Azzurra Onofri

Role of maspin in cancer

Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible “molecules binds” to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis.Further studies in these directions are necessary to better define the therapeutic implication of maspin.

State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: A literature review

Cardiotoxicity is a common complication of many anti-cancer agents and it remains a major limitation, strongly impacting the quality of life and the overall survival, regardless of the oncologic prognosis. Cardiotoxicity may occur during or shortly after treatment (within days or weeks), or it may become evident months, and sometimes years, after completion of chemotherapy. Cardiotoxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes. The aim of this review is to summarize potential cancer chemotherapeutics-related cardiovascular toxicities in adult cancer-patients and to suggest monitoring and treatment options for each agent, that can serve as a tool in the clinical practice.

Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients: Recent insights and future challenges

Anti-programmed death (PD)-1 agents pembrolizumab and nivolumab have recently obtained enthusiastic results in terms of progression-free survival (PFS), overall survival (OS) and tolerability in cancer patients. Despite these promising data, the high cost of these agents needs careful consideration. Indeed, the evaluation of cost-effectiveness analysis (CEA) and quality-adjusted life year (QALY), as well as different drug reimbursement modalities, will represent fundamental tools in order to guarantee the economic sustainability of health system and the access to care for all cancer patients. In this review, we discussed the recent results obtained by immunotherapy in cancer patients and we evaluated the economic impact of recently approved nivolumab and pembrolizumab in patients with advanced melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC).

Performance at Preoperative Stair-Climbing Test Is Associated With Prognosis After Pulmonary Resection in Stage I Non-Small Cell Lung Cancer

BACKGROUND This investigation evaluated whether the performance at a preoperative symptom-limited stair-climbing test was a prognostic factor in resected pathologic stage I non-small cell lung cancer (NSCLC). METHODS Observational analysis was performed on a prospective database that included 296 patients who underwent pulmonary lobectomy for pathologic stage T1 N0 or T2 N0 NSCLC (2000 to 2008). Patients who received induction chemotherapy were excluded. Survival was calculated by the Kaplan-Meyer method. The log-rank test was used to assess differences in survival between groups. The relationships between survival and baseline and clinical variables were determined by Cox multivariate analyses. RESULTS Median follow-up was 43 months. The best cutoff associated with prognosis was an 18-meter stair climb. Median (months) survival and 5-year survival of patients who climbed more than 18 meters were significantly longer than those who climbed less than 18 meters (97 vs 74; 77% vs 54%, p=0.001). Cox regression model (hazard ratio) showed that climbing more than 18 meters (0.5; p=0.003), diffusion capacity of the lung for carbon monoxide (0.98; p=0.02), and pT stage (1.8; p=0.02) were independent prognostic factors. Patients who climbed less than 18 meters had increased deaths from cancer (24% vs 15%, p=0.1) or other causes (19% vs 9%, p=0.02). CONCLUSIONS Preoperative cardiopulmonary fitness is a significant prognostic factor in patients after resection for early-stage NSCLC. Interventions aimed at improving exercise tolerance can be useful to improve long-term prognosis after NSCLC operations.

Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey

Study Type – Therapy (case series)

Preoperative quality of life predicts survival following pulmonary resection in stage I non-small-cell lung cancer

OBJECTIVES The objective of this study was to assess the prognostic role of preoperative quality of life (QoL) in patients operated on for early-stage non-small-cell lung cancer (NSCLC). METHODS This is an observational analysis of 131 consecutive patients (2003-08) submitted to pulmonary lobectomy and systematic nodal dissection for pathological pT1N0 or pT2N0 stages NSCLC with a complete follow-up (median 40 months). QoL was measured by the Short Form 36v2, a multidimensional survey assessing eight domains and two composite scales (physical component score [PCS] and mental component score [MCS]). Survival was calculated by the Kaplan-Meier method. The log-rank test was used to assess differences between groups. The relationships between survival and QoL composite scales were determined by Cox proportional hazards regression analysis adjusting for the effect of several baseline and clinical variables. PCS and MCS were categorized according to their values greater or lower than 50 percentiles (general population norms). RESULTS Fifty-three (40%) patients had PCS <50 and 71 (54%) had MCS <50. Results from physical functioning (P = 0.03) and general health (P = 0.03) scales were directly associated with survival. Multivariable regression showed that significant factors associated with overall survival were age >70 (hazard ratio [HR] 2.4, 95% confidence interval [95% CI] 1.2-4.8, P = 0.01) and PCS <50 (HR 2.3, 95% CI 1.4-4.4, P = 0.01). MCS, pT stage, histology, forced expiratory volume in 1 s, DLCO were not associated with prognosis. Patients with PCS >50 lived longer than those with PCS <50 (5-year overall survival 79 vs 49%, P = 0.01), in both pT1 (5-year overall survival 80 vs 49%) and pT2 stages (5-year overall survival 78 vs 48%). Cancer-specific 5-year survival was better in patients with a preoperative PCS >50 compared with those with PCS <50 (89 vs 73%, P = 0.05). Deaths due to cancer recurrence were similar in patients with PCS <50 and >50 (55 vs 53%, P = 0.9). CONCLUSIONS The physical component of QoL was associated with overall and cancer-specific survivals in patients operated on for early-stage NSCLC. Supportive interventions aimed at improving the perception of physical well-being should be tested to verify whether they can improve long-term prognosis after lung cancer surgery.

Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer

In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite initial responses and long-lasting remissions, resistance to tyrosine kinase inhibitors invariably develops, most commonly due to the emergence of secondary T790M mutations or to the amplification of mesenchymal–epithelial transition factor (c-Met), which inevitably leads to treatment failure. Several clinical studies are ongoing (http://www.clinicaltrials.gov), aimed to evaluate the efficacy and toxicity of combined approaches and to develop novel irreversible or multitargeted tyrosine kinase inhibitors and mutant-selective inhibitors to overcome such resistance. This review is an overview of ongoing Phase I, II, and III trials of novel small molecule epidermal growth factor receptor inhibitors and combinations in non-small cell lung cancer patients.

Chromium Exposure and Germinal Embryonal Carcinoma: First Two Cases and Review of the Literature

The aim of the study was to determine the potential role of occupational exposures to chromium (Cr) in the onset of extragonadal germinal embryonal carcinoma. The first two cases of workers in a company with Cr exposure are reported. The published scientific literature regarding the topic in peer-reviewed journals including MEDLINE and CancerLit databases was extensively reviewed. Two young patients who were coworkers in the same company, exposed to Cr, developed extragonadal germinal embryonal carcinomas. One of them also developed angiosarcoma of the mediastinum. To the best of our knowledge these are the first two cases of germinal embryonal carcinoma in patients with occupational exposure to Cr.

Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy—A literature review

Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different malignant potential and behavior. Many treatment options are available. Surgery should be considered for localized tumors and in some selected cases of metastatic disease. Somatostatin analogs, useful for symptoms control in functioning tumors, are also effective to inhibit tumor progression in specific settings. The multi-TKI sunitinib and of the mTOR-inhibitor everolimus are efficacy for metastatic pancreatic NET (P-NET) treatment. Chemotherapy is generally used in symptomatic and progressive NETs. Peptide receptor radionuclide therapy (PRRT) should be recommended after failure of medical therapy. For tumors confined to the liver ablative techniques should be considered. Nevertheless a shared therapeutic sequence for GEP-NET treatment still does not exist. In this review, we analyzed available data trying to identify the better treatment strategy and to suggest potential therapeutic algorithms distinguishing P-NETs from gastrointestinal NETs (GI-NETs).

Locally advanced rectal cancer: The importance of a multidisciplinary approach

Rectal cancer accounts for a relevant part of colorectal cancer cases, with a mortality of 4-10/100000 per year. The development of locoregional recurrences and the occurrence of distant metastases both influences the prognosis of these patients. In the last two decades, new multimodality strategies have improved the prognosis of locally advanced rectal cancer with a significant reduction of local relapse and an increase in terms of overall survival. Radical surgery still remains the principal curative treatment and the introduction of total mesorectal excision has significantly achieved a reduction in terms of local recurrence rates. The employment of neoadjuvant treatment, delivered before surgery, also achieved an improved local control and an increased sphincter preservation rate in low-lying tumors, with an acceptable acute and late toxicity. This review describes the multidisciplinary management of rectal cancer, focusing on the effectiveness of neoadjuvant chemoradiotherapy and of post-operative adjuvant chemotherapy both in the standard combined modality treatment programs and in the ongoing research to improve these regimens.