACKGROUND/AIM: To investigate whether neutrophil-to-lymphocyte ratio (NLR) might represent an additional biological criterion able to identify patients with worse prognosis within the 8th edition TNM prognostic staging system for breast cancer (BC). PATIENTS AND METHODS: Pre-treatment NLR was retrospectively analyzed in 475 BC women prospectively followed for a mean time of 3.8 years. The optimal NLR cutoff, identified by ROC analysis, was set at 2. RESULTS: Elevated pre-treatment NLR was associated with worse disease-free survival (DFS) (HR=2.28) and overall survival (OS) (HR=3.39). The prognostic value of NLR was mostly evident in stage I BC (HR for DFS=2.89; HR for OS=1.30), in whom NLR significantly stratified patients who developed distant metastasis (HR= 4.62), but not local recurrence. CONCLUSION: NLR might provide important information in risk stratification, especially in stage I BC patients in whom the presence of a high NLR might raise the question as to whether they should be more aggressively managed.

Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter "real life" study.

BACKGROUND: To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate. METHODS: A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic. RESULTS: We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4-2100). The median exposure to AA was 10 months (range 1-35). The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% "greatly improved", 38% "improved", 24% "not changed", 5.5% "worsened". Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline. CONCLUSIONS: The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a "real life" setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline. TRIAL REGISTRATION: The study was retrospectively registered at ISRCTN as DOI: 10.1186/ISRCTN 52513758 in date April the 30th 2016.

Abiraterone Acetate for Treatment of Metastatic Castration-resistant Prostate Cancer in Chemotherapy-naive Patients: An Italian Analysis of Patients' Satisfaction.

INTRODUCTION: Abiraterone acetate (AA) gives a significant improvement in survival for patients with metastatic castration-resistant prostate cancer (mCRPC) before and after chemotherapy and has a favorable effect on patients' health-related quality of life and pain. Only a few studies have investigated patient-reported outcomes (PROs) in AA treatment for mCRPC. The aim of this study was to investigate patients' satisfaction in men affected by mCRPC treated with AA. MATERIALS AND METHODS: This was a retrospective analysis of a database of consecutive chemonaive patients with progressive mCRPC. Patients were treated with AA until disease progression, death, or unacceptable toxicity. Evaluation was performed at baseline and every 4 weeks by means of physical examination and laboratory studies. Eastern Cooperative Oncology Group score, pain symptoms, treatment-related toxicity, prostate-specific antigen (PSA), and overall and progression-free survival were recorded. Satisfaction with treatment was investigated at 6 months by means of a 4-point arbitrary scale. RESULTS: One-hundred twenty-eight patients were enrolled. Patients' satisfaction with treatment was "greatly improved" in 36.1% of patients and "improved" in 32.4% of them. Patients with higher satisfaction had lower baseline and final PSA values (P < .05), lower PSA levels at 12 weeks (P = .080), and less pain symptoms and lower Brief Pain Inventory scores (P = .001). Satisfaction with treatment was significantly correlated with baseline PSA level (P = .018), presence of pain (P = .007), duration of androgen deprivation therapy >12 months (P = .025), and number of hormonal manipulations (P = .051). Progression-free survival significantly correlated with patient satisfaction (P < .001). CONCLUSION: AA is safe and well tolerated in chemonaive mCRPC patients, ensures good oncological and PROs. Patient's satisfaction is a predictor of progression-free survival.

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression.

BACKGROUND: Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients. PATIENTS AND METHODS: Fasting blood glucose, insulin and HbA1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated. RESULTS: Fasting blood glucose level (mean ± SD: 99 ± 26 vs. 85 ± 15 mg/dL), insulin level (median: 10.0 vs. 6.8 µIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA1c level, were significantly elevated in BC patients compared with control subjects. Receiver operating characteristics analysis showed comparable areas for blood glucose and insulin levels, and HOMA index (ranging from 0.668 to 0.671). Using a cutoff level of 13 µIU/mL, insulin had the best specificity (92%) and sensitivity (41%), was significantly associated with disease stage, and acted as a negative prognostic marker of progression-free survival (hazard ratio: 2.17; 95% confidence interval: 1.13-4.20) independently of menopausal status, disease stage, hormone receptor status, and human epidermal growth factor receptor 2 and Ki67 expression. CONCLUSION: These results suggest that insulin determination might provide prognostic information in BC and support the hypothesis that lifestyle and/or pharmacological interventions targeting glucose metabolism could be considered to improve survival outcome of selected BC patients. IMPLICATIONS FOR PRACTICE: Pretreatment insulin levels may represent a biomarker of adverse prognosis in nondiabetic women with breast cancer, independently of other well-established prognostic factors (i.e., stage, hormone receptors, HER2/neu, and Ki67). This finding has important implications, because it provides the rationale for lifestyle or insulin-targeting pharmacologic interventions as a means of improving breast cancer outcomes not only in early stages, but also in advanced-stage breast cancer patients with aggressive tumor phenotypes (HER2-negative hormone-resistant, or triple-negative breast cancer), in which treatments are still challenging. The possibility of using insulin as a biomarker to guide insulin-targeted interventions also should be taken into account.

Estimated glomerular filtration rate is an easy predictor of venous thromboembolism in cancer patients undergoing platinum-based chemotherapy.

Reduced estimated glomerular filtration rate (eGFR) has been associated with increased venous thromboembolism (VTE) risk in the general population. VTE incidence significantly increases in cancer patients, especially those undergoing chemotherapy. Despite the evidence that a substantial number of cancer patients have unrecognized renal impairment, as indicated by reduced eGFR in the presence of serum creatinine levels within the reference value, chemotherapy dosage is routinely adjusted for serum creatinine values. Among chemotherapies, platinum-based regimens are associated with the highest rates of VTE. A cohort study was designed to assess the value of pretreatment eGFR in the risk prediction of a first VTE episode in cancer outpatients without previous history of VTE who were scheduled for platinum-based chemotherapy. Methods. Serum creatinine and eGFR were evaluated before the start of standard platinum-based chemotherapy in a cohort of 322 consecutive patients with primary or relapsing/recurrent solid cancers, representative of a general practice population. Results. Patients who experienced a first VTE episode in the course of chemotherapy had lower mean eGFR values compared with patients who remained VTE free. Multivariate Cox analysis demonstrated that eGFR had an independent value for risk prediction of a first VTE episode during treatment, with a 3.15 hazard ratio. Indeed, 14% of patients with reduced eGFR had VTE over 1-year follow-up compared with 6% of patients with normal eGFR values. Conclusion. The results suggest that reductions in eGFR, even in the presence of normal serum creatinine, are associated with an increased VTE risk in cancer outpatients undergoing platinum-based chemotherapy regimens. Determining eGFR before chemotherapy could represent a simple predictor of VTE, at no additional cost to health care systems.

von Hippel Lindau disease with colon adenocarcinoma, renal cell carcinoma and adrenal pheochromocytoma.

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome characterized by the presence of heterogeneous tumors derived from different organs. VHL is caused by germline mutations in the VHL tumor suppressor gene located on chromosome 3p25-26. The loss of functional VHL protein contributes to tumorigenesis. VHL tumors are most frequently derived from the kidneys, adrenal gland, central nervous system, eyes, inner ear, epididymis and pancreas. We herein describe the case of a 64-year-old man carrying the VHL gene mutation affected by simultaneous colon adenocarcinoma, renal clear cell carcinoma and adrenal pheochromocytoma.

Impact of chemotherapy on activated protein C-dependent thrombin generation--association with VTE occurrence.

Chemotherapy has been associated with an increased risk of venous thromboembolism (VTE). However, the prevalence of coagulation abnormalities or VTE occurrence as a consequence of different anti-cancer agents or treatment schemes is largely uncharacterized. Thus, this study was aimed at analyzing the impact of different anticancer drugs on the prothrombotic status of cancer out-patients scheduled for chemotherapy. To this purpose, a mono-institutional study was prospectively conducted to monitor serial changes of activated protein C (APC) function in 505 consecutive cancer out-patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. The results obtained showed that age >65 years (p = 0.01), ECOG performance status (p = 0.01), platinum-based (p = 0.035) and fluoropyrimidine-based regimens (p = 0.008) were independent predictors of an acquired APC resistance during the first chemotherapy cycle. Multivariate model of Cox proportional hazards survival analysis demonstrated that a decline in APC functionality (HR = 2.4; p = 0.013) and platinum-based regimens (HR = 2.2; p = 0.042) were both capable of predicting the occurrence of a first VTE episode during chemotherapy. Indeed, 14% of patients with platinum-associated APC impairment had VTE over a 1-year follow-up, compared to 3% of patients treated with other regimens and in whom APC functionality remained stable (HR = 1.5; p = 0.003). We may, thus, conclude that use of platinum-based regimens is responsible for induction of an acquired thrombophilic condition and represents a predictor for VTE even after adjustment for other risk factors.

Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients--a pilot study.

PURPOSE: Identifying cancer patients who are most at risk for venous thromboembolism (VTE) is essential to improve timely delivery of chemotherapy. Several studies have been performed to identify novel candidate biomarkers, but no agreement has yet been reached. In this light, we sought to analyze whether a dynamic evaluation of early changes of activated protein C (APC) function during chemotherapy could be predictive of a first VTE episode in cancer outpatients, thus improving risk stratification. METHODS: A retrospective single-center pilot study was conducted to investigate the adequacy of a dynamic evaluation of a novel APC-dependent thrombin generation assay (HemosIL ThromboPath (ThP)) in predicting VTE in 208 ambulatory cancer patients, enrolled on the basis of tight inclusion criteria, prior to start and before the second cycle of a new chemotherapy regimen. RESULTS: Retrospective analysis of samples showed the occurrence of an acquired APC resistance during chemotherapy, which was predictive of VTE. Univariate Cox proportional hazards survival analysis showed that early ThP changes predicted VTE (stable vs. decreasing ThP: hazard ratio (HR) 0.21; 95% CI 0.10-0.19; p < 0.0001), which was confirmed in the multivariate model (HR 0.25; CI 0.12-0.52, p < 0.0001). Stratification of patients according to a risk assessment model showed a 0.18 HR for stable vs. decreasing ThP assay results in an intermediate risk group. CONCLUSIONS: We may thus conclude that early changes of ThP assay in patients on active chemotherapy enhance VTE risk stratification, helping in identifying a population of cancer patients who might benefit from thromboprophylaxis.

Prognostic significance of serum adipokine levels in colorectal cancer patients.

BACKGROUND: Adipokines may significantly influence the growth and proliferation of tumor stroma and malignant cells within. Reduced adiponectin and increased leptin serum levels were found in colorectal cancer (CRC) patients. Recently, it has been demonstrated that tumor necrosis factor-alpha (TNF-alpha) is able to induce dose-dependent changes in serum adipokine levels. Thus, aims of this study were to evaluate the possible associations between adipokines, TNF-alpha and clinicopathological variables of CRC patients and to analyze their possible prognostic value in predicting relapse-free and overall survival. MATERIALS AND METHODS: Baseline leptin, adiponectin and TNF-alpha levels were analyzed in 90 patients with histologically diagnosed primary or newly diagnosed metastatic CRC treated at 'Tor Vergata' Clinical Center and followed up for a median period of 3 years. RESULTS: Serum leptin levels were higher in CRC patients than in controls (p<0.0001). Conversely, serum adiponectin levels were lower in CRC patients than in controls (p<0.0001). Leptin inversely correlated with adiponectin (p<0.005). The leptin/adiponectin (L/A) ratio was eight-fold greater in CRC compared to controls (p<0.0001). Kaplan-Meier analysis of relapse-free and overall survival time showed that the L/A ratio was an independent predictor for adverse outcome in CRC. CONCLUSION: Serum adipokine levels might have a role in the biology of CRC and the combined measurement of leptin and adiponectin levels might provide useful prognostic information in the management of patients with CRC.

Prognostic value of pre-surgical plasma PAI-1 (plasminogen activator inhibitor-1) levels in breast cancer.

INTRODUCTION: Plasminogen activator inhibitor (PAI-1) may have an independent prognostic value in breast cancer (BC). PAI-1 4G/5G polymorphism may have significance for antigen expression. Thus, we analyzed the possible associations between PAI-1 4G/5G polymorphism, plasma PAI-1 levels, and clinicopathological features of breast cancer (BC) patients. PATIENTS AND METHODS: PAI-1 4G/5G polymorphism (both on germinal and tumor DNA) and plasma PAI-1 levels were investigated in 99 BC patients and 50 unrelated healthy women similar for age and menopausal status. RESULTS: No association was found between allele frequencies and clinicopathological features of BC or plasma antigen levels. Plasma PAI-1 levels were higher in BC compared to controls (p=0.002), particularly in patients with large tumors (p<0.001). 5-year follow-up was achieved in 79 patients: 30% had relapsing disease, 63% with positive compared to 37% with negative PAI-1 levels (p<0.05). 5-year relapse-free survival rate of positive PAI-1 was 46% vs., 77% of negative patients (p=0.02). CONCLUSIONS: We may conclude that plasma PAI-1 levels in BC patients could represent a useful prognostic variable for relapse, although PAI-1 polymorphism might not represent a genetic susceptibility factor.

Telomerase activity, hTERT expression, and phosphorylation are downregulated in CD4(+) T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1).

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by a progressive decrease of CD4(+) T cells accompanied by other immune dysfunctions. Telomerase is transiently activated in lymphocytes during activation and is able to compensate for the progressive telomeric loss that occurs at each cell division, contributing to ensure the telomere length necessary for multiple proliferative events. The effect of HIV-1 infection on telomerase activity and on the expression of some of the factors involved in its regulation in CD4(+) T cells was investigated. Telomerase was found to be downregulated in both nuclear and cytoplasmic compartments, together with an impairment of human telomerase reverse transcriptase (hTERT) expression and of the cell machinery involved in hTERT phosporylation.

Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized study.

Although surgical resection is considered the adequate treatment in early stages of nonsmall cell lung cancer, long-term survival is not satisfactory and recurrence rate is high. We previously showed that postoperative chemotherapy at stage IB reduces recurrences and prolongs overall survival. We extended size and observation period of the study sample and performed a separate analysis for minimally resected patients. The trial was designed as a randomized, 2-armed study with postoperative adjuvant chemotherapy versus surgery alone as control group. All patients had stage IB disease (pT2N0) assessed after a radical surgical procedure (defined as anatomical or minimal). Chemotherapy consisted of cisplatin (100 mg/m2 day 1) and etoposide (120 mg/m2 days 1-3) for 6 cycles. The primary endpoint was overall survival; secondary endpoint was disease-free survival (DFS). One hundred and forty patients entered the study: 70 were assigned to the adjuvant chemotherapy group and 70 to the control group. Groups were homogeneous for conventional risk factors. There was no clinically significant morbidity associated to chemotherapy. Patients were followed for a mean period of 40.31 +/- 30.86 months. A significant difference in overall (p = 0.02) and disease-free (p = 0.0001) survival was observed between patients undergoing adjuvant chemotherapy vs. control group. Adjuvant chemotherapy significantly improved both overall (p = 0.02) and DFS (p = 0.003) of anatomically resected patients, but only the DFS (p = 0.02) of minimally resected patients. Our results confirm that adjuvant chemotherapy may have a real impact on long-term survival in patients with stage IB nonsmall cell lung cancer being this effect especially evident for those anatomically resected.

Plasma von Willebrand factor antigen levels in non-small cell lung cancer patients.

BACKGROUND: To analyze the behavior of circulating von Willebrand factor antigen (vWf:Ag) in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Pre-surgical vWf:Ag levels were measured in 64 patients with histologically diagnosed NSCLC compared to 64 patients with benign pulmonary diseases, as well as 64 age- and sex-matched controls. RESULTS: Patients with NSCLC had mean vWf:Ag concentrations lower than either controls or benign patients (p =0.001). CEA was the only variable predictive of low vWf:Ag levels (p<0.01). Five of the 64 NSCLC patients had abnormally low vWf:Ag concentrations (<36 IU/dL). When these patients were excluded from the analysis, the vWf:Ag levels of NSCLC patients did not differ from those of controls (p=0.19). CONCLUSION: The vWf antigen levels of NSCLC patients are not substantially altered. A small subset of these patients will have a depletion of circulating vWf:Ag, probably because of a paraneoplastic process associated with an advanced stage of disease.

Radiofrequency Heat Ablation and Vertebroplasty in the treatment of neoplastic vertebral body fractures.

BACKGROUND: Metastatic cancer is the most common malignant disease of the skeletal system. Traditionally, conventional fractionated external beam radiotherapy has been the treatment of choice. Recently, minimally invasive surgical techniques (MISS) have been added to the therapeutic armamentarium. The purpose of our study was to assess the effectiveness and safety of Radiofrequency Heat Ablation and Vertebroplasty in the treatment of neoplastic Vertebral Compressive Fractures (VCF). The aim of radiofrequency heat ablation is to destroy the tumor tissue before stabilizing the vertebra through the intrasomatic injection of cement. PATIENTS AND METHODS: We treated patients with unremitting pain over spine, in absence of symptomatic spinal cord or roots compression and refractory to conventional therapeutic options such as radiation therapy, chemotherapy, surgery and use of analgesics. RESULTS: The method demonstrated swift pain relief associated with an evident augmentation in the weight-bearing resistance. CONCLUSION: The association of Radiofrequency Heat Ablation and Vertebroplasty is an effective, simple and safe treatment of vertebral collapse consequent to metastases.