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This contribution illustrates the preliminary results of the research activities carried out within the PhD in Information and Communication Technology for Health (ICTH) on the topic of Delivery Manager of Cognitive Computing for Neuroncology, at the Department of Electrical Engineering and Information Technologies (DIETI) of the University of Naples “Federico II”. Main goal of this research activity is the development of computational models based on Visual Recognition and Cognitive Computing algorithms for the analysis of Magnetic Resonance Imaging (MRI) derived data in patients with brain neoplasm of unknown origin, in order to obtain a semi-supervised classification model which allows the timely identification of various brain tumors types, requiring therapeutic strategies and clinical-radiological monitoring different from each other. The final purpose of this research activity is to propose a cognitive computing-based support able to supplement information that can help the neuroradiologist in decision-making for daily clinical practice.

Background Both docetaxel and androgen-receptor-axis-targeted (ARAT) agents are approved in metastatic castration-sensitive prostate cancer (mCSPC) patients. Predictive factors of therapy efficacy are lacking. Methods We included articles reporting data about randomized-controlled clinical trials (RCTs) testing an ARAT agent plus ADT vs. ADT. We aimed to obtain pooled estimates of efficacy outcomes and assess differences in pooled estimates of efficacy outcomes between sub-groups. Results A total of 5427 mCSPC patients enrolled in five RCTs were evaluable for OS (Overall Survival) and PFS (Progression-free survival). Pooled OS-HR (Hazard Ratio) was 0.66 (95 % CI: 0.60−0.74), while pooled PFS-HR was 0.46 (95 % CI: 0.40−0.53). Combined treatment with docetaxel was associated with differential OS outcomes, while tumor volume according to the CHAARTED criteria and visceral metastasis were associated with differential PFS outcomes. Conclusion Our results add evidence that ARAT agents improve OS in mCSPC and discourage their combined use with docetaxel in this setting.

Background: Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks. Methods: In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m2 dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1 hour every 2 weeks at either 120 or 140 mg/m2 doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24). Results: Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140 mg/m2 dose level and in 3 of 31 patients treated at 120 mg/m2. Median PFS and overall survival were 12.1 (1–40.2) weeks and 19.7 (1–102) weeks, respectively. Conclusion: We conclude that fotemustine can be safely administered at 120 mg/m2 biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80 mg2 and the standard weekly schedule at 80 to 100 mg/m2.

Aim: To assess the efficacy and safety of alternative fotemustine administration schedule in elderly patients with recurrent glioblastoma. Patients & methods: Patients aged >65 years with recurrent glioblastoma received fotemustine (80 mg/m2; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety. Results: 58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3–4 hematological toxicities occurred. Conclusion: The alternative fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.

UNLABELLED What's known on the subject? and What does the study add? Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? We show that (i) docetaxel re-treatment, after a treatment-free interval, preserves activity; (ii) the treatment is especially well tolerated in patients who were effectively pretreated with docetaxel; and (iii) it could be speculated that combining docetaxel with other agents in this setting might be safe and result in greater activity. OBJECTIVE To determine the activity and tolerability of docetaxel re-treatment after first-line therapy with docetaxel in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re-treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as >50% prostate-specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression-free survival (PFS) and overall survival (OS). RESULTS Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1–2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months. CONCLUSIONS Docetaxel re-treatment preserves anti-tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.

2047Background: The Stupp regimen for newly diagnosed glioblastoma (GBM) consists of radiotherapy with concomitant and adjuvant temozolomide (TMZ) up to 6 cycles. A number of Institutions prolong the duration of the adjuvant chemotherapy up to 12 or more cycles, but it is unknown whether the prolongation of the adjuvant phase favorably impacts the length of survival. The aim of this retrospective study was to investigate this issue in an homogeneous population of GBM patients (age 18-70 years), receiving the Stupp regimen and the nitrosourea fotemustine at first relapse. Methods: Patients were collected through a national registry (Gliostry), that was established by the Italian Association for Neuro-Oncology (AINO). The survival of 556 patients receiving up to 6 cycles of TMZ was compared with that of 365 patients receiving more than 6 cycles of TMZ. Results: Median PFS following the Stupp regimen was 8.4 months for the group TMZ ≤ 6 cycles and 14.3 months for the group TMZ ˃ 6 cycles (p < 0.001). The adv...

What's known on the subject? and What does the study add? Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving10 patients each, showed that cisplatin plus continuous infusion of 5-fluorouracil (5-FU) may be effective and well tolerated. Cisplatin, methotrexate and bleomycin, cisplatin and irinotecan and taxanes can also play an important role for patients with locally advanced/metastatic SCCP. Finally, anti-EGFR therapy may also be effective in advanced SCCP. Although cisplatin plus continuous infusion of 5-FU is widely used in clinical practice for palliation of SCCP, toxicity and efficacy data regarding this schedule include a total of 14 patients with SCCP, treated more than two decades ago. In our retrospective study, cisplatin plus continuous infusion of 5-FU was used for palliative purposes in a homogenous sample of 25 patients with SCCP. Partial responses and stable disease were observed in 8 (32%) and 10 (40%) patients, respectively, with a median progression-free survival of 20 weeks. Neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. These data provide confirmation that such a combination regimen is moderately effective and well tolerated in patients with SCCP.• To investigate the activity and toxicity of 5-fluorouracil (5-FU) as a first-line treatment in metastatic squamous cell carcinoma of the penis (SCCP).• The medical records of 78 patients with SCCP treated between January 2000 and June 2011 at the four participating centres were reviewed. • Data regarding patients treated with first-line 5-FU were extracted. • Patients were included in the study if radiological reports were available for determination of response and progression-free survival (PFS) according to response evaluation criteria in solid tumours (RECIST) 1.1.• Between January 2000 and June 2011, 25 patients were treated with i.v. cisplatin on day 1 followed by 5-FU as a continuous 24-h infusion for 4 days every 3 weeks until disease progression or unacceptable toxicity. Partial responses and stable disease were observed in eight (32%) and 10 (40%) patients, respectively, with a disease control rate of 72%. • Severe neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. • The median (interquartile range [IQR]) PFS was 20 (11-20) weeks and the median (IQR) overall survival (OS) was 8 (7-12) months.• 5-FU is associated with a moderate response rate and is well tolerated in patients with metastatic SCCP.

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.

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12-15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood-brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel(®), are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM.

Glioblastoma multiforme (GBM), the highest grade malignant glioma, is associated with a grim prognosis— median overall survival is in the range 12–15 months, despite optimum treatment. Surgery to the maximum possible extent, external beam radiotherapy, and systemic temozolomide chemotherapy are current standard treatments for newly diagnosed GBM, with intracerebral delivery of carmustine wafers (Gliadel). Unfortunately, the effectiveness of chemotherapy can be hampered by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which confers resistance both to temozolomide and nitrosoureas, for example fotemustine and carmustine. MGMT activity can be measured by PCR and immunohistochemistry, with the former being the current validated technique. High-dose chemotherapy can deplete MGMT levels in GBM cells and has proved feasible in various trials on temozolomide, in both newly diagnosed and recurrent GBM. We here report the unique case of a GBM patient, with high MGMT expression by immunohistochemistry, who underwent an experimental, high-dose fotemustine schedule after surgery and radiotherapy. Although treatment caused two episodes of grade 3–4 thrombocytopenia, a complete response and survival of more than three years were achieved, with a 30% increase in dose intensity compared with the standard fotemustine schedule.

Both typical carcinoid and atypical carcinoid (AC) of the lung are surgically curable, but AC carries a considerably worse prognosis because of a relatively high rate of recurrence. Adjuvant therapy can be conducted with radiotherapy, chemotherapy, and somatostatin analogs (SST-As), but its effectiveness in preventing locoregional and distant recurrences is yet to be fully investigated. A 48-year-old woman, presenting with AC, was free of both radiographical and biochemical signs of residual disease, after surgery and chemotherapy. To prevent disease recurrence, she underwent long-term adjuvant treatment based on SST-As. During the 10-year follow-up period, no side effects referable to SST-As have been reported and no evidence of recurrence of the disease has been detected. In consideration of the relatively high recurrence rate of the disease and of excellent tolerance for SST-As, long-term adjuvant treatment based on SST-As could become a therapeutic option for surgically cured patients with AC. Clinical investigations, conducted in large samples of patients, are necessary to evaluate the effectiveness of such an approach.

The correlation between prolactin (PRLR) and oestrogen (ER) or progesterone receptors (PgR) in breast cancer and a possible prognostic significance of PRLR at 10 year follow-up have been investigated in the Naples (GUN) adjuvant trial. A total of 308 pre- and post-menopausal patients with early breast cancer, who entered the trial from 1 February 1978 to 31 December 1983, received randomly Tamoxifen (TM), 30 mg per die for 2 years, or no therapy. PRLR status was known in 229 (74.3\%) patients. Values of specific binding less than 1\% were considered negative. PRLR was positive in 75/229 (32.8\%). ER was assayed in 210/229 (91.7\%) patients and PgR in 188/229 (82.1\%). No significant correlation, by the Spearman test, was found between PRLR and ER or PgR, while ER status was highly interrelated with PgR status. By the Cox model no evidence of an independent prognostic role of PRLR on disease-free survival (DFS) was observed, nor an interaction between PRLR and adjuvant treatment with TM was found.

2054 Background: patients with glioblastoma failing radiotherapy plus temozolomide are treated in Europe with nitrosourea-based regimens, but factors influencing survival are not entirely known.We ...

Purpose: We evaluated the pain response and daily discomfort in patients with painful bone metastases treated by merging Sr-89-chloride and zoledronic acid. The results were compared with those of patients who received 89Sr-chloride or zoledronic acid separately. Methods: 25 patients (12 women; mean age 65 +/- 13 years) chronically treated with zoledronic acid underwent bone pain palliation with 150 MBq of Sr-89-chloride at least 6 months later that bisphoshonate therapy started (group A). 13 patients (6 women; mean age 70 +/- 12 years) received Sr-89-chloride alone (group B) and 11 patients (5 women; mean age 69 +/- 12 years) were chronically treated and continued to receive only zoledronic acid therapy (group C), both constituted the control groups. Patients kept a daily pain diary assessing both their discomfort and the pain of specific sites by using a visual analog scale (VAS), rating from 0 (no discomfort-no pain) to 10 (worst discomfort-pain). These diaries were reviewed weekly for 2 months and three different physicians rated the pain response on a scale of -2 (considerable deterioration) to +2 (considerable improvement). Results: Baseline characteristics were similar in the three groups. The reduction of total discomfort and of bone pain in the group A was significantly greater as compared to group B (P < 0.01) and group C (P < 0.01). During the monitored period, a significant improvement of clinical conditions was observed in the group A, varying the rate from -1 to 1 as compared to both groups B and C in which the rate changed from -1 to 0. Conclusion: Our findings indicate that combined therapy of Sr-89-chloride and zoledronic acid in patients with painful bone metastases is more effective in treating pain and improving clinical conditions than Sr-89-chloride or zoledronic acid used separately

Ten year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%). ER and PgR were assayed by dextran-coated charcoal technique in a single laboratory. The effect of adjuvant TM was significantly related to ER and PgR concentration of the primary tumor. The greatest TM benefit on DFS was evident in patients with the highest levels of receptors. The interaction between the treatment effect and receptor concentration was found whether ER and PgR were considered separately or together.

725 Background: The orally active EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) gefitinib (‘Iressa’, ZD1839) has antitumor activity and additive or synergistic activity when combined with docetaxel in preclinical models (Clin Cancer Res 2000; 6: 2053–63). This Phase II study investigated gefitinib and docetaxel as first-line combination therapy in patients with metastatic breast cancer. Methods: Fourteen patients received gefitinib (250 mg/day orally) and docetaxel (75 mg/m2 iv) on Day 1 every 3 weeks. If there was no unacceptable toxicity, up to 28 additional patients would receive gefitinib and docetaxel (100 mg/m2 iv). After 6 cycles, patients would continue on gefitinib monotherapy until disease progression or unacceptable toxicity. RECIST and Kaplan-Meier analyses were used to evaluate response or median duration of response and time to progression, respectively. Results: From August 2002 to November 2003, 28 patients were enrolled (14 at each docetaxel dose) and evaluated for...

9673 Background:Cardiac side effects of several antineoplastic drugs are dose-limiting and dose-dependent, thus they are a limitation to the optimal delivery of dose-intensive chemotherapy. Aim of present study was to construct a model to evaluate cardiac damage after chemotherapy. Methods: 45 male Sprague-Dawley rats, about 7 weeks old and weighing 200–225 g were divided into two groups: one group of 30 rats, each animal receiving 5Fluoruracil, 20 mg/kg/wk by intraperitoneal injection, Epirubicin, 3 mg/kg/wk by intravenous injection, Cyclophosphamide, 20 mg/kg/wk by intraperitoneal injection once weekly for 3 consecutive weeks (FEC group) and a second group of 15 rats receiving no drugs (Control group). Observation for mortality and clinical signs was carried out daily, body weight and blood pressure were recorded basally, before each drug administration and weekly until sacrifice. 15 animals, 10 in the FEC group and 5 in the control group, were sacrificed at weeks 3, 5 and 6 after the end of treatment. ...

The effect of adjuvant CMF (cyclophopshamide, methotrexate, and 5-fluorouracil) and tamoxifen (TM) on hypothalamic-pituitary-ovarian function was studied in 120 women with stage I-II operable breast cancer. Sixty patients were premenopausal, of whom 25 were treated with CMF for 9 cycles, 25 with CMF for 9 cycles + TM for 2 years, started concurrently, and 10 with TM alone for 2 years. Sixty patients were postmenopausal and they were all treated with TM alone for 2 years. In all groups treatment was started within 4 weeks of mastectomy. Plasma levels of estrone (E1), estradiol-17β (E2), follicle-stimulating hormone, luteinizing hormone (LH), prolactin (Prl), testosterone (T) and thyroid-stimulating hormone (TSH) were determined in all patients before surgery and again at 3-month intervals from initiation of the adjuvant therapy. In ten patients of each treatment group FSH-LH and Prl-TSH release was determined following stimulation with releasing hormones. CMF and CMF + TM therapy resulted in amenorrhea in 42/50 premenopausal patients with decrease of E1 + E2 (p < 0.001) and elevation of FSH (p < 0.001) and LH (p < 0.01) plasma concentration to postmenopausal levels. In premenopausal women treated with TM a marked increase of E1 + E2 (p < 0.001) was observed with unaltered FSH-LH plasma concentration. A significant fall of Prl also occurred in these patients. In postmenopausal women and premenopausal patients with CMF-induced amenorrhea TM produced a marked fall of FSH-LH and a decrease of Prl plasma level. Plasma TSH and T were not affected in any patient by any of the treatment regimens. The results of the stimulatory tests are in agreement with the hormonal changes observed under basal conditions and indicate that, whereas CMF suppresses the ovary and does not alter hypothalamic-pituitary function, TM induces profound changes of the hypothalamic-pituitary-ovarian axis.

Treatment with tamoxifen (TM), alone or in combination with cyclophosphamide, methotrexate, and fluorouracil (CMF), was used as an adjuvant to surgery in 433 patients with stage I, II, or III(T3a) breast cancer. Oestrogen receptors (ER) and progesterone (PgR) receptors were assayed in most cases. 308 premenopausal node-negative and postmenopausal node-negative or node-positive patients were randomised to receive TM, 30 mg daily for 2 years, or no further therapy. 125 premenopausal node-positive patients were randomised to receive either CMF for nine courses plus TM or CMF alone. After a median follow-up of 63 months TM significantly reduced the incidence of relapses and deaths compared with no therapy. A significant interaction between treatment effect and ER/PgR status was seen. Disease-free and overall survival were similar after treatment with CMF + TM or CMF.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. No effective systemic treatment has been established, except for sorafenib chemotherapy. In fact, sorafenib has proved to provide a statistically significant survival extension of about two months in two phase HI trials in the North America-Europe area and in the Asia-Pacific area, which respectively reported a median survival after treatment of 10.7 and 6.5 months, respectively. We report the case of an HCC patient, who received a four-month therapy with sorafenib with a clinical, biochemical and radiographic response, but had to interrupt treatment because of a myocardial infarction. Surprisingly, despite no antitumor treatment having been administered for about a year, the patient has shown no tumor progression and is currently on a close follow-up. Should other similar cases be presented, a subset of patients with long-lasting response to sorafenib might be identified. Copyright © by BIOLIFE, s.a.s.