Urinary volatile Organic compounds in non-alcoholic fatty liver disease (NAFLD), type two diabetes mellitus (T2DM) and NAFLD-T2DM coexistence.

INTRODUCTION: Accumulating evidence have shown a significant correlation between urinary volatile organic compounds (VOCs) profile and the manifestation of several physiological and pathological states, including liver diseases. Previous studies have investigated the urinary metabolic signature as a non-invasive tool for the early discrimination between non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), which nowadays represents one of the most important challenges in this context, feasible only by carrying out liver biopsy. OBJECTIVES: The aim of the study was to investigate the differences in the urinary VOCs profiles of non-alcoholic fatty liver disease (NAFLD) patients, diabetes mellitus (T2DM) subjects and NAFLD/T2DM patients. METHODS: Headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS) was applied to profile the urinary VOCs. Urine samples were analysed both under acid and alkaline conditions, to obtain a range of urinary volatiles with different physicochemical properties. RESULTS: Urinary VOCs profiles of 13 NAFLD patients, 13 T2DM subjects and 13 NAFLD/T2DM patients were investigated by multivariate and univariate data analysis techniques which allowed to identify 21 volatiles under alkaline conditions able to describe the NAFLD/T2DM group concerning the other two groups. CONCLUSION: Our results suggest that VOCs signatures can improve the knowledge of the pathological condition where NAFLD coexists with T2DM and discovering new features that are not simply the sum of the two diseases. These preliminary findings may be considered as hypothesis-generating, to be clearly confirmed by larger prospective investigations.

Comparative analysis of volatile metabolites, quality and sensory attributes of Actinidia chinensis fruit.

Volatile organic compounds, quality and sensory parameters of four yellow- ('Dorì', 'G3', 'Jintao' and 'Soreli') and two green-fleshed ('Hayward' and 'Summer') kiwifruit cultivars were assessed. Statistical analysis was performed on volatiles, quality and sensory data for the identification of biomarkers of different kiwifruit cultivars. Principal component analysis showed that for all six samples a very good discrimination based on the cultivar was achieved. In particular, 2-pentylfuran can be used to distinguish between the green- and yellow-fleshed kiwifruit cultivars, while seven volatiles, can be identified as biomarkers of 'Dorì'. These findings are in agreement with the sensory analysis, which revealed that 'Dorì', the richest cultivar in esters, showed very high values of both ripe fruit smell and sweet sensory traits. Altogether, these results could offer recommendations for future breeding efforts for the production of kiwifruit cultivars with improved nutritional and aroma quality.

Volatile metabolites, quality and sensory parameters of "Ferrovia" sweet cherry cold stored in air or packed in high CO2 modified atmospheres.

Volatile organic compounds, quality and sensory attributes of sweet cherry cv "Ferrovia", cold packaged in Air or in different modified atmospheres (Low-O2 = 1% O2/0.03% CO2; High-CO2 = 16% O2/20% CO2; Mix = 1% O2/20% CO2), were monitored until 21 days of conservation. Results showed that sweet cherry cv "Ferrovia" is sensitive to CO2 accumulation (over 20%) in low oxygen (about 1%) modified atmosphere, as showed by the increase in respiration rate, biosynthesis of fermentative volatile metabolites, and sensory perception of off-odours. However, High-CO2 treatment seemed to preserve quality and sensory traits, presumably due to the high initial concentration of O2 (16%) that could limit the synthesis of ethyl esters and γ-butyrolactone, keeping the accumulation of off-flavours below their sensory perception threshold. Finally, PLSR analysis allowed to select 1-pentanol as putative marker of sensory alteration and hexanal and 2-hexenal as possible predictors of freshness for "Ferrovia" sweet cherries.

Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.

Background: The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer. Patients and methods: Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS). Results: Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5-63.7] for combination therapy, and 60% (95% CI: 47.8-72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6-12.7) for combination therapy, and 6.5 months (95% CI: 5.4-8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4-1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3-0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months. Conclusion: Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. Clinical trial information: NCT02549430.

Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer.

Skeletal metastases from thyroid cancer are poorly responsive to medical or radioiodine treatment. Bone destruction in skeletal metastases results from osteoclast-induced bone resorption. Therefore, a new approach in the therapy of bone metastases consists in using aminobisphosphonates, such as pamidronate, which are potent inhibitors of osteoclastic activity. In the present study, 10 thyroid cancer patients with painful osteolytic bone metastases were administered pamidronate (90 mg, as a 2 hour intravenous infusion) monthly for 12 consecutive cycles. Bone pain, quality of life, performance status, analgesic consumption and disease staging were evaluated before and during the trial. The patients who had been administered pamidronate showed a significant decrease in bone pain (P = 0.0052). Performance status improved nearly significantly (P = 0.051), while the quality of life showed a remarkable amelioration. However, no significant decrease in analgesic consumption was recorded. Partial radiographic response of bone lesions was observed in 2/10 patients. The side effects of pamidronate were mild and transient. In conclusion, monthly infusion of pamidronate is a well-tolerated treatment that induces significant relief from bone pain and improves the quality of life of thyroid cancer patients with symptomatic and osteolytic bone metastases.

Cancer patients as 'experts' in defining quality of life domains. A multicentre survey by the Italian Group for the Evaluation of Outcomes in Oncology (IGEO).

Although the subjective nature of quality of life is generally accepted, less attention has been paid to the procedure of selecting domains to be explored with questionnaires. To explore what contributes to cancer patients' quality of life, a survey was conducted with the aim of identifying contents of quality of life using cancer patients as 'experts'. A questionnaire with open-ended items aimed at exploring the meaning of quality of life and at determining the contents of health and not health related quality of life, was submitted to a sample of cancer patients stratified by residence, cancer site and stage of disease. The 248 questionnaires received were transcribed and broken down into phrases to allow coding. A content analysis was performed, using as a conceptual framework, the domains identified by the Italian Society of Psycho-Oncology. Overall, 43 domains and a list of symptoms were identified. The two most frequently reported symptoms were pain (21.4% patients) and fatigue (14.1% patients). Social relationships and psychological domains were heavily represented. Twenty sub-domains related to the domain 'psychological well-being'. This study suggests that information on the content of quality of life questionnaires to be submitted to people affected by a specific disease, should be derived by studying people suffering the specific disease. These results reinforce the criticism that available quality of life instruments are more likely to reflect the perspective of health professionals than patients.

Interferon alpha-2b at low doses as long-term antiangiogenic treatment of a metastatic intracranial hemangioendothelioma: a case report.

We describe a case of intracranial haemangioendothelioma in a 20-year old female patient who presented severe neurological symptoms and relapsed after two surgical interventions. The patient was treated with low doses of recombinant interferon alpha-2b (1 MUI three times a week) after surgical resection which led to recovery of daily function and work activity. To our knowledge, this is the ninth patient reported with intracranial hemangioendothelioma, but the only one having diffuse and painful bone metastases resolved by treatment with interferon. After 30 months the patient is free from symptoms and recurrence. The effectiveness shown by recombinant interferon alpha-2b against vascular neoplasms prompted us to look for the possible biological basis of such a property.

Role of surgery in thymic disorders.

Thymomas are relatively slow-growing neoplasms that should be considered malignant tumours. When treated in the early stages, however, they have an excellent prognosis for long-term survival. Surgery, radiation therapy and chemotherapy all play a role in the management of these neoplasms. Surgery is the treatment of choice in thymoma patients and has become an increasingly accepted procedure in the treatment of myasthenia gravis (MG) since 1936, when thymectomy was performed for this disease for the first time. Improvement in myasthenic symptoms is nearly always observed following thymectomy, but the rates of complete remission vary from 7% to 63%. We have studied the potential preoperative factors predicting the evolution of MG.

Role of somatostatin analogue-based therapy in unresponsive malignant thymomas.

Thymomas are rare neoplasms that are usually associated with parathymic syndromes, pure red cell aplasia, myasthenia gravis, hypogammaglobulinaemia and other mainly immunological disorders. Therefore, the management of thymoma patients is often complex and presents many diagnostic and therapeutic issues. Controversies concerning the definition of the histological subtypes and the role played by thymoma-associated syndromes are of primary importance in determining the oncological approach. Although low-stage thymomas have a high percentage of recovery, thymomas which are locally advanced, metastatic or previously treated with standard therapeutic options have no well-defined and effective treatment approaches. The data previously described by us on somatostatin receptor scintigraphy showing high uptake of indium-labelled octreotide by thymic masses and the successful treatment of a patient with thymoma and pure red cell aplasia with octreotide and prednisone has provided us the rationale for using such treatment in patients with advanced thymoma.

Immunological findings in thymoma and thymoma-related syndromes.

Human thymoma is a neoplasm of thymic epithelial cells associated with several clinical syndromes ranging from autoimmune disease to immunodeficiency. The aim of our research was to investigate T cell-mediated immune response in patients with thymoma. Initially eight patients were enrolled in this study. Four patients underwent surgical removal of the thymus, while four were submitted to diagnostic procedures only. Inversion of the CD4:CD8 ratio was found in three patients. Only one subject displayed a normal CD19 count in peripheral blood. The mean value (+/-SD) of the CD19 percentage in the patient group was 2 +/- 2.2. Notably, the patients with thymoma had fewer mature B lymphocytes than the thymectomized patients. The T-cell receptor (TCR) repertoire was investigated in three individuals affected by thymoma: one underwent thymectomy, while the two others, one of which presented with lymphocytosis, were submitted to diagnostic biopsies only. The preliminary results showed a marked alteration in the CD8 repertoire of the thymectomized patient but not in that of the lymphocytotic patient. However, alterations in the TCR repertoire were also found in one patient with thymoma. Altogether, these preliminary findings reveal that loss of CD19+ lymphocytes in peripheral blood is a frequent phenomena in thymoma patients. In this article we discuss this aspect in the context of alterations of the TCR repertoire.

The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer.

To increase the dose-intensity of two drugs in metastatic breast cancer, we tested the feasibility, in phase I studies, of two schedules of epirubicin (E) and cyclophosphamide (C) - sequential (E--> C) and alternating (E/C) - with respect to the standard combination (EC). Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8%). Non-haematological toxicity was mild: about 20% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61% of patients) and bone pain (55.5% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active.

Daily low-dose subcutaneous recombinant interleukin-2 by alternate weekly administration: antitumor activity and immunomodulatory effects.

A phase II clinical trial of subcutaneous recombinant Interleukin 2 (rIL-2) given by 5 days pulses followed by a 9 days rest has been performed in patients affected by renal cell carcinoma, malignant melanoma and colorectal cancer. A total of 25 patients entered the study, completed at least six courses of treatment, and were evaluable for toxicity and response to treatment. This schedule of subcutaneous rIL-2 was well tolerated and no World Health Organization grade 3 side effects were observed. A 33.3% response rate was recorded in patients affected by renal cell carcinoma, although no major responses were achieved in patients with malignant melanoma and colorectal cancer. A durable increase of natural killer activity retained by poeripheral blood mononuclear cells was demonstrated in these patients and was paralleled by increased serum levels of interferon gamma and tumor necrosis factor a without changes of circulating interleukin-1d. It is concluded that this schedule of pulse administration of subcutaneous rIL-2 has antitumor activity in renal cell carcinoma and produces durable biomodulatory effects.

[Evaluation of quality of life in oncology. Rationale and objectives of the first phase of the Quality of Life in Oncology project]. / La valutazione della qualità di vita in oncologia. Razionale ed obiettivi della prima fase del progetto QvOnc.

Although the subjective nature of quality of life perception is generally accepted, less attention has been paid to the procedure of selecting domains to be explored with questionnaires. In most cases domains are selected by panel of experts. It is not known whether these domains are relevant for the patients. Moreover, questionnaires developed in 'foreign' countries may not be culturally sound or relevant for patients living in different cultural background. In order to explore what really contributes to quality of life of Italian patients, a survey was conducted with the aim of identifying any dimension of quality of life, positively or negatively impacted on from the illness and therapies. A sample of two hundred and eighty eight cancer patients with previously specified characteristics (primary tumor, stage of disease and place of residence) were identified. After consenting to partecipate to the study, a staff member (a physician, a nurse or a psychologist) asked the patient to complete an open-ended questionnaire in the out-patient clinic or at home. This questionnaire, partially derived from a study by Padilla et al. made up of 5 questions: 'What does the term quality of life mean to you?', 'What contributes to a good quality of life?', 'What contributes to a poor or bad quality of life?', 'Which either physical or psychological symptom interferes with your quality of life?', 'State any positive or negative change in your quality of life, due to illness or treatments'. The first question was asked to explore the meaning of quality of life for the patient; the second and third question were asked to determine the contents of quality of life not health related; the fourth question and the diary provided information about quality of life contents related to his own experience of disease. Two hundred and forty eight questionnaires (86.1%) were obtained from 7 Cancer Centres participating to the study (Genova, Milano, Roma, Perugia, Napoli, Cagliari, Palermo). All the questionnaires were transcribed and subsequently broken down in phrases on a form that allowed coding. Three raters (a research nurse, an oncologist and a clinical psychologist) made the content analysis using as conceptual framework the list of domains identified by the Italian Society of Psycho-Oncology. The present study shows the possibility to define the content domain of quality of life attributes for cancer patients, using patients as experts.

Prognostic-significance of multifocality in primary breast-cancer.

The impact of multicentricity in primary breast cancer on relapse or death after radical or modified radical mastectomy was evaluated in 1336 consecutive patients. Multiple tumor foci were found in 11.7% of breast cancers: in 8.4% multicentricity was infiltrating, while in 3.3% of cases an in situ growth pattern was observed. There was a statistically significant association between multicentric primaries and lobular infiltrating carcinoma, age less than or equal to 50 years, large tumors and metastatic axillary nodes, while no relationship was observed with histological grade. Both 5-year disease-free survival and overall survival were shorter in patients with infiltrating multicentric primary tumors. Multivariate analysis confirmed the prognostic role of infiltrating multicentric tumors after adjusting for nodal status, tumor size, age and adjuvant therapy.