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In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician’s expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of this class of drugs. Moreover, we describe some of the possible strategies to overcome the mechanisms of resistance and their clinical experimentation, with particular focus on novel mTOR inhibitors and the combinations of mTOR inhibitors and other anti-cancer drugs.

Background Immunotherapeutic drugs, such as domperidone, have been shown to be promising treatments against canine leishmaniosis (CanL), but limited data are available. The aim of this pilot study (therapeutic, prospective and non-controlled) was to evaluate the effect of domperidone on serum antibody titers of Leishmania infantum, globulins, gamma globulins, acute-phase proteins (e.g. C-reactive protein [CRP]), big endothelin-1 (big ET-1), serum creatinine (SC) and proteinuria in dogs with leishmaniosis affected by chronic kidney disease (CKD). Methods Dogs were recruited if “exposed” to or “infected” with L. infantum and affected by CKD (IRIS stage 1 [proteinuric] or IRIS stage 2–3a [SC Results Of the 14 recruited dogs, nine showed a statistically significant reduction in SC (χ2 = 9.1, df = 3, P = 0.028), but not in the urine protein/creatinine ratio (χ2 = 6.43, df = 3, P = 0.092). All dogs showed a significant reduction in antibody titers for L. infantum (χ2 = 9.56, df = 2, P = 0.008), globulins (χ2 = 11.08, df = 3, P = 0.011) and gamma globulins (χ2 = 12.38, df = 3, P = 0.006) during the study period. There was also a statistically significant reduction in CRP (χ2 = 16.7, df = 3, P = 0.001), but not in big ET-1 (χ2 = 2.04, df = 3, P = 0.563). Conclusions This study provides preliminary results on the ability of domperidone to improve SC and reduce anti-L. infantum antibody titers, globulins, gamma globulins and CRP in dogs with leishmaniosis and CKD. Graphical abstract

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design, setting, and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

Introduction: HemoDialysis eXpanded (HDx) represents an innovative strategy to remove uremic toxins of Large-Medium Molecular weight (LMMs, up to 45 Kda) thanks to the medium cutoff membranes (MCO) and internal convection Transcription of pro-inflammatory cytokines in peripheral leukocytes is markedly reduced and removal of soluble mediators of inflammation is enhanced after HDx Also in vitro studies confirmed that HDx is associated with a limitation of neutrophil activation: decrease of ROS, TNF-alpha and IL6 production, and increase of apoptosis The aim of this study is to evaluate the clinical response to treatment with HDx during AKI related to sepsis Methods: An 88 year old woman with a history of ischemic heart disease,heart failure and chronic kidney disease stage III-B KDOQI (eGFR 31 ml/m') had been in his usual state of health until 10 days before admission, when fever developed associated with diarrhea and urinary tract infection (UTI) Treated at home with Ceftriaxone 1 g/day without improvement, for the onset of oligoanuria and the detection of sepsis associated with bronchopneumonia and AKI, she was hospitalized Microangiopathic hemolitic anemia (MAHA) is excluded He then comes to daily renal replacement theraphy (RRT) through sustained low efficiency dialysis (SLED) and start antibiotic therapy with Imipenem and Teicoplanina After 72 hours, for the worsening of leukocytosis, the persistence of high values of inflammation indexes and anuria the patient was undergo to daily HDx using Theranova® 400 (1 7m2, Baxter) Antibiotic therapy was still unchanged After 9 days of this treatment there was a normalization of the inflammation indexes, diuresis recovery and HDx stop At T0-T3-T12 were evaluated: complete blood count, Procalcitonin (PCT), C-Reactive Protein (CRP) and albumin Serum creatinine, urea and the daily urine output have been monitored to follow progression of renal dysfunction Results: HDx (Qb = 255 ± 45ml/min, TT 235 ± 27 m) shows a significant reduction at 12 days for Leukocyte (WBC), Nutrophils, Lymphocytes, Platelets (PLT), PCT and CRP, whereas the albumin is unchanged (Tab 1) HDx also induces relevant RR of Urea (73 5%) and serum creatinine (75 2%) Conclusions: HDx theraphy, through the use of a MCO membrane, effectively is involved on resolution of sepsis and AKI of our patient compared to SLED, despite unchanged antibiotic therapy Probably this is due to interesting results of HDx on inflammation and increased clearance of cytokines His possible support in the treatment of positive COVID-19, in fact, has recently been postulated in some Italian dialysis centers, even in the absence of trials to confirm these evidences [Formula presented] No conflict of interest

Simple Summary This study describes clinical findings in Boxer dogs with renal maldevelopment and proposes a possible mode of inheritance. Medical records of 9 female Boxer dogs, older than 5 months and with a clinical diagnosis of proteinuric chronic kidney disease prior to one year of age, showed the presence of polyuria and polydipsia, decreased appetite, weight loss, lethargy and weakness in all affected dogs. Common laboratory findings were proteinuria and diluted urine, non-regenerative anemia, azotemia, hyperphosphatemia, hypoalbuminemia and hypercholesterolemia. Histopathology of the kidneys identified the presence of immature glomeruli in all dogs. In 7 out of 9 related dogs, the pedigree analysis showed that a simple autosomal recessive trait may be a possible mode of inheritance. Renal glomerular immaturity should be suspected in Boxer dogs with a history of polyuria, polydipsia, decreased appetite, weight loss, lethargy, weakness and proteinuria. A prompt diagnosis of renal maldevelopment, potentially hereditary, may help to evaluate if relatives of the affected dogs might be at risk, thus assisting clinicians in reaching an early diagnosis. A routine clinical renal screening evaluation in this breed, especially when this disease is suspected, should be strongly recommended. Abstract Renal maldevelopment (RM) has been proposed to replace the old and sometimes misused term “renal dysplasia” in dogs. Although renal dysplasia has been described in Boxers, hereditary transmission has only been hypothesized. This study reports clinical and renal histological findings in Boxer dogs with RM, proposing a possible mode of inheritance. Medical records of 9 female Boxer dogs, older than 5 months and with a clinical diagnosis of chronic kidney disease prior to one year of age, were retrospectively reviewed. Polyuria and polydipsia (PU/PD), decreased appetite, weight loss, lethargy and weakness were described in all affected dogs. Common laboratory findings were proteinuria, diluted urine, non-regenerative anemia, azotemia, hyperphosphatemia, hypoalbuminemia and hypercholesterolemia. Histopathology of the kidneys revealed the presence of immature glomeruli in all dogs, which is consistent with RM. In 7 related dogs, the pedigree analysis showed that a simple autosomal recessive trait may be a possible mode of inheritance. Renal maldevelopment should be suspected in young Boxer dogs with a history of PU/PD, decreased appetite, weight loss, lethargy, weakness and proteinuria. Due to its possible inheritance, an early diagnosis of RM may allow clinicians to promptly identify other potentially affected dogs among the relatives of the diagnosed case.

Background:This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events.Patients and methods:Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported.Results:Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3–2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5–3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated ( p = 0.009, p Conclusion:COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

Pregnancy is increasingly undertaken in patients with chronic kidney disease (CKD) and, conversely, CKD is increasingly diagnosed in pregnancy: up to 3 % of pregnancies are estimated to be complicated by CKD. The heterogeneity of CKD (accounting for stage, hypertension and proteinuria) and the rarity of several kidney diseases make risk assessment difficult and therapeutic strategies are often based upon scattered experiences and small series. In this setting, the aim of this position statement of the Kidney and Pregnancy Study Group of the Italian Society of Nephrology is to review the literature, and discuss the experience in the clinical management of CKD in pregnancy. CKD is associated with an increased risk for adverse pregnancy-related outcomes since its early stage, also in the absence of hypertension and proteinuria, thus supporting the need for a multidisciplinary follow-up in all CKD patients. CKD stage, hypertension and proteinuria are interrelated, but they are also independent risk factors for adverse pregnancy-related outcomes. Among the different kidney diseases, patients with glomerulonephritis and immunologic diseases are at higher risk of developing or increasing proteinuria and hypertension, a picture often difficult to differentiate from preeclampsia. The risk is higher in active immunologic diseases, and in those cases that are detected or flare up during pregnancy. Referral to tertiary care centres for multidisciplinary follow-up and tailored approaches are warranted. The risk of maternal death is, almost exclusively, reported in systemic lupus erythematosus and vasculitis, which share with diabetic nephropathy an increased risk for perinatal death of the babies. Conversely, patients with kidney malformation, autosomal-dominant polycystic kidney disease, stone disease, and previous upper urinary tract infections are at higher risk for urinary tract infections, in turn associated with prematurity. No risk for malformations other than those related to familiar urinary tract malformations is reported in CKD patients, with the possible exception of diabetic nephropathy. Risks of worsening of the renal function are differently reported, but are higher in advanced CKD. Strict follow-up is needed, also to identify the best balance between maternal and foetal risks. The need for further multicentre studies is underlined.

Background: Pregnancy during dialysis is increasingly being reported and represents a debated point in Nephrology. The small number of cases available in the literature makes evidence-based counselling difficult, also given the cultural sensitivity of this issue. Hence, the need for position statements to highlight the state of the art and propose the unresolved issues for general discussion. Methods: A systematic analysis of the literature (MESH, Emtree and free terms on pregnancy and dialysis) was conducted and expert opinions examined (Study Group on Kidney and Pregnancy; experts involved in the management of pregnancy in dialysis in Italy 2000–2013). Questions regarded: timing of dialysis start in pregnancy; mode of treatment, i.e. peritoneal dialysis (PD) versus haemodialysis (HD); treatment schedules (for both modes); obstetric surveillance; main support therapies (anaemia, calcium-phosphate parathormone; acidosis); counselling tips. Main results: Timing of dialysis start is not clear, considering also the different support therapies; successful pregnancy is possible in both PD and HD; high efficiency and strict integration with residual kidney function are pivotal in both treatments, the blood urea nitrogen test being perhaps a useful marker in this context. To date, long-hour HD has provided the best results. Strict, personalized obstetric surveillance is warranted; therapies should be aimed at avoiding vitamin B12, folate and iron deficits, and at correcting anaemia; vitamin D and calcium administration is safe and recommended. Women on dialysis should be advised that pregnancy is possible, albeit rare, with both types of dialysis treatment, and that a success rate of over 75% may be achieved. High dialysis efficiency and frequent controls are needed to optimize outcomes.

Kidney transplantation (KT) is often considered to be the method best able to restore fertility in a woman with chronic kidney disease (CKD). However, pregnancies in KT are not devoid of risks (in particular prematurity, small for gestational age babies, and the hypertensive disorders of pregnancy). An ideal profile of the potential KT mother includes “normal” or “good” kidney function (usually defined as glomerular filtration rate, GFR ≥ 60 ml/min), scant or no proteinuria (usually defined as below 500 mg/dl), normal or well controlled blood pressure (one drug only and no sign of end-organ damage), no recent acute rejection, good compliance and low-dose immunosuppression, without the use of potentially teratogen drugs (mycophenolic acid and m-Tor inhibitors) and an interval of at least 1–2 years after transplantation. In this setting, there is little if any risk of worsening of the kidney function. Less is known about how to manage “non-ideal” situations, such as a pregnancy a short time after KT, or one in the context of hypertension or a failing kidney. The aim of this position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology is to review the literature and discuss what is known about the clinical management of CKD after KT, with particular attention to women who start a pregnancy in non-ideal conditions. While the experience in such cases is limited, the risks of worsening the renal function are probably higher in cases with markedly reduced kidney function, and in the presence of proteinuria. Well-controlled hypertension alone seems less relevant for outcomes, even if its effect is probably multiplicative if combined with low GFR and proteinuria. As in other settings of kidney disease, superimposed preeclampsia (PE) is differently defined and this impairs calculating its real incidence. No specific difference between non-teratogen immunosuppressive drugs has been shown, but calcineurin inhibitors have been associated with foetal growth restriction and low birth weight. The clinical choices in cases at high risk for malformations or kidney function impairment (pregnancies under mycophenolic acid or with severe kidney-function impairment) require merging clinical and ethical approaches in which, beside the mother and child dyad, the grafted kidney is a crucial “third element”.

Breast, prostate, lung and kidney cancer all manifest with a high predilection for metastasis to bone, which is a prevalent cause of morbidity, increased risk of death and decreased quality of life for patients. The avidity of some cancers to grow in bone is because of the peculiar microenvironment predisposed by bone. In metastatic prostate cancer, many novel therapeutic agents are programmed to contrast the signal pathway, including the androgen receptor, osteoclast and stromal inhibitors. Therapy with new drugs in prostate cancer has been shown to decrease the risk of skeletal-related complications and, therefore, provide an overall survival and quality of life benefit. An improved sequence of administration of these drugs may improve efficacy.

Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3–4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed “per cycle” incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel. The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis. “Per cycle” incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86–0.93; P 2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86–1; P = 0.07), but decreased odds of having G3 to 4 anemia. Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.

Although Metformin (MT) is a first-line therapy for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of MALA (metformin-associated lactic acidosis), an exceptionally rare but fatal adverse event. Then, the drug is contraindicated in many individuals with impaired kidney function because of concerns of MALA. MT, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma MT concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupt lactate production or clearance (e.g., acute illness in diabetic patients where cardiac, hepatic, pulmonary, or renal function are compromised), are typically necessary to cause MALA. As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, MT has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic MT levels and MALA. However, the reported incidence of MALA in clinical practice has proved to be very low. Several groups have suggested that current renal function cutoffs for MT are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of MT therapy. In keeping with these data the FDA and the EMA recently revised the warning regarding MT. Considering these new recommendations the authors propose a territorial diagnostic and therapeutic path on the use of MT in the Chronic Kidney Disease.

Preeclampsia (PE) is a protean syndrome causing a transitory kidney disease, characterised by hypertension and proteinuria, ultimately reversible after delivery. Its prevalence is variously estimated, from 3 to 5% to 10% if all the related disorders, including also pregnancy-induced hypertension (PIH) and HELLP syndrome (haemolysis, increase in liver enzyme, low platelets) are included. Both nephrologists and obstetricians are involved in the management of the disease, according to different protocols, and the clinical management, as well as the role for each specialty, differs worldwide. The increased awareness of the role of chronic kidney disease in pregnancy, complicating up to 3% of pregnancies, and the knowledge that PE is associated with an increased risk for development of CKD later in life have recently increased the interest and redesigned the role of the nephrologists in this context. However, while the heterogeneous definitions of PE, its recent reclassification, an emerging role for biochemical biomarkers, the growing body of epidemiological data and the new potential therapeutic interventions lead to counsel long-term follow-up, the lack of resources for chronic patients and the increasing costs of care limit the potential for preventive actions, and suggest tailoring specific interventional strategies. The aim of the present position statement of the Kidney and Pregnancy Study Group of the Italian Society of Nephrology is to review the literature and to try to identify theoretical and pragmatic bases for an agreed management of PE in the nephrological setting, with particular attention to the prevention of the syndrome (recurrent PE, presence of baseline CKD) and to the organization of the postpartum follow-up.

BACKGROUND: In the last decade, significant improvements have been achieved in maternal-fetal and diabetic care which make pregnancy possible in an increasing number of type 1 diabetic women with end-organ damage. Optimal counseling is important to make the advancements available to the relevant patients and to ensure the safety of mother and child. A systematic review will help to provide a survey of the available methods and to promote optimal counseling. OBJECTIVES: To review the literature on diabetic nephropathy and pregnancy in type 1 diabetes. METHODS: Medline, Embase, and the Cochrane Library were scanned in November 2012 (MESH, Emtree, and free terms on pregnancy and diabetic nephropathy). Studies were selected that report on pregnancy outcomes in type 1 diabetic patients with diabetic nephropathy in 1980-2012 (i.e. since the detection of microalbuminuria). Case reports with less than 5 cases and reports on kidney grafts were excluded. Paper selection and data extraction were performed in duplicate and matched for consistency. As the relevant reports were highly heterogeneous, we decided to perform a narrative review, with discussions oriented towards the period of publication. RESULTS: Of the 1058 references considered, 34 fulfilled the selection criteria, and one was added from reference lists. The number of cases considered in the reports, which generally involved single-center studies, ranged from 5 to 311. The following issues were significant: (i) the evidence is scattered over many reports of differing format and involving small series (only 2 included over 100 patients), (ii) definitions are non-homogeneous, (iii) risks for pregnancy-related adverse events are increased (preterm delivery, caesarean section, perinatal death, and stillbirth) and do not substantially change over time, except for stillbirth (from over 10% to about 5%), (iv) the increase in risks with nephropathy progression needs confirmation in large homogeneous series, (v) the newly reported increase in malformations in diabetic nephropathy underlines the need for further studies. CONCLUSIONS: The heterogeneous evidence from studies on diabetic nephropathy in pregnancy emphasizes the need for further perspective studies on this issue.

The differential diagnosis of postpartum acute renal failure associated with microangiopathic hemolytic anemia and thrombocytopenia includes, among others: severe preeclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzyme, low platelet), acute fatty liver of pregnancy (AFLP), thrombotic thrombocytopenic purpura/hemolytic uremic syndrome associated with pregnancy (TTP/aHUS), acute onset or flare of SLE in pregnancy and catastrophic antiphospholipid syndrome (CAPS). These conditions are potentially life threatening due to the presence of multi-organ dysfunction. The occurrence of an hypercoagulable state with decreasing concentration of ADAMTS 13 in pregnancy and in postpartum increases the risk of developing thrombotic thrombocytopenic purpura (TTP). Yet there is a considerable overlap of the clinical and laboratory tools detecting these conditions, therefore the diagnosis may be problematic even for experienced clinicians. However, it is important to establish an accurate diagnosis as the m...

ABSTRACT Aims: The intermittent administration of chemotherapy is a means of preserving patients’ quality of life (QL). The aim of this study was to verify whether the intermittent administration of docetaxel (DOC) improves the patients’ QL. Patients & methods: All patients received DOC 70 mg/m2 every 3 weeks for eight cycles. The patients were randomized to receive DOC continuously or with a fixed 3-month interval after the first four DOC courses. Results: The study involved 148 patients. There was no difference in QL between the groups receiving intermittent or continuous treatment. Intermittence had no detrimental effects on disease control. Conclusion: Although feasible and not detrimental, our results showed that true intermittent chemotherapy in metastatic castration-resistant prostate cancer patients failed to improve the patients’ QL.

The coexistence of multiple myeloma (MM) and mycosis fungoides (MF), and hence of both B- and T-cell neoplastic clones, is a rare event. We describe a case of plaque-stage MF associated with IgG lambda MM. The clinical onset of MF preceded that of MM, supporting the hypothesis that MF predisposed to the development of the B-cell proliferative disorder. The skin tumor cells were found to originate from CD4(+) T-lymphocytes, characterized by a V beta 8 receptor and no proviral human T-lymphotropic virus (HTLV)-I monoclonal integration. They also displayed a polarized Th1-type cytokine profile containing mRNAs for interleukin (IL)-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-beta, but not for IL-4, IL-5, or IL-10. The CD8(+)/CD57(+) suppressor-cytotoxic subpopulation was significantly increased in the peripheral blood and was associated with MM progression. Expression of p16INK4A, a gene from the INK family that inhibits cyclin-dependent kinases and regulates the cell cycle, was lacking in MF cells and bone marrow (BM) plasma cells. The p16INK4A gene was silenced by hypermethylation, suggesting that it plays a role in the early phase of the pathogenesis of both diseases. Thus, a lymphoid precursor cell presumably contains aberrations that induce the development of both clonal diseases in a multistep process.

Aim: The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. Patients & methods: Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). Results: Median OS was 17.2 months (95% CI: 15.5–19.6): 19.9 months (95% CI: 15.9–25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1–18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9–6.7): 6.6 (95% CI: 4.9–9.3) and 5.3 months (95% CI: 4.3–6.0) in first- and second-line patients, respectively. Conclusion: The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

ABSTRACT: Aim: Cabazitaxel is a novel taxane that is approved for use in metastatic castration-resistant prostate cancer based on the Phase III TROPIC study, which showed improved overall survival with cabazitaxel/prednisone versus mitoxantrone/prednisone. A global early-access program was initiated in order to provide early access to cabazitaxel in docetaxel-pretreated patients and to obtain real-world data. Patients & methods: We report interim safety results from an Italian prospective, single-arm, multicenter, open-label trial of 218 patients receiving cabazitaxel 25 mg/m2 every 3 weeks plus prednisolone 10 mg/day, until disease progression, unacceptable toxicity, investigator’s decision or death. Results: Patients completing treatment received a median of six cabazitaxel cycles. The most common grade 3/4 adverse events were neutropenia (33.9%), leukopenia (15.6%), anemia (6%) and asthenia (6%). No peripheral neuropathy or nail disorders were observed. Conclusion: These results confirm that cabazitaxel has a manageable safety profile in daily clinical practice and support its use in patients with prostate cancer who progress during or after a docetaxel-based therapy.

The purpose of the study was to examine the relationship between the endothelin-1 (ET-1) concentration and the metabolic variables characteristic of the insulin resistance syndrome ([IRS] hyperinsulinemia, insulin resistance, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, visceral obesity, and glycemic abnormalities). The measurement of circulating ET-1 is a well-recognized marker of endothelial atherosclerotic and cardiovascular disease. Two hundred subjects were divided into 3 groups. Group 1 included 50 subjects with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) with IRS. Group 2 included 50 subjects with IGT or NIDDM without IRS. Group 3 included 100 normal subjects as controls. ET-1 levels were higher in group 1 versus groups 2 and 3 in women (11.2 +/- 0.7 v 7.9 +/- 0.5 and 6.6 +/- 0.4 pg/mL, P.01) and men (10.1 +/- 0.6 v 6.5 +/- 0.8 and 7.2 +/- 0.3 pg/mL, P.01). No differences were found between groups 2 and 3. With simple regression analysis, ET-1 levels significantly correlated with insulin, glycosylated hemoglobin, body weight, waist to hip ratio, and triglyceride values. However, with multiple regression analysis, only triglycerides (P.009) and glycosylated hemoglobin (P.001) remained independently correlated with ET-1. In conclusion, this cross-sectional study indicates that glycosylated hemoglobin and triglycerides are independently correlated with ET-1 levels in patients with IRS.

e16534Background: AA is a potent inhibitor of CYP17; common adverse events include fluid retention and hypertension. In COU-AA-301 study a 13.3% of cardiovascular (CV) toxicity was reported. The ai...

349 Background: Among novel hormonal therapeutic targets for post docetaxel mCRPC, Enzalutamide is an oral androgen-receptor blocker disrupting the androgen-receptor nuclear translocation that significantly increases the OS. In this study we evaluated the potential association of both PTH and Ca levels change in pts with mCRPC after the first Enzalutamide administration. Methods: Between 01 and 05/2015, 20 mCRPC pts relapsed after 2-3 prior lines of therapy (docetaxel, cabazitaxel, abiraterone) have been treated with Enzalutamide that was orally administered at 160 mg/day as continuous dosing. Patient characteristics included: median age 67 years (range 50-84), median baseline PSA 120 ng/ml (range 6-1200), median ECOG P S: 1 (range 0-2), Gleason score ≥ 7. In addition 80% of pts had ≥ 2 metastatic sites. Pretreatment baseline and follow up data including measurement of serum Ca and PTH levels (6.5-36.8 pg/ml), ALP, PSA and QoL parameters were evaluated through all lines of therapy. Pts with bone metastasis received zoledronic acid or denosumab with Ca and vitamin D supplementation. Results: In 18/20 pts with bone disease progression we recorded increased PTH levels and, contrarily, decreased Ca levels after 1 month of Enzalutamide despite vit. D and Ca supplementation. PTH levels remained unchanged after 3 months. In 2/20 pts without bone disease progression PTH ranged normal. All pts reported PSA response ≥ 50%, with improved QoL and are still on treatment since Enzalutamide is well tolerated. We did not find PTH change in bone mCRPC pts treated with prior therapy. Conclusions: Our study showed that increase in PTH levels and reduction in Ca levels and increase in PTH levels after 1 month of Enzalutamide treatment is associated with a dramatic reduction of PSA level. These data support a relationship between PTH and Ca changes in pts treated with Enzalutamide and, thus, their changes level may be adopted in clinical practice as surrogate to reflect the drug activity. No studies have evaluated the variations in serum PTH levels following Enzalutamide treatment and whether these early changes relate to the clinical outcome.

Central nervous system (brain or leptomeningeal) metastases (BLm) are considered rare in castration-resistant prostate cancer (CRPC) patients. Now that docetaxel has become the reference drug for first-line treatment of CRPC, patients whose disease is not controlled by hormonal manipulations may live much longer than before and have higher risk of developing BLm. We retrospectively reviewed the records of all patients with CRPC attending our centres from 2002 to 2010, and identified all of those who were diagnosed as having BLm and received (or were considered to have been eligible to receive) docetaxel-based treatment. We identified 31 cases of BLm (22 brain metastases and 9 leptomeningeal metastases) with an incidence of 3.3%. BLm-free survival was 43.5 months, and survival after BLm discovery was 4 months. With six patients surviving for more than 1 year after developing BLm, the projected 1-year BL-S rate was 25.8%. The findings of our study may be relevant in clinical practice as they indicate that incidence of BLm in CRPC patients in the docetaxel era seems to be higher than in historical reports, meaning that special attention should be paid to the appearance of neurological symptoms in long-term CRPC survivors because they may be related to BLm.

The use of interferon for the induction treatment of multiple myeloma has been shown to be effective in about 20 percent of patients. We studied its effects on long-term survival when it was used for maintenance treatment. Between April 1985 and May 1988, 101 patients with symptomatic multiple myeloma who had had a substantial objective response or a lesser objective response with disappearance of symptoms ("disease stabilization") after 12 courses of induction chemotherapy were randomly assigned to receive recombinant interferon alfa-2b as maintenance therapy (n = 50) or to receive no treatment (n = 51). As of December 1989, 66 of the 101 patients have relapsed (25 given interferon and 41 not treated). The median duration of response (from the time of randomization) was 26 months in the patients given interferon and 14 months in the untreated patients (P = 0.0002). A total of 37 patients have died (14 given interferon and 23 not treated). The median duration of survival (from randomization) was 52 months in the interferon group and 39 months in the control group (P = 0.0526). Among the patients who had had a substantial objective response to induction chemotherapy, the difference in survival time was statistically significant (P = 0.03526). Interferon had to be stopped because of toxic effects in 3 of 12 patients initially treated with 10 MU (megaunits) per square meter of body-surface area. After the dose was reduced to 3 MU per square meter, the only toxic effect was a mild influenza-like syndrome lasting two to three weeks. We conclude that maintenance treatment with interferon prolongs response and survival in patients with multiple myeloma who have responded to conventional induction chemotherapy.

225 Background: Cabazitaxel-based chemotherapy provides a survival benefit after docetaxel failure in patients with prostate cancer. Grade 3-4 neutropenia and febrile neutropenia were relatively frequent in the registrative trial, but their incidence in clinical practice is likely to be lower, as shown by data collected in the Expanded Access Program (EAP). While cumulative doses of docetaxel are associated to neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this study, we assessed 'per cycle' incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel. Methods: The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant side effects identified was assessed using a Generalised Estimating Equations (GEE) model at univariate and multivariate analysis. Multivariate logistic regression analysis was performed using a backward selection procedure. Variables with a p value ⩽0.1 were kept in the final model. Results: Per cycle incidence of grade 3-4 neutropenia was 8.7%, while febrile neutropenia occurred only in 0.9% of cycles and was an early event, occurring during the first three cycles only. Multivariate logistic regression analysis showed that the odds of having grade 3 – 4 neutropenia, febrile neutropenia and anemia were statistically significantly reduced by 10, 48 and 7%, respectively, every 10 mg/m2 increase of total prior dose of cabazitaxel. Interestingly, a body surface area > 2 m2 was associated to increased odds of having grade 3-4 neutropenia. In this regard, it must be noted that all patients with body surface area > 2 m2 had their total dose capped to 50 mg, with a mean (95% CI) and median (IQR) dose reduction of 7.1 (7.58-6.69) and 5.9 (2.76-10.27) % with respect to planned dose. Conclusions: Cumulative doses of cabazitaxel are associated to decreased risk of bone marrow toxicity. Patients with body surface area >2 m2 are at increased risk of bone marrow toxicity and dose capping should be considered. These data indicate that cabazitaxel should not be arbitrarily suspended because of concerns of cumulative toxicity.

e16081 Background: Cabazitaxel (Cab) is a novel taxane for treatment of mCRPC in progression during or after Docetaxel therapy. However, the management of elderly pts also depends on comorbidities that may impact the performance status and influence the treatment decisions. This study was aimed to assess both activity and safety of Cab in a cohort of ≥ 65 yrs aged patients with mCRPC unresponsive to Docetaxel. Methods: Between 11/2011 and 01/2013, 26 pts with mCRPC relapsing after Docetaxel as first line treatment were enrolled following their comprehensive geriatric assessment for eligibility to the study also extended as EAP. The Cab schedule included 25 mg/m2 every three weeks plus 10 mg Prednisone (P) daily. Comorbidities were assessed using the cumulative illness rating geriatric scale (CIRS-G) with 0-4 score. Median age was 73 yrs (65-89), ECOG PS 0-2, median baseline PSA was 107 ng/ml, whereas comorbidities included pneumonia, arterial hypertension, arrhythmias and diabetes. Pts were managed every 3 months by CT, whereas both response rate (RR) and correlations between comorbidities and toxicity were the endpoints of the study. Results: Pts received the CabP schedule with none dose reduction. Minimal adverse effects were recorded as grade 3-4 anemia whereas no episodes of neutropenic fever were observed. Sexteen/26 pts entered in EAP study. Comorbidities were recorded as GIRS-G1-2 in 17 pts, G3 in 7, and G4 in 2. 9/26 pts received total previous docetaxel dose < 1200 mg/tot and 17/26 pts received ≥ 1200 mg/toto. Among the CabP-treated pts, 3 of them showed partial response with one year of median duration and PSA response ≥ 50%, whereas 8 maintained a stable disease with 9 months of median duration and PSA response < 50%. Conversely, 15 pts underwent progression after 5 months of CabP treatment. Conclusions: Our data suggest that comorbidities in mCRPC ≥ 65 yrs aged pts do not interfere with the toxicity of CabP thus supporting its efficacy and safety in older pts unresponsive to previous Docetaxel therapy. Therefore, CabP does not impact the quality of life and emphasizes a proper disease control (PR+SD) in 11/26 pts.

189 Background: A significant percentage of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) progressing during or after a docetaxel (D) based therapy are candidates for additional effective treatments. Taxanes remain the mainstay of treatment for a wide range of tumours including mCRPC. Cabazitaxel, a next generation of taxane, was approved based on results from the TROPIC study (NCT00417079). Cbz plus prednisone (P) was associated with a higher overall survival than mitoxantrone (MTX) (15.1 vs 12.7 mo, HR=0.70; P2(intravenous every 3 weeks) plus P 10 mg (oral daily). Results: Median age was 70 years (21.8% of the cases were ≥75 years); pts with PS 0-1=98.2%; median number of previous D cycles was 8; 30.8% received 450 ÷ 675 mg, 14.7% received 675 ÷ 900 mg and 28.2% received ≥ 900 mg of D. Median time from last D dose to first CbzP dose was 5 months including any other eventual chemotherapy treatment. 49.1% of the pts entered in this EAP because refractory to D (PD during or within 3 months since the last D administration), overall 72 % of pts had 2 or more met sites. At the time of this analysis approximately 50% of pts received 4 cycles. A total of 68 pts discontinued CbzP due to PD (38.2%), AEs related and not related (38.2)%, Investigator’s decision (2.9%) or other reasons (20.6%). The most common G 3/4 AEs were neutropenia (35.2%), leukopenia (17.6%), anaemia (5.5%) febrile neutropenia (4.2%); main non-haematological AEs were asthenia (4.8%) and fatigue (4.2%). Conclusions: This large analysis confirms a manageable safety profile of cabazitaxel in routine clinical practice. The safety profile showed in EAP study suggests cabazitaxel a safe and effective treatment option in mCRPC pts progressing during or after a docetaxel based therapy. Clinical trial information: NCT01254279.

415 Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. Methods: RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. Results: From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 – 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. Conclusions: The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.

e15160 Background: Pts who receive first line for CRPC are usually treated with 8-10 consecutive courses of D. The pts quality of life (QL) may be worsened and an I administration could limit this effect. E is an old drug showing a synergistic action with D. This study is aimed to compare QL of C and I D and whether E added to D improved its activity, in a 2 × 2 factorial design. Methods: CRPC pts were randomized to: C D 70 mg/m2 IV q 3 wks for 8 courses alone (arm A) or with E 280 mg/TID PO for 5 days starting 1 day prior to D (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 128 pts evaluable at this time. The median age was 69 (range 42-81) and the median baseline PSA was 55.6 (range 0.33-4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). Comparing C and I, QL outcomes were not statistically different in terms of general QL items. Comparing D and DE, 1-y PFS was superimposable (10% and 13.5%, respectively). The 2-y overall survival was not different between I and C arms 42.5% and 53.7% respectively) and between D and DE arms (42.8% and 53.5% respectively). Conclusions: These preliminary results suggest that I treatment did not produce a QL advantage compared to C treatment, while the addition of E to D did not improve 1-y PFS of CRPC pts.

210 Background: The incidence of CNS metastasesin prostate cancer is very low. Recent data suggest that HER-2/neu is involved in progression of prostate cancer. Docetaxel-based chemotherapy has provided a survival advantage for mCRPC. The purpose of this retrospective study was to evaluate the relation between HER-2 status and risk of CNS metastases in pts with mCRPC treated with docetaxel. Methods: From 2003 to 2010, 130 pts with mCRPC were treated with 3wk docetaxel 75 mg/mq. 72/130 pts were retreated with the same regimen on disease progression. 50 out of these 72 pts received second docetaxel retreatment. All pts had bone metastases. Pts underwent total body CT scan before starting docetaxel chemotherapy and every 6 months during treatment. The median age was 66 (41–88), median baseline PSA: 110 ng/ml (range 5–1100), median ECOG Performance Status: 1 (range 0–2). The data on 130 pts, who underwent diagnostic biopsy or potentially curative resection , were reviewed. Tissue blocks from primary prostate cancer tissues were obtained. Grade 3 of the HER-2 by IHC staining was defined as a positive result or gene amplification by FISH. 10 out of these 50 pts receiving second docetaxel retreatment were diagnosed with CNS metastases. Results: CNS metastases were observed in HER-2 positive pts. 6/10 pts presented parenchymal metastases: 4 pts were asymptomatic, 3 pts underwent metastasectomy and all of them received palliative whole-brain RT. 4/10 pts presented leptomeningeal metastases with neurological symptoms and 2 of them received palliative whole-brain RT. The median time from prostate cancer diagnosis to the date of diagnosis of CNS metastases was 6 years (1–8). The median time from first cycle of docetaxel to the date of diagnosis of CNS metastases was 3 years (1.5–4). Conclusions: These preliminary data demonstrated that HER-2 expression confers an increased risk of CNS metastases in mCRPC and constitutes a therapeutic challenge. The apparent increase of CNS presentation may be related to the effectiveness of systemic therapy. These informations support the further evaluation of neurological symptoms in long-term docetaxel treated pts.

e15190 Background: The incidence of CNS metastases, including parenchyma and leptomeninges, in prostate cancer is very low. Prostate cancer mainly metastasizes to bones. HER-2/neu is a proto-oncoge...

217 Background: The occurrence of BMm is usually viewed as an exceptional event in the history of prostate cancer (PC) patients (pts). In two large retrospective series the incidence of BMm in PC pts was about 0.5%. Since the introduction of DOC as first line treatment has improved survival of CRPC pts, we have retrospectively evaluated the occurrence of BMm in such setting of pts, to explore whether the incidence of BMm has changed. Methods: The clinical records of a series of 801 pts with CRPC treated from 2002 to 2010 were reviewed. All pts met the definition of CRPC according to international guidelines: all pts received or were eligible for DOC-based treatment. Results: We collected a series of 28 pts with BMm (incidence 2.9%). Sixteen pts had a median number of 1 brain metastases (range 1-8) and neurological symptoms were present in 11 cases. Teen cases presented meningeal metastases: in this case all but one pt were symptomatic. To date, no detailed information are available for the 2 remaining cases. After BMm diagnosis, local treatments were proposed in 16 pts: 5 pts underwent metastasectomy (M) + external brain irradiation (BI), 1 M alone, 9 BI alone, 1 gamma-knife. Eleven pts received chemotherapy after BMm, while the remaining received only best supportive care. The median interval from the PC diagnosis and the achievement of CRPC was 23 mos (range 7-141) while the appearance of BMm was documented after 6-173 mos (median 42) The median survival after BMm was 3 mos (range 1-29) with 6 pts surviving more than 1 year. These long-term survivors had brain metastases in 5 cases and meningeal metastases in 1 case and were managed with surgery in 3 cases, radiotherapy in 2 cases and DOC in 1 case. Conclusions: It appears from our data that in the DOC era 1) the incidence of BMm in CRPC pts is higher than in the historical reports; 2) the interval from PC diagnosis and the appearance of BMm is clearly longer (42 mos) compared to that reported in historical series (28 mos). These findings could be related to the changes in survival of CRPC, produced by DOC introduction in the clinical practice. A special attention should be reserved to the appearance of neurological symptoms in a long-term CRPC survivor due to a possible relation with BMm. No significant financial relationships to disclose.

161 Background: Comorbidities are considered a therapeutically limiting problem in elderly patients (pts) with mCRPC. We analysed correlations between comorbidity, toxicity and efficacy of docetaxel re-treatment in pts ≥ 70 years with mCRPC. Methods: Pts were evaluated according to comprehensive geriatric assessment (CGA). From 2003 to 2010, 70 pts ≥ 70 years with mCRPC received 3-wk first line docetaxel therapy followed by retreatment on biochemical disease progression. Each patient was assessed according the Cumulative Illness Score Rating-Geriatrics (CISR-G) manual. The score was 0-4. The median age was 77 (70-84), ECOG PS 0-2, median baseline PSA 180 ng/ml (15-1200). The more frequent comorbidities were hypertension, diabetes, arrhythmias, chronic obstructive pulmonary disease. The endpoints were: PSA response proportion to first-second-third line chemotherapy, median survival in responding patients and toxicity. Results: All pts received a standard 3-wk regimen, dose was reduced by 25% for pts score 4. The incidence of adverse events was relatively low and no pts died on therapy. There were no episodes of neutropenic fever. Pts with score 1-2 were 70% (49 pts); pts with score 3 were 20% (14); pts with score 4 were 10% (7). 70 pts (score 0-4) received first line docetaxel chemotherapy with a median no of cycles 14 (6-18), a median survival of 18 months (mos), PSA response 70%. Of these pts 26 (score 0-3) were re-treated with the same regimen with no of cycles 12 (8-18), a median survival of 14 mos, PSA response 45%, duration of first chemotherapy holiday 5 mos (median). Of these pts, 4 (score 0-3) received third line treatment with no of cycles 10 (6-14), a median survival of 10 mos, PSA response 22%, duration of second chemotherapy holiday 4 mos (median). Of these pts only 1 (score 1) received third re-treatment with 8 cycles, PSA response 20%, third chemotherapy holiday 4 mos. 80% of symptomatic pts reported an improvement in symptoms control with docetaxel chemotherapy. Conclusions: Re-treatment with docetaxel is safe in mCRPC elderly pts despite the association of important comorbidities. Median survival in responding pts was approximately 40 mos from the first to the third line. No significant financial relationships to disclose.

398 Background: SOR is a multikinase inhibitor with activity in mRCC. Older patients (pts) benefit from SOR as reported in the subgroup analysis of the TARGET study populations. We evaluated the efficacy and safety in elderly pts (≥ 70) with comorbidities. Methods: A comprehensive geriatric assessment (CGA) was used in older mRCC pts. From 2007 to 2010, 30 pts (23 males and 7 females) received SOR 400 mg BID continuous dosing. Comorbidities were evaluated using the cumulative illness rating scale for geriatrics (CIRS-G). The total score was 0–4. 10 pts with CIRS-G 1, 12 pts with CIRS-G 2, 8 pts with CIRS-G 3/4. Median age was 76 (70–84), ECOG PS 0–2, 24/30 had undergone prior nephrectomy. The most frequent comorbidities were arrhythmias, hypertension, chronic bronchitis, diabetes mellitus, neurological disease. The endpoints were response rate (RR) evaluated by RECIST criteria and correlations between comorbidities and toxicity. Results: Dose reduction (400–600 mg/die) were required for pts with CIRS-G 3–4. No correlations were found between comorbidities (CIRS-G) and response to SOR. 18 pts (14 pts CIRS-G 1/2, 4 pts CIRSG 3/4) had partial response (PR)with a duration of 24 months (9-30) and 12 pts (8 pts CIRS-G 1-2, 4 pts CIRS-G 3/4) stable disease (SD) for 24 months (7–32). 17/30 pts (12 pts CIRS-G 1/2, 5 pts CIRS-G 5) remain on therapy. Drug related adverse events were mainly grade 1 and 2 and were medically manageable. 4 pts required dose interruption (3 pts CIRS-G 1/2, 1 pt CIRS-G 3/4). Pts with CIRS-G score 3–4 had poorer quality of life but the clinical benefit achieved with SOR therapy was high. Conclusions: Comorbidities in pts with mRCC ≥ 70 years did not result in increased incidence of toxicity on SOR treatment. These data suggest that SOR is effective and safe in elderly pts with an overall clinical benefit rate (PR + DS) particularly high. No significant financial relationships to disclose.

e15020 Background: In 2004 docetaxel was approved and has become the standard of care in first- line for metastatic CRPC. The optimal treatment duration with docetaxel is not known and the 2nd line...

e16123 Background: The recent development of new targeted agents for the treatment of advanced RCC has definitely changed the approach and the outcome of this disease. Among them, SOR, has proved to be highly active in the treatment of mRCC. The aim of this study was to assess the activity and the safety of SOR in pts with mRCC relapsed after prior systemic therapy. Methods: Between 2/2007 and 10/2008, 22 pts with mRCC relapsed after 1–2 prior lines of chemotherapy (gemcitabine, vinorelbine, 5-FU) have been treated with SOR orally administered at the dose of 400mg b.i.d. continuous dosing. They were18 males and 4 females, with a median age 67 years, an ECOG PS 0–2, and the majority (96%) had undergone prior nephrectomy. Patients were assessed for activity every three months (mos.) by CT. The primary endpoints were response rate (RR) evaluated by RECIST criteria and time to progression (TTP). Results: To date, 20 pts are evaluable for response: of them, 13 (59%) achieved a partial response (PR) after 3 mos. of therapy whose median duration was 13 mos. (range, 7–18), while 7 (31%) remained with stable disease (SD) with a median length of 14 mos. (range, 5–17). No complete responses have been observed. Among those who progressed (2 pts), the median time to disease progression was 7 mos. At a median length of time of 15 mos., 18 pts. are continuing the therapy with SOR and in all of them the benefit achieved remained unchanged. Two pts discontinued the treatment because of the onset of side effects, while in 4 pts dose reductions were required. Grade 3/4 toxicities were: hypertension in 3 pts (13%), hand-foot skin reactions in 5 (22%), rash/desquamation in 4 (18%), diarrhoea in 2 (9%), fatigue in 6 (27%), bleeding in 2 (9%). Conclusions: These data confirm other experiences showing the efficacy of SOR in previously treated patients with mRCC. However, notwithstanding the rather small sample size of pts., the overall clinical benefit rate (PR+SD) turned out particularly high (> 90%): chiefly, the evidence of a long lasting disease control both for patients achieving partial response and for those with stable disease makes SOR a very useful treatment for patients with mRCC. No significant financial relationships to disclose.

15528 Background: The neuroendocrine (NE) cells in prostate cancer are indistinguishable from non-NE cancer cells morphologically and are usually detected by immunohistochemical study for NE markers. We analyzed the expression of Chromogranin A (Chr A) in malignant prostate tissue as prognostic factor for docetaxel response in metastatic HRPC. Methods: From January 2003 to December 2006, 40 patients with metastatic HRPC received a median of 12 cycles (range 2–18) of Docetaxel 75 mg/mq every 21 days and 5 mg of prednisone twice daily as initial therapy. Tissue blocks from primary prostate cancer tissues were obtained and immunostaining for Chr A was performed. The median age was 70 years (range 46–82); median baseline PSA: 310 ng/ml (range 0.15–700); median ECOG Performance Status: 1 (range 0- 2). PSA level was measured every 4 weeks and the treatment was considered effective if a rate of PSA-decline > 50% from baseline was found. TTP was the preliminary end point. Results: Response to Docetaxel was assessed at every 3 cycles of treatment. The Chr A expression was found in 19/40 patients with Gleason = 7, PSA < 20, bone and soft tissue metastasis; 10 of them showed PR (decrease in PSA < 50%), 4 SD and TTP was 9.2 months. Moreover they received second line chemotherapy without significant efficacy. 5/19 patients with Chr A expression showed PD, the PSA level was not correlated with clinical outcome, TTP was 5 months and were chemoresistant to different line treatment. Besides, Chr A was not detected in 21/40 patients with Gleason = 7, PSA > 20 and bone metastasis; 10 of them showed CR (PSA normalized) and 11 PR, TTP was 20 months. Conclusions: NE differentiation do not constituite a different histopathological category of prostate cancer but the NE phenotype can be correlated with poorly differentiated adenocarcinoma. NE differentiation can be considered a factor that influences prognosis and treatment in advanced prostate cancer; cases with Chr A expression did not benefit from Docetaxel and had poor prognosis. These preliminary data indicate that initial therapeutic approach should be different according to Chr A expression. No significant financial relationships to disclose.

e15524 Background: With several agents available for the treatment of metastatic renal cell carcinoma (mRCC) a better understanding of their use in daily clinical practice is fundamental in the decision-making process. Methods: The REtrospective analysis of Sorafenib (So) as 1st or 2nd targET therapy (RESET) in mRCC was a retrospective, observational field study that assessed the use and safety of So in clinical practice in Italian centers. Treatments were determined by physicians per local prescribing guidelines. Patients (pts) treated with So single agent as 1st or 2nd target therapy (TT) for mRCC between 1st Jan 2008 and 31st Dec 2010 were eligible for inclusion. Endpoints included safety, overall survival (OS), progression-free survival, response rate and treatment duration. Subgroup analyses included age, ECOG performance status, prior therapy, number of metastases and line of TT with So. Results: From Feb to Jul 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.7%), rash (2.2%), hypertension, fatigue and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.4 – 19.6 mos) and median PFS was 5.9 mos (95% CI 4.9-6.7 mos). Median duration of treatment with So was 5.03 mos. Disease control (complete response + partial response + stable disease) was observed in 198(56%) pts. In pts receiving So as first or as second TT median OS was 19.9 mos (95% CI 15.9-25.3 mos) and 16.3 mos (95% CI 13.0-18.2 mos) respectively. In the subgroup of pts treated with So 1st TT followed by sunitinib (Su) 2nd TT (44 pts) and Su 1st TT followed by So 2nd TT (173 pts), median OS was 30.4 mos (95% CI 22.0-34.8 mos) and 16.6 mos (95% CI 13.1-18.2 mos) respectively. There were 269(76%) pts that received a total of 2 lines of therapy for mRCC, 133(38%) pts 3 lines and 43(12%) pts 4 lines of therapy. Conclusions: The efficacy and safety profile of So in the setting of Italian community-based daily clinical practice was similar to data reported in prospective clinical trials. The efficacy of So was observed in both the subgroups of pts receiving So as either the first or second TT for mRCC, with intriguing OS data in first line.