Correction: Mediterranean diet and quality of life in women treated for breast cancer: A baseline analysis of DEDiCa multicentre trial.

[This corrects the article DOI: 10.1371/journal.pone.0239803.].

[Genomic profiling and personalized approach, utopia or future reality? A clinical case.] / Profilazione genomica e approccio personalizzato, utopia o realtà futuribile? Un caso clinico.

The management of advanced lung cancer has changed in recent years, young and long-surviving patients with chronic diseases and good clinical conditions are frequently observed. These patients need complex, integrated and personalized treatments. The possibility of obtaining more information about the genomic profile would allow the identification of patients who could benefit from chemotherapy rather than immunotherapy or molecular target therapies. Below is the case of a 44-year-old man, ECOG PS 0, with stage IV lung cancer. This clinical history confirms the importance of a personalized approach. The patient, with non-oncogene addicted lung adenocarcinoma, achieves a good clinical-instrumental response after a first line of treatment, followed by a long maintenance phase for a total of 52 weeks. Upon progression, the patient maintains excellent clinical conditions over time, and three additional lines of therapy are carried out. At the end of this sequence, we have proposed a genomic profiling test on a tissue sample of the disease (next generation sequencing - NGS). The study, which also included the state of microsatellites and tumour mutational burden, identified the genetic alteration ATM - Q2762fs*6 (ataxia telangiectasia mutated, ATM) and for this reason we have administered niraparib for off-label use. Although this is not a standard clinical practice context, the case presented can be considered an example of a future strategy in which the ab initio identification of the rare genetic alteration, driver for tumour disease, could represent the first step in the diagnostic-therapeutic process. By improving knowledge on genetic alterations and identifying the most influential alterations for each single solid tumour, it will be possible to identify the most effective therapy, probably with even lower costs in terms of overall patient management.

Mediterranean diet and quality of life in women treated for breast cancer: A baseline analysis of DEDiCa multicentre trial.

Evidence suggests a beneficial role of the Mediterranean Diet (MedDiet) on health-related quality of life (HRQoL) in healthy subjects. HRQoL is relevant in cancer therapy and disease outcomes, therefore we investigated the association between adherence to the MedDiet and HRQoL in breast cancer survivors participating in the multicentre trial DEDiCa. Diet and HRQoL were assessed at baseline in a subgroup of 309 women enrolled within 12 months of breast cancer diagnosis without metastasis (stages I-III, mean age 52±1 yrs, BMI 27±7 kg/m2). The 14-item PREDIMED questionnaire was used to analyse adherence to the MedDiet. HRQoL was assessed with three validated questionnaires measuring physical, mental, emotional and social factors: EQ-5D-3L, EORTC QLQ-C30 and EORTC QLQ-BR23. Analysis of variance (ANOVA) and multivariate analyses were performed to assess the possible role of the MedDiet on HRQoL. Patients with higher adherence to MedDiet (PREDIMED score >7) showed significantly higher scores for physical functioning (p = 0.02) and lower scores on the symptomatic pain scale (p = 0.04) assessed by the EORTC QLQ-C30 questionnaire compared to patients with a lower adherence to MedDiet (PREDIMED score ≤7). Higher scores from the EQ-5D-3L indicating higher well-being were observed mainly in participants with higher MedDiet adherence (p = 0.05). In adjusted multivariate analyses significant positive associations were found between MedDiet, physical functioning (p = 0.001) and EQ 5D-3L score (p = 0.003) while inverse associations were found with pain and insomnia symptoms (p = 0.005 and p = 0.029, respectively). These results suggest that higher adherence to the MedDiet in breast cancer survivors is associated with better aspects of quality of life, specifically higher physical functioning, better sleep, lower pain and generally higher well-being confirming findings in healthy subjects.

Quality of Life in Women Diagnosed with Breast Cancer after a 12-Month Treatment of Lifestyle Modifications.

Healthy lifestyles are associated with better health-related quality of life (HRQoL), favorable prognosis and lower mortality in breast cancer (BC) survivors. We investigated changes in HRQoL after a 12-month lifestyle modification program in 227 BC survivors participating in DEDiCa trial (Mediterranean diet, exercise, vitamin D). HRQoL was evaluated through validated questionnaires: EQ-5D-3L, EORTC-QLQ-C30 and EORTC QLQ-BR23. Baseline changes were tested using analysis of variance. Multiple regression analyses were performed to assess treatment effects on HRQoL. Increases were observed in global health status (p < 0.001), physical (p = 0.003), role (p = 0.002) and social functioning (p < 0.001), body image (p < 0.001), future perspective (p < 0.001), well-being (p = 0.001), and reductions in fatigue (p < 0.001), nausea and vomiting (p = 0.015), dyspnea (p = 0.001), constipation (p = 0.049), financial problems (p = 0.012), sexual functioning (p = 0.025), systematic therapy side effects (p < 0.001) and breast symptoms (p = 0.004). Multiple regression analyses found inverse associations between changes in BMI and global health status (p = 0.048) and between serum 25(OH)D levels and breast symptoms (p = 0.002). A healthy lifestyle treatment of traditional Mediterranean diet and exercise may impact positively on HRQoL in BC survivors possibly through reductions in body weight while vitamin D sufficiency may improve BC-related symptoms. These findings are relevant to BC survivors whose lower HRQoL negatively affects treatment compliance and disease outcomes.

Bevacizumab in the treatment of NSCLC: patient selection and perspectives.

Non-small-cell lung cancer (NSCLC) represents about 85% of all lung cancers, and more than half of NSCLCs are diagnosed at an advanced stage. Chemotherapy has reached a plateau in the overall survival curve of about 10 months. Therefore, in last decade novel targeted approaches have been developed to extend survival of these patients, including antiangiogenic treatment. Vascular endothelial growth factor (VEGF) signaling pathway plays a dominant role in stimulating angiogenesis, which is the main process promoting tumor growth and metastasis. Bevacizumab (bev; Avastin®) is a recombinant humanized monoclonal antibody that neutralizes VEGF's biologic activity through a steric blocking of its binding with VEGF receptor. Currently, bev is the only antiangiogenic agent approved for the first-line treatment of advanced or recurrent nonsquamous NSCLC in "bev-eligible" patients. The ineligibility to receive bev is related to its toxicity. In the pivotal trials of bev in NSCLC, fatal bleeding events including pulmonary hemorrhage were observed with rates higher in the chemotherapy-plus-bev group. Therefore, in order to reduce the incidence of severe pulmonary hemorrhage, numerous exclusion criteria have been characteristically applied for bev such as central tumor localization or tumor cavitation, use of anticoagulant therapy, presence of brain metastases, age of patients (elderly). Subsequent studies designed to evaluate the safety of bev have demonstrated that this agent is safe and well tolerated even in those patients subpopulations excluded from pivotal trials. This review outlines the current state-of-the-art on bev use in advanced NSCLC. It also describes patient selection and future perspectives on this antiangiogenic agent.

Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer.

Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib.

Malignant melanoma in elderly patients: biological, surgical and medical issues.

Malignant melanoma is an aggressive tumor with a poor prognosis for patients with advanced disease. Over the last decades, its incidence and mortality has increased in elderly population, impacting significantly on healthcare costs, considering the increase in average age of the world population. Older age is recognized as an independent poor prognostic factor for melanoma, but the scientific community now is wondering if elderly melanoma patients have worse outcome because they are not receiving the same treatment as their younger counterparts. This article summarizes current data on elderly melanoma prevention and early detection and its subsequent management, underling the differences observed between older and younger patients. It also describes age-associated alterations in immunity and how these may impact on anti-melanoma response.

Neoadjuvant therapy for locally advanced melanoma: new strategies with targeted therapies.

Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma.

Is there still a role for mitomycin-based combination chemotherapy in treating patients with nonsmall cell lung cancer? A single institution experience.

BACKGROUND: Mitomycin and irinotecan are widely used in the treatment of colorectal cancer, furthermore both of these drugs are active agents against nonsmall cell lung cancer and their combination has shown synergism in preclinical studies. The aim of the study was to evaluate the efficacy and safety of mitomycin- and irinotecan-based chemotherapy combination in patients with advanced nonsmall cell lung cancer progressing after previous antineoplastic therapies. METHODS: Thirty-one consecutive patients suffering from nonsmall cell lung cancer, who underwent mitomycin- plus irinotecan-based chemotherapy as salvage treatment after failure of at least two previous systemic treatments, were retrospectively identified in our database. Between September 2003 and March 2011, 31 patients with histologically proven stage IIIB or IV nonsmall cell lung cancer, received mitomycin 5 mg/m(2) on day 1 followed by irinotecan 150 mg/m(2) on day 2. Cycles were repeated at 2-week interval. RESULTS: A total of 164 cycles of treatment were given with a median of five per patient (range 1-10). The objective responses included partial response in 6 patients (19.3%), stable disease in 4 (13%), and progressive disease in 21 (67.7%). Median time to disease progression was 4 months, and median survival was 9+ months. Twelve patients (38%) reached 1-year survival. Grade 3-4 toxicities occurred in seven patients (22.5%), mainly myelosuppression (neutropenia, anemia, and thrombocytopenia), mucositis, and diarrhea. No treatment-related death was recorded. CONCLUSION: The mitomycin- and irinotecan-based combination chemotherapy seems to be tolerated and active in this subset of heavily pretreated patients with advanced nonsmall cell lung cancer. However, evaluation or recruitment of a larger number of patients would be needed to provide more adequate data on safety and activity of the described combination.

Low molecular weight heparin administration in cancer patients with hypercoagulability-related complications and carrying brain metastases: a case series study.

BACKGROUND: Venous thromboembolism (VTE) and brain metastases (MTS) are significant clinical problems in the cancer patient population. Brain MTS and deep vein thrombosis are life-threatening conditions because of the risk of fatal endocranic hypertension and pulmonary embolism. Low molecular weight heparin (LMWH) is a major treatment for cancer patients suffering from VTE with regard to the management of the acute phase and subsequent secondary prophylaxis. Treatment with anticoagulants is feared because of the risk of triggering a massive intracranial hemorrhage. METHODS: The medical records of patients with hypercoagulability-related complications and carrying brain MTS treated with LMWH, in a 10-year period, were scrutinized. The authors aimed to focus on the occurrence of intracranial hemorrhage in anticoagulated patients; furthermore, data were collected with regard to the characteristics of the administered LMWHs along with the duration and dosing of the anticoagulative treatment. RESULTS: A total of 38 patients (pts) carrying an intracranial metastatic tumor were administered LMWHs: calcium nadroparin (32 pts); enoxaparin (2 pts); reviparin (2 pts); parnaparin (2 pts). Reason for LMWH therapy: deep vein thrombosis and/or pulmonary embolism (15 pts); superficial thrombophlebitis (15 pts); intracardiac thrombus (1 pt); mild DIC (5 pts); acute DIC (1 pt); Raynaud phenomenon (1 pt); atrial fibrillation (1 pt). Median duration of LMWH therapy: 13 weeks (range 1-52). None of the patients developed clinical and/or radiographic findings imputable to intracranial hemorrhage. CONCLUSION: There is no standard medical approach for the management of patients who require anticoagulant treatment and are suffering from brain MTS. These patients as necessary, might be anticoagulated with LMWH and its dose reduction is to be considered.

Successful administration of a low dose of calcium nadroparin in patients suffering from pulmonary embolism and brain metastases: a report of two cases.

OBJECTIVE: To focus on the optimal management of thromboembolic complication in patients who have undergone chemotherapy with concomitant brain metastases and referred to a Division of Clinical Oncology. BACKGROUND: Thromboembolic diseases are common events in cancer patients due to clotting activation by tumor cells. On the other hand, brain metastases are common complication of systemic cancers. Postmortem studies show that a quarter of patients dying from cancer have intracranial metastases. Brain metastases and pulmonary embolism are life-threatening conditions because of the risk of fatal endocranic hypertension and severe dyspnea. Calcium nadroparin is a low molecular weight heparin usually administered in patient with venous thromboembolism at a dose level of 180 IU/kg/daily. CASE SUMMARIES: The authors report the cases of two patients with intracranial metastases and pulmonary embolism-related dyspnea successfully treated with low dose of calcium nadroparin. A patient suffering from metastatic breast cancer and another one with metastatic nonsmall cell lung cancer were recently referred to our department because of severe dyspnea occurring during chemotherapy treatment. Both patients had cerebellar intracranial metastases. Massive pulmonary embolisms were shown by means of the computerized tomography. Despite the administration of a lower heparin dose than the usual one, around three-quarters of the calcium nadroparin daily conventional dose, quickly regressed dyspnea. Significant pulmonary embolism regression was revealed with computerized tomography scan within 8 weeks from the beginning of the thromboembolic complications. None of the patients showed any heparin treatment-related complications. CONCLUSION: The authors conclude that, with regard to cancer patients carrying brain metastases who require anti-coagulant therapy, increased risk of intracranial hemorrhage should be kept in mind. An initial low molecular weight heparin dose reduction could be effective, and safely administered, also in case of pulmonary embolism with severe dyspnea.