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The growing demand for personalized medicine we are currently witnessing has given rise to more in-depth research in the field of biomarker discovery and, thus, in biological banks that hold the ability to process, collect, store, and distribute "high-quality" biological specimens. However, the notion of "specimen quality" is subject to change with technological advancements. In this perspective, we propose that the notion of sample quality should shift from a broad definition of "high-quality" to a "fit-forpurpose" concept more suitable for precision medicine studies. Digital twins are a digital replica of real entities. These are largely adopted in any digitalized domain and are currently finding applications in biomedicine. The adoption of digital twins for biosamples, proposed in this paper, can provide prompt information about the whole lifecycle of the physical twin (i.e., the biosample) and substantially extend the possible matching criteria between the available samples and the researchers' and physicians' requests. This finetuning matching could greatly contribute to improving the "fit-for-purpose" quality, not only for studies based on current needs, but also to improve the identification of the best available samples in future situations, determined by the evolution of technologies and biosciences. Assuming and exploiting a data-science view in our biobank perspective, the more (accurate) data there are available, the more information can be extrapolated from them, the more opportunities there are for matching future, currently unknown, needs. This should be a mandatory principle that the 'time machines' called biobanks should follow. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) is an autosomal dominant hereditary disorder characterized by episodic swelling of many body regions (especially throat and abdomen), potentially triggered by medication. No data are available for HAE in patients with cancer assigned to standard chemotherapy. The aim of our study was to identify circulating mediators potentially predictive of acute HAE attacks during chemotherapy., Patient and Methods: Repeated blood testing (approximately every week) for complement system members (C3, C4, CH50, C1 inhibitor, C1-inhibitor functional C1Q), D-dimers and for routine haematochemistry were performed in a 42-year-old male affected by type 2 HAE during standard adjuvant oxaliplatin/fluorouracil-based chemotherapy administered for stage III radically resected rectal cancer. Pre-medication with 1,000 U Berinert inhibitor C1 was administered every week throughout treatment. Mann-Whitney U-test was used to determine statistical differences in measures between the first 30 days of therapy and beyond day 30 of therapy., Results: Pre-chemotherapy values of tested variables (day 0) were: C3: 101 mg/dl, C4: 5.71 mg/dl, CH50: 74%, C1 inhibitor: 43.4 mg/dl, C1-inhibitor functional: 18%, C1Q: 150 mg/dl, and D-dimers: 113 g/ml. A significant change in circulating values was observed for C3, D-dimers and C1-inhibitor functional. Four HAE attacks were observed, they started from the forth cycle of treatment and all were manageable. Changes in C3, D-dimers and C1-inhibitor functional preceded the attacks., Conclusion: The stress induced by chemotherapy such a standard oxaliplatin/fluorouracil increases the risk of attacks in patients with HAE. However, circulating biomarkers such as D-dimers, C3 and C1-inhibitor functional may serve as early predictors of acute HAE crisis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Emergency departments (EDs) often face overcrowding issues while simultaneously confronting with the increasing clinical needs of patients, such as cancer patients, with both acute and chronic illnesses. In order to guarantee a prompt and specialized treatment of ED-attending cancer patients and reduce inappropriate inpatient admissions, a dedicated ED cancer pathway (EDCP) consisting of ED-bound Medical Oncology (MO) resident doctor and direct admission for candidate patients exclusively to the MO division was established at the Tor Vergata University Hospital in April 2015., Patients and Methods: Consecutive cancer patients attending the ED in two reference three-month periods were enrolled: pre-EDCP period, from 1st October 2014 to 31st December 2014, and post-EDCP period, from 1st October 2014 to 31st December 2015. Inpatient admission rate, mortality rate and both ED and inpatient length of stay were compared between the two analyzed periods, pre- and post-EDCP., Results: In the pre- and post-EDCP periods 127 and 123 cancer patients, respectively, were included. Most of the analyzed indicators were improved by EDCP implementation: Inpatient admission rate from 70% to 41% (p<0.0001), ED mortality rate from 10-4% (p=0.04), mean ED length of stay, from 58 to 42 h (p=0.03), mean inpatient length of stay, from 15.5 to 6.5 days (p<0.0001), in the pre- and post-EDCp period, respectively., Conclusion: EDCP implementation led to a significant improvement of health care delivery to cancer patients attending the Emergency Department., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Breast metastases from extra mammary tumors are extremely rare., Case Report: Here we report the case of a 50-year-old female with histologically-confirmed gastric cancer metastasis to the breast who was adequately treated with loco-regional hyperthermia plus standard second-line chemotherapy (paclitaxel plus ramucirumab). The best response achieved was a relatively long disease stabilization., Conclusion: Chemotherapy plus regional hyperthermia has been shown to have a synergistic antitumor effect and possible favorable immunomodulatory effects. Such an approach merits further investigation especially for the treatment of rare superficial metastatic sites., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The growing demand of personalized medicine marked the transition from an empirical medicine to a molecular one, aimed at predicting safer and more effective medical treatment for every patient, while minimizing adverse effects. This passage has emphasized the importance of biomarker discovery studies, and has led sample availability to assume a crucial role in biomedical research. Accordingly, a great interest in Biological Bank science has grown concomitantly. In biobanks, biological material and its accompanying data are collected, handled and stored in accordance with standard operating procedures (SOPs) and existing legislation. Sample quality is ensured by adherence to SOPs and sample whole life-cycle can be recorded by innovative tracking systems employing information technology (IT) tools for monitoring storage conditions and characterization of vast amount of data. All the above will ensure proper sample exchangeability among research facilities and will represent the starting point of all future personalized medicine-based clinical trials., (Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)

Background: Signaling pathways triggered by increased thrombin or plasminogen activator inhibitor-1 (PAI-1) expression drastically alter the tumor microenvironment, contributing to an adverse outcome. This study aimed to evaluate the prognostic value of coagulation/fibrinolytic activities in breast cancer (BC)., Materials and Methods: Coagulation/fibrinolytic activities were investigated in 187 patients with breast cancer, with respect to possible associations with clinicopathological features and survival outcomes., Results: Levels of plasma PAI-1 (p<0.001), D-dimer (p=0.037) and activated protein C-dependent thrombin generation (p=0.003) were higher in women with breast cancer compared to 187 healthy women. PAI-1 directly correlated with D-dimer levels (p=0.009) and Ki67 expression (p=0.027), which were both predictors of elevated PAI-1 levels at multivariate regression analysis. Cox analysis demonstrated that an elevated plasma PAI-1 level had a negative prognostic impact in terms of relapse-free (hazard ratio=2.5, p=0.021) and overall survival (hazard ratio=2.7, p=0.002)., Conclusion: Determination of plasma PAI-1 levels might provide important prognostic information in risk stratification and survival outcomes for patients with breast cancer.

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract characterized, in the majority of cases, by activating mutations in the KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) or PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) genes. Mutations affecting these tyrosine kinase receptors are also responsible for the mechanisms of primary and secondary drug resistance during the treatment with tyrosine kinase inhibitors. We performed mutational analysis to evaluate the pharmacotherapy susceptibility of GISTs, adopting a comprehensive procedural approach, in order to optimize the identification of mutations that may result in cellular resistance to conventional therapy., Materials and Methods: DNA from paraffin-embedded tumor sections from 40 GISTs were analyzed using microdissection, direct sequencing analysis and allelic separation by cloning., Results: KIT mutations were found in 55.0% of the tumor samples. PDGFRA mutations were present in 5.0% of cases. Allelic cloning assay allowed for better definition of the extent of the mutations and clarification of the exact nucleotidic position of complex mutations., Conclusion: Our experience suggests that sequential microdissection, direct sequencing and allelic separation by PCR cloning of large variants may improve the approach to mutational analysis and interpretation of sequence data of KIT and PDGFRA in patients with GIST.

Perianal Paget's disease is a rare condition characterized by an intraepidermal growth of neoplastic cells with apocrine glandular differentiation (Paget's cells), often associated with an underlying malignancy. Fewer than 200 cases have been reported in the literature over the past 20 years. Here we discuss the clinical case of a young woman who was referred to our institution for this rare disorder and briefly review the literature.

Background: Mutations in the Kirsten Ras 1 (KRAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) genes may be predictive of response to drugs directly linked to the Epidermal Growth Factor Receptor (EGFR) signaling pathway., Materials and Methods: A total of 230 samples from patients with metastatic colorectal cancer were analyzed for KRAS exon 1 and 2 and for BRAF exon 15 mutations. DNA from paraffin-embedded tumor sections was analyzed using microdissection, direct sequencing analysis and allelic separation by cloning., Results: KRAS mutations were present in 44.3% of the tumor samples. The mutation frequency at hot-spot codons of exon 1 was 84.2%, whereas non-canonical variants had a frequency of 11.8%. Approximately 4% of the cases exhibited concomitant variations. BRAF mutations were present in 3.9% of the tumor samples., Conclusion: Our experience suggests that sequential microdissection, direct sequencing and allelic separation by cloning may improve the approach to mutational analysis of KRAS and BRAF in patients with colorectal cancer.

(51)Cr-prelabelled colon cancer cells (simulating 'circulating tumor cells', CTCs) were added to human peripheral blood and exposed to staurosporine (ST) to increase carcinoembryonic antigen (CEA) expression. CTCs were captured with immunomagnetic beads coated with Ber-EP4 monoclonal antibody, recognizing the common epithelial antigen present in the majority of cancer cells of epithelial origin, with capture efficiency of more than 80%. Moreover, ST treatment increased CEA expression without compromising Ber-EP4 capture efficiency. In a pilot clinical study on 37 patients, CTCs were captured using Ber-EP4 beads, and recognized by RT-PCR set for CEA or cytokeratin-19 (CK) mRNA detection. The results showed that: (a) the percentage of CEA-positive CTCs (CTC(CEA), 54.1%) was lower than that of CK-positive CTCs (CTC(CK), 70.3%); (b) in vitro ST treatment converted a significant number of CTC(CEA)-negative into CTC(CEA)-positive cases. Therefore, immunomagnetic capture combined with exposure to ST provides a feasible and sensitive technique for the detection of functionally-active CTCs responsive to ST-mediated CEA up-regulation.

Background: Principal caregivers (PCs) of cancer patients experience high levels of stress that may significantly impact their quality of life (QoL). PCs' QoL during early phases of the disease (when patients were still on chemotherapy) were assessed., Patients and Methods: The PCs of all patients meeting the inclusion criteria (chemotherapy, performance status 0/1) treated at our institution between June 2007 and March 2008 were asked to answer a dedicated questionnaire., Results: One hundred and four PC-patient pairs participated in the study. Most of the caregivers (52%) spent more than 8 h daily caring for the patient, they also frequently reported the occurrence of new psychosomatic disorders, with the most reported symptoms being sleep disruption (24%), headaches (20%) and asthenia (16%). High levels of anxiety and depression were demonstrated in nearly a quarter of the study subjects. In nearly half of the cases, a substantial increase in monthly family expenses and restriction of recreation activities were reported. The overall gravity of the medical situation was perceived as severe by 86% of the PCs., Conclusion: Demonstrable PC QoL impairment occurs even at early phases of disease, therefore intervention strategies for caregivers should be considered early during cancer treatment.

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.

Background: Activating mutations in the K-ras oncogene mainly occur in codons 12 and 13 and may be predictive of response to drugs directly linked to the K-ras signaling pathway, such as panitumumab and cetuximab., Materials and Methods: K-ras analysis was carried out on DNA extracted from paraffin-embedded tumor samples after microdissection. Exons 1 and 2 were amplified by PCR and then sequenced., Results: A never-reported K-ras mutation (CAG>TAG) determining a premature stop signal at codon 22 (Gln22Stop) was found in a patient with metastatic colorectal cancer. BRAF and p53 were not found to be modified and microsatellite instability was not present. The patient, however, was found to be unresponsive to an anti-EGFR MAb treatment., Conclusion: This study is the first report of a novel K-ras truncating mutation in a patient with metastatic colorectal cancer and is also suggestive for the evaluation of alternative pathways to better identify individuals who are likely to benefit from targeted therapies.

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. One third of RCC presents metastatic disease at the time of diagnosis, usually leading to a fatal outcome. Small response rates were seen with most cytotoxic agents including gemcitabine and vinorelbine, whereas systemic therapy with high doses of interleukin 2 (IL-2) has been shown to provide durable complete remissions. However, in consideration of its severe toxicity, IL-2 immunotherapy is restricted to selected patients. Aerosol IL-2 has been introduced as an alternative therapy in cancer patients. However, only very few data are available on its use in patients with pulmonary metastatic RCC. This paper briefly summarizes current clinical experience with the use of inhaled IL-2 therapy, either as a single therapy or in combination with other treatments. In addition, we report on a male patient with pulmonary metastasized RCC who achieved a durable complete response to combined gemcitabine/vinorelbine and interleukin-2 inhalation therapy.

Background: Radiofrequency thermal ablation (RFTA) has recently been introduced for the treatment of painful bone metastases. We report the outcome of one combined protocol session of percutaneous RFTA and cementoplasty on a painful sternal breast cancer metastasis of a 66-year-old patient., Patients and Methods: A sternal lesion was identified at a repeated CT scan during the oncological follow-up. Due to severe chest pain, the patient was treated percutaneously to obtain pain relief and bone stabilization. Percutaneous RFTA was performed using a 15-gauge needle electrode (MIRAS TX-120) coaxially introduced through a 13-gauge bone biopsy needle. The lesion was heated up to 80 degrees C for 3 minutes. A percutaneous injection of 1 cc polymethylmethacrylate in the central part of the lesion was performed immediately after the RFTA procedure., Results: Immediate symptomatic improvement was documented., Conclusion: Combined percutaneous therapy showed feasibility and effectiveness and can be considered as an alternative for the treatment of painful bone metastases.

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) can be regarded as an effective approach for cancer chemoprevention, as demonstrated by a bulk of clinical and experimental evidence. However, the clinical use of these drugs as chemopreventive agents is limited by many open questions about the optimal drug, dose, duration of therapy and knowledge about the mechanism(s) by which these drugs act. In particular, the recent data on cardiovascular toxicity of coxibs has posed some limitations on the use of NSAIDs for cancer chemoprevention in the general population. The situation is different in certain genetically susceptible subgroups, such as in individuals with genetic mutations associated with hereditary nonpolyposis colon cancer (HNPCC) or familiar adenomatous polyps (FAP) in whom lifetime risk increases up to 70-90% and in whom the benefit of a chemopreventive drug might justify its use even in the presence of adverse effects.

In the last decade a growing body of epidemiological and clinical data has emerged to support the concept that longstanding inflammation potentiates or promotes tumor development, growth and progression. Among pro-inflammatory gene products involved in such interactions are tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and vascular endothelial growth factors (VEGFs), whose expression is mainly regulated by the transcription nuclear factor (NF)-kappaB. Clinically, several reports have detected abnormally high levels of circulating cytokines in cancer patients, and inflammation is currently being investigated as a target of anticancer therapies. To date three main groups of antiangiogenic drugs approved for clinical use and experimentation can be identified: secreted VEGF inhibitors, tyrosine kinase (TK) inhibitors (mainly VEGFR inhibitors) and drugs that inhibit angiogenesis with a complex mechanism. More recently, TNF-alpha antagonists have become available. The first clinical data on anti-TNF-alpha showed that this drug can be used in cancer patients without major sideeffects. Further investigations are needed to understand if anti-TNF-alpha or NF-kappaB inhibitors may really represent a novel approach in cancer treatment, probably as adjuvant to other therapies, such as anti-angiogenic or cytotoxic agents.

Background: Circulating adiponectin levels are inversely correlated with the risk of colorectal cancer (CRC). This study was designed to evaluate the association between adiponectin levels and the clinicopathological variables of CRC and to analyze the possible prognostic value of adiponectin in predicting relapse-free survival., Patients and Methods: Baseline adiponectin and serum tumor markers were analyzed in 60 patients with non-metastatic CRC followed-up from time of surgery for at least three years or until relapse., Results: The median adiponectin levels were lower in CRC patients (8.3 microg/ml) than controls (13.1 microg/ml, p <0.001). Moreover, median adiponectin concentration gradually decreased with increase in tumor stage. Low pre-surgical adiponectin levels were found in 52% of the relapsing patients compared to 26% (p=0.037) of the non-relapsing patients. Logistic regression analysis demonstrated that stage of disease (OR (odds ratio)=15.9, p

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.

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.

Background: Residual telomerase activity (TA) could be used as a marker of malignant or normal cell survival after exposure to cytotoxic agents. Therefore TA after treatment with ionizing radiation was used in a radiosensitivity assay., Materials and Methods: Radiosensitive MOLT-4 and relatively radioresistant Jurkat leukemia cells or normal peripheral blood mononuclear cells (MNC) were irradiated with 5-160 Gy. Cell count, MTT assay and telomerase activity were evaluated on day 3 and clonogenic assay on day 10., Results: In Jurkat cells, irradiation inhibited tumor growth and total TA per culture (TA/culture), but up-regulated TA per viable cell (TA/cell). TA/culture and TA/cell were profoundly depressed by irradiation of MOLT-4 or phytohemagglutinin-activated MNC., Conclusion: Susceptibility of normal or neoplastic cells to high-dose radiation can be monitored by evaluating residual TA/culture. In some cases, however, difficulties in the interpretation of the results could stem from radiation-induced increase of TA/cell, as observed for the Jurkat cell line.