Papers by Daniele Santini
Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) ... more Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC. Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed. Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; P<0.05). RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.
Cancer treatment reviews, 2015
RCC is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, una... more RCC is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Evasion of immune surveillance, a process defined immune-editing, leads to malignant progression. The striking improvement of knowledge in immunology has led to the identification of immune checkpoints (such as CTLA-4 and PD-1), whose blockage enhances the antitumor immunity. The interaction between PD-1, an inducible inhibitory receptor expressed on lymphocytes and DCs, and PD-L1 ligand, expressed by tumor cells, results in a down-regulation of the T-cell response. Therefore, the PD-1/PD-L1 axis inhibition by targeted-antibodies, increasing the T-cell proliferation and cytotoxicity, represents a promising mechanism to stimulate the anti-tumor activity of the immune system, improving the outcomes of cancer patients. Several PD-1 and PD-L1 inhibitors have been evaluated in different tumor types, showing promising results. The interesting correlation between ly...
Cell death & disease, 2013
Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term res... more Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cel...
La Clinica terapeutica, 2010
Sunitinib malate (SU11248) is a multitarget oral tyrosine kinase receptor (RTKs) inhibitor which ... more Sunitinib malate (SU11248) is a multitarget oral tyrosine kinase receptor (RTKs) inhibitor which was approved by FDA in renal cells carcinoma (RCC) and imatinib-resistant or imatinib-intollerant gastrointestinal stromal tumour (GIST). Sunitinib is able to inhibit RTKs such as receptors for platelet-derived growth factor (PDGF-R alpha and beta) and for vascular endothelial growth factor (VEGFRs). It is able to inhibit KIT receptor, colony stimulating factor type 1 receptor (CSF- 1R), glial cell line neutrophic factor receptor (RET), fms-like tyrosine kinase receptor-3 (FLT-3 or CD135), signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in tumour cells. Many sunitinib targets play important roles in growth and survival of human breast cancer (BC). The "rationale" of sunitinib in BC (with or without others antiagiogenetic therapy) is its ability to block simultaneously intracellular portion of RTKs inhibiting many downstream signals. We over...
British journal of cancer, Jan 12, 2010
European review for medical and pharmacological sciences, 2010
Biliary Tract Cancer is a rare and aggressive tumor characterized by unresponsiveness to chemothe... more Biliary Tract Cancer is a rare and aggressive tumor characterized by unresponsiveness to chemotherapy and radiotherapy in the vast majority of cases. Surgery offers the only possibility of a cure, though post-operative disease recurrence is common. Only few randomized trials with few patients have been conducted to in this setting of patients and standard chemotherapy has not been established yet. This article summarizes the most important clinical trials regarding chemotherapy for biliary tract cancer and the first evidences regarding the adjuvant treatment. Moreover the clinical trials evaluating targeted therapy will be described, especially those assessing the role of anti-EGFR and antiangiogenic agents.
British journal of cancer, Jan 4, 2008
No established second-line chemotherapy is available for patients with advanced gastric cancer fa... more No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20-40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16-2.77; P=0.008), haemoglobin </=11.5 g l(-1) (HR, 1.48; 95% CI, 1.06-2.05; P=0.019), CEA level >50 ng ml(-1) (HR, 1.86; 95% CI, 1.21-2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16-2.53; P=0.006), and time-to-progression under first-line chemotherapy </=6 months (HR, 1.97; 95% CI, 1.39-2.80; P<0.0001). A prognostic index...
European review for medical and pharmacological sciences
We report a case of an adult woman with an Eagle's Syndrome (ES) treated with medical therapy... more We report a case of an adult woman with an Eagle's Syndrome (ES) treated with medical therapy. ES is characterized by an aspecific orofacial pain secondary to calcification of the stylohyoid ligament or elongated styoid process. In about 4% of general population an elongated styloid process occurs, while only about 4% of these patients are symptomatic. We report a case of a 49-year-old lady with a 1-year history of oro-pharyngeal foreign body sensation localized at the left tonsillar fossa, associated with a dull intermittent pain. A bony projection was palpable with bimanual transoral exploration. A lateral radiograph and a computed tomography scan of head and neck showed an elongated styloid process of 57 mm on the left side and 48 mm on the right one. The patient refused surgical treatment as first choice. She underwent a non-steroidal anti-inflammatory local treatment, with progressive disappearance of symptoms. After 6 months she had no recurrence of symptoms. In conclusion...
BMC cancer, 2006
Elderly patients have been often excluded from or underrepresented in the study populations of co... more Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%-56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall...
BMC cancer, 2006
The combination of capecitabine and gemcitabine at Fixed Dose Rate (FDR) has been demonstrated to... more The combination of capecitabine and gemcitabine at Fixed Dose Rate (FDR) has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. FDR gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. The goals of this phase I study were to determine the maximum-tolerated dose (MTD) of chronomodulated capecitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT), the safety profile of this way of administration. Patients with advanced solid tumours who had failed to response to standard therapy or for whom no standard therapy was available were eligible for this study. Capecitabine was administered orally according to following schedule: 1/4 of dose at 8:00 a.m.; 1/4 of dose at 6:00 p.m. and 1/2 of dose at 11:00 p.m. each day for 14 consecutive days, followed by a 7-day rest period. All 27 patients enrolled onto the study were assessable for toxicity. The mo...
Histology and histopathology, 2006
It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic change... more It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. The recent progress of scientific research has notably increased knowledge about biological events involved in lung cancer pathogenesis and progression, thanks to the use of molecular biology and immunohistochemistry techniques. Lots of the genetic alteration found in small cells lung cancer (SCLC) and in not small cells lung cancer (NSCLC) concern the expression of cell cycle genes, actually recognized as onco-suppressor genes and the lack of equilibrium between oncogenes and oncosuppressor genes. The present review of literature widely describes the cell cycle control, the lung cancer molecular pathogenesis, the catalog of known genetic alterations and the recent advances in global expression profiles in lung tumors, on the basis of the various hystological types too. Such data suggest the ...
Medical oncology (Northwood, London, England), 2004
The primary aims of this study were activity and toxicity evaluation of a new raltitrexed and oxa... more The primary aims of this study were activity and toxicity evaluation of a new raltitrexed and oxaliplatin-based regimen, as a first-line chemotherapy, in patients with metastatic colorectal cancer (MCC). Survival evaluation was considered a secondary endpoint. Forty-four patients were enrolled into this phase II trial. Treatment consisted of raltitrexed 3 mg/m2 iv on d 1 and oxaliplatin 70 mg/m2 iv on d 1 and d 8 every 3 wk. Twenty patients (45.5%) achieved a response [95% confidence interval (CI): 30.1% to 54.1%], 18 (40.9%) had stable disease, and only 6 (13.6%) developed progressive disease. After a median follow-up time of 14.7 mo (range 6.3-18.6 mo), the median time to disease progression was 6 mo (range 2.0-16.7) (95% CI: 4.4-7.6) and the overall survival was 14.8 mo (range 3-23) (95% CI: 11.2-18.4). Neutropenia was the most common hematological side effect, while transient AST/ALT increase, neurotoxicity, asthenia, and diarrhea were the most common nonhematological side effec...
British journal of cancer, Jan 20, 2003
The incidence of gastric cancer (GC) increases significantly after the fifth decade and palliativ... more The incidence of gastric cancer (GC) increases significantly after the fifth decade and palliative chemotherapy is the ultimate treatment in the majority of patients. We investigated safety and efficacy of a weekly regimen with cisplatin, fluorouracil and leucovorin as first-line chemotherapy for elderly patients with advanced GC. Chemotherapy-naive patients older than 65 years were considered eligible for study entry. Frail elderly patients were identified and excluded according to the following criteria: age >85 years, dependence in one or more activities of daily living (activities of daily living and instrumental activities of daily living scales), three or more comorbid conditions, one or more geriatric syndromes. Chemotherapy consisted of 1-day per week administration of intravenous cisplatin 35 mg m(-2), 6S-stereoisomer leucovorin 250 mg m(-2) and fluorouracil 500 mg m(-2) (PLF). Patients were re-evaluated after eight weekly cycles and six additional weekly administrations...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2003
The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to... more The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug. Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050...
Anticancer research
Colorectal cancer (CRC) is one of the major health problems of the Western world and the proporti... more Colorectal cancer (CRC) is one of the major health problems of the Western world and the proportion of elderly patients with CRC is growing. Raltitrexed ('Tomudex'), a specific thymidylate synthase inhibitor, has shown efficacy and manageable toxicity in elderly CRC patients. In this retrospective study, the tolerability of raltitrexed in patients with CRC was examined in relation to age. Toxicity parameters, graded according to World Health Organization criteria, were assessed in two patient groups: < 70 and > or = 70 years old. In total, 56% (50 out of 90) of patients treated with raltitrexed (3 mg/m2 as a 15-minute intravenous infusion every 3 weeks) were aged > 70 years (M:F 28:22; Eastern Cooperative Oncology Group performance status 0-1:2 38:12). Overall, 437 cycles of chemotherapy were administered and grade 3-4 toxicity was reported in < 10% of patients. There were no clinically significant differences between the two age groups, apart from grade 3-4 asth...
Anticancer research
In the past the unfavourable profile of toxicity of antineoplastic drugs employed (i.e. cisplatin... more In the past the unfavourable profile of toxicity of antineoplastic drugs employed (i.e. cisplatinum) weakened the role of chemotherapy in aged patients with non-small cell lung cancer (NSCLC). Recently, new active drugs with lesser toxicity have became widely used in this setting. In this prospective study we evaluated the efficacy and tolerability of gemcitabine in elderly patients with stages III-IV NSCLC. From December 1996 to April 1999, we enrolled 52 previously untreated elderly patients with advanced/metastatic NSCLC. Gemcitabine was administered at 1000 mg/mq i.v. over 30 minutes weekly for three consecutive weeks every 28 days. The planned number of cycles was three while responding or stable patients received chemotherapy until disease progression or the ninth cycle. A total of 291 cycles were delivered with a median number of 6 cycles (range: 3-9). An evaluation of the quality of life was performed every three courses of gemcitabine. After three cycles of treatment, a com...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2002
Recently, new experimental data suggested that, besides inhibiting osteoclasts, bisphosphonate ma... more Recently, new experimental data suggested that, besides inhibiting osteoclasts, bisphosphonate may also have an antitumor effect. Antiangionetetic activity is one of the possible mechanisms of anticancer activity attributed to bisphosphonates. The purpose of this study was to evaluate the modifications in angiogenic cytokines levels after pamidronate infusion. Twenty-five consecutive cancer patients with bone metastases treated monthly with disodium pamidronate infusion were evaluated prospectively for circulating levels of vascular endothelial growth factor (VEGF), gamma-IFN, interleukin (IL)-6, and IL-8 at different time points: just before and after 1, 2, and 7 days after pamidronate infusion. Basal VEGF levels decreased significantly 1, 2, and 7 days after pamidronate infusion. gamma-IFN and IL-6 levels increased 1 day after the infusion but rapidly decreased after 2 days. Moreover, our data showed a statistically significant negative correlation between VEGF and gamma-IFN level...
Medical oncology (Northwood, London, England), 2001
The rates of delayed nausea and vomiting by moderately emetogenic chemotherapy in patients with p... more The rates of delayed nausea and vomiting by moderately emetogenic chemotherapy in patients with previous experience of acute emesis are usually quite high. This is a pilot study aiming to evaluate the safety of a new antiemetic schedule to prevent delayed emesis in this subset of patients. During 5 consecutive cycles of moderately emetogenic chemotherapy, we evaluated 50 patients (15 males) who experienced acute emesis in the first cycle of treatment. The regimen for prevention of delayed emesis consisted of daily tropisetron (5 mg orally from d 2 to d 6 of each chemotherapeutic cycle) associated to ACTH-Depot (1 mg intramuscularly 24 and 68 h after the initiation of chemotherapy). In 77% of chemotherapy cycles, there was a total elimination of nausea and vomiting, whereas in the remaining 23% of cycles, there was a major response defined as < or = 2 vomiting episodes per cycle or nausea grade 1 according to the WHO. The efficacy of the antiemetic regimen persisted during the ent...
Anticancer research
The first cyclin dependent kinase inhibitor to be discovered was the p21 cdk interacting protein ... more The first cyclin dependent kinase inhibitor to be discovered was the p21 cdk interacting protein (a.k.a., WAF1, Cip1, CAP20, Sdi1, mda6). p21 expression may or may not be dependent on p53. This pathway also inhibits DNA replication by merit of p21's interaction with PCNA, but it has also been shown that this same inhibitory interaction with p21 does not affect PCNA DNA repair abilities. We assessed the immunohistochemical expression of p21 protein in 60 curative surgical resected non small cell lung cancers relating it to the expression of PCNA to clarify the contribution of the p21/PCNA pathway to the development of NSCLC. We did not find any relationship between PCNA and p21 expression. This last result may indicate that the mechanism by which PCNA controls the DNA repair is the most important activity of this protein during lung cancer progression and development, compared to its contribution to cell proliferation. In fact, this last event is strongly counteracted by p21 expr...
In vivo (Athens, Greece)
CASE REPORT: The case of a breast cancer patient with a progressive increase of CA 19.9 that indi... more CASE REPORT: The case of a breast cancer patient with a progressive increase of CA 19.9 that indicated gastrointestinal metastasis is reported. After the observation of an increased CA 19.9 serum value (104.00; n.v. 0.0-37.00) a colonoscopy was performed. This examination showed the presence of an erythematous and granular zone near the ileocecal valve. Histological examination of biopsies taken during the colonoscopy revealed atypical monomorphic cells between the organoid pattern of the colon-type ducts. Immunohistochemical staining was positive for cytokeratin 7 and for estrogen receptors, consistent with metastatic epithelial malignancy. After eleven months, the patient presented with signs of intestinal obstruction, requiring an ileocolic bypass. At definitive histological examination, the tumor exhibited features of mammary metastases. CONCLUSION: This is the first report in the literature of an ileocecal valve metastasis from breast cancer diagnosed by an increase of CA 19.9,...
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Papers by Daniele Santini