Abnormalities of the hypothalamus-pituitary-adrenal axis and hypersensitivity to corticosteroids have been suggested as major determinants of the development of visceral obesity. Since at the ...cellular level most effects of corticosteroids are mediated by specific receptors, we evaluated the number of type I and type II corticosteroid receptors in mononuclear leucocytes of 26 obese and 13 control subjects. We also studied the relationship between corticosteroid receptors, measured by radioreceptor assay, and abdominal visceral fat, evaluated by computed tomography scan, plasma and urine corticosteroid hormone concentrations and overall glucose metabolism, assessed by euglycaemic-hyperinsulinaemic clamp. We observed a decrease in type II receptors in the obese subjects (1746 +/- 160 vs 2829 +/- 201 per cell; P < 0.0001), with no change in type I receptors. Type II receptors decreased in relation to body mass index (r = -0.53; P < 0.005) and total glucose disposal (r = 0.51; P < 0.01). Abdominal visceral fat did not correlate with type II receptor number, but did correlate with total glucose disposal (r = -0.35; P < 0.05); the rate of glucose disposal was lower in obese subjects (3.3 +/- 0.3 vs 7.4 +/- 0.4 mg/kg per min; P < 0.001). Plasma and urine cortisol did not differ between the two groups. However, a direct correlation between type II receptor number and both plasma (r = 0.43; P < 0.02) and urine cortisol concentrations (r = 0.60; P < 0.05) was observed. In conclusion, the number of type II corticosteroid receptors in mononuclear leucocytes was found to be lower in obese subjects. This abnormality appears to be related to the degree of adiposity and to the main endocrine-metabolic features of the obesity syndrome, further supporting the hypothesis of involvement of hypothalamus-pituitary-adrenal axis hyperactivity in the pathophysiology of obesity.
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373
Background: VHL is a rare hereditary condition caused by germline alteration of VHL gene predisposing to multiple renal and other tumors. Since acquired dysregulation of ...VHL-dependent pathways is often present in patients with sporadic RCC treated with first-line sunitinib (SUN), there is a strong rationale to use the same drug in VHL patients with progressive disease in the kidneys or other sites.
Methods: We performed a retrospective analysis of SUN therapy in genetically confirmed VHL patients treated at our Institution for multifocal or advanced RCC.
Results: From February 2007 to October 2010, 9 VHL patients were proposed first-line SUN for RCC, mean age 44 yrs (26-60), F:M ratio 2:1. SUN was administered for a mean of 9 cycles (1-20). Eight of 9 pts received at least two cycles and were considered for response evaluation: all 8 were stable according to RECIST criteria, but decrease in radiological density of lesions was observed in 7 of 8 pts (87.5%). Density decrease was noted not only in renal and hepatic lesions but also in some pancreatic nodules; all CNS haemangioblastoma lesions remained stable (see table). Preliminary median PFS is > 13 months (8 censored, 1 deceased).
Conclusions: SUN treatment in VHL patients appears to achieve good disease control not only in renal tumors but also in synchronous VHL-related lesions, especially pancreatic solid nodules whose exact nature (metastatic RCC or neuroendocrine tumor) cannot be ruled out without invasive biopsies.
Table: see text
No significant financial relationships to disclose.
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16006
Background: The mechanism of action of PLD+Ox suggests that and carriers of BRCA mutations might have better survival compared to sporadic ovarian cancer even when pre-treated in ...advanced EOC. Methods: Inclusion criteria: Performance Status<=2, relapse or progression after 1–3 lines of therapy; <=4 prior antiblastic drugs; life expectancy >3 months; LVEF >50%, informed consent. Treatment consisted of 1 hr infusion of PLD 30–35 mg/m
2
on day 1 and 70 mg/m
2
of Ox in 2 hrs on day 2 for 8 cycles, then 2 cycles of PLD alone. Clinical response was evaluated by CT scan every 3 cycles. Primary endpoints were overall survival and its correlation with BRCA mutations and p53. Results: From June 2000, 63 pre-treated pts with advanced EOC were enrolled. Median age = 62 yrs, range 41–83, (18pts >70 yrs). 17 had known germline BRCA1/2 mutations (10pts) or family history of ovarian cancer (4pts). In this BRCA/high-risk population 15 pts were evaluable for response with ORR=93.3% (8 CR, 6 PR>50%, 1 SD). 139 courses were administered (median = 10 courses/pt). There was 1 episode of G3 toxicity: mucositis; G1–2 toxicity was gastrointestinal (16 episodes), mucositis (11 episodes), neutropenia (9 episodes). Median LVEF showed no significant changes during treatment. There is no clear correlation between OS and amount of Platinum/Taxol administered previously. p53 was analyzed for expression and mutations. Mutations were sought in exons 5, 6, 7 and 8. 5/6 CR evaluable for p53 showed overexpression. p53 overexpression was seen in 9/11 evaluable pts; of these 4/9 also had p53 mutations. 3/4 of these patients obtained a complete response. Median survival from 1
st
cycle has not been reached; mean survival is 63.6 months vs 24.7 for sporadic EOC (p<.001). Presently 15/17 are alive. The 5-yr survival after first course of therapy is estimated at 82%. BRCA/high-risk patients in PLD-Ox therapy also fared better than counterparts from an historical population (OS from diagnosis 179.4 vs 141.1 months, p=.005). Conclusions: PLD+Ox is well tolerated and highly effective in BRCA/high-risk patients and in p53 positive/mutated pts in this population. This therapy offers low toxicity providing good quality of life.
No significant financial relationships to disclose.
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4585
Background: There is no gold standard pharmacological treatment for HCC not suitable for loco-regional therapy. Antracyclines have been often used for the chemotherapy of HCC with ...low efficacy and well known toxicity. Availability of new drugs and in particular of PLD could enhance the chance of treatment and contain side-effects. Gemcitabine is active against the most solid tumors. Patients and Methods: We enrolled 35 patients (PTS) with histological diagnosis of HCC not suitable for loco-regional treatment and adequate haematological function.; median age was 63.2 (range 44.0–77.4); male/female=29/6; PS=0 in 30 PTS, PS=1 in 4 PTS and PS=2 in 1 PT. Eighteen PTS had metastatic disease. Prior treatments were TACE in13 PTS, PEI in 9, surgery in 12, RFTA in 5 and chemotherapy in 3. Nineteen patients had Child-Pough A-B cirrhosis HBV-HCV related. PLD was administered at the dose of 30mg/m
2
over a 60’ infusion every 28 days and G at the dose of 1,000mg/m
2
over 30’ infusion days 1 and 8 every 28 days. Instrumental response evaluation was performed every 3 cycles and treatment was continued until disease progression or major toxicity evidence. Results: All PTS were valuable for toxicity: G1–2 toxicity was neutropenia in 5 PTS, thrombocytopenia in 7, mucositis in 3 and PPE in 3. G3–4 toxicity was neutropenia in 6 PTS and thrombocytopenia in 1. Thirty-four PTS were valuable for response with CR in 2, PR in 6, SD in 12 and PD in 14. Thirty-four PTS were valuable for TTP: median was 6.2+ months (range 1.9–31.7+). All PTS were valuable for OS: median was 8.8+ months (range 1.9–36.5+). Conclusions: The combination of PLD and G is safe and effective in treatment of HCC. No life-threatening toxicity was experienced and disease control rate was about 60%.
No significant financial relationships to disclose.
In recent years with the development of targeted agents such as bevacizumab, sunitinib, sorafenib, temsirolimus, and everolimus, the treatment of metastatic renal cell carcinoma has changed ...dramatically. In clinical practice, sunitinib and bevacizumab are reserved for first-line treatment, but despite various guidelines, optimal treatment is still uncertain. We present, for the first time, a case of a good response to second-line bevacizumab and interferon-a in a patient who failed classical sunitinib treatment.
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10789
Background: On the basis of general and our own experience neoadjuvant therapy is justified in patients with locally advanced breast cancer to reduce cancer and to perform a ...conservative surgery. In this study we evaluated the efficacy of G plus D and PLD as first-line therapy in LABC. Methods: To date sixteen consecutive patients with LABC have been enrolled into the study. All patients before neoadjuvant treatment, underwent biopsy for hormonal receptors and c-erb-B2 assessment. Patients received G 1250 mg/m
2
on day 1 and G 1000 mg/m
2
, T 75 mg/m
2
and D 25–30 mg/m
2
on day 8 (escalation dose was 25 mg/m
2
at first cycle, 27.5 mg/m
2
at second cycle and 30 mg/m2 at third cycle), every 21 days with G-CSF support on day 3, 10, 12 and 14. Tumor response was evaluated on the basis of surgeon consultation and breast MRI after 4 cycles. If tumor response was higher than 50% patients underwent 2 more cycles; if it was 50% ore less or because of unacceptable toxicity they underwent surgery after 4 cycles. Microscopic assessment of the extent and type of residual tumour was made. Results: 16 patients were enrolled comprehensive of 2 with no symptomatic bone metastases. Median age was 50 years-old, and 100% had a WHO performance status (PS) of 0 and EORTC QoL was submitted. Four patients were submitted to surgery after 4 cycles, one after 5 cycles of CT with 5 pPR more than 50%. Three patients had a pathological complete response, 2 partial response more than 50% and 1 stable disease after 6 cycles. (a total of 70% of pPR, 30% of pRC, 10% of pSD). Five patients are still on treatment. One patient died because of acute respiratory distress syndrome. Major toxicity was mucositis G3–4 in one patient. PPE was G3–4 in 3 patients, one discontinued chemotherapy with PLD and continued with Epirubicin. 2 patients received Epirubicin after the first cycle of PLG because of acute allergic reaction. Conclusions: This regimen of chemotherapy seems feasible and active in LABC. At the interim analysis results it has been noted that the best response to chemotherapy was among patients having worse prognostic factors (histology and staging).
No significant financial relationships to disclose.
The dexamethasone suppression test (DST) is considered an indicator of the function of the adrenal pituitary axis. The effect of the steroid is mediated by its binding to corticosteroid receptors. We ...previously suggested that the measurement of corticosteroid receptors in lymphocytes is an index of an analogous pattern in brain. In the present study, corticosteroid Type I and Type II receptors in mononuclear leukocytes were measured in 10 elderly subjects and in 9 young adults, before and after overnight DST (1 mg). Receptors were measured by radioreceptor assay. In all the subjects, dexamethasone was able to suppress plasma cortisol. The number of Type I and Type II receptors before the test was lower in elderly subjects than in adults. In the control group, dexamethasone produced a significant depression of Type I receptors (from 267 +/- 72 to 169 +/- 71 receptors per cell), which can be interpreted as a primary involvement of Type I receptors in the response to dexamethasone; Type II receptors decreased in half the subjects (from 2849 +/- 703 to 2345 +/- 569 receptors per cell). In elderly healthy subjects, Type II receptors were also significantly decreased (from 1796 +/- 671 to 720 +/- 345). We suggest that in young subjects Type II receptors are initially up-regulated by dexamethasone, and then down-regulated, while in aged subjects an up-regulation cannot be achieved, as suggested by the higher values of plasma cortisol usually found in aging subjects.
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14632
Background: ARCC is still an untreatable disease because high dose IL2 therapy is feasible and effective only in a small percentage of patients (pts). Standard dose IL2 is ...palliative as well as every other treatment. G is a well tolerated agent, even in aged pts and is moderately effective in ARCC. FIR of 10 mg/m
2
/min increases intracellular G active metabolites and may enhance therapeutic and toxic effect. Aim of study was to evaluate the FIR-G effectiveness in ARCC. Methods: G was administered IV at 10 mg/m
2
/min FIR for 50 to 1250 min according to age and PS on day 1,8,15 every 28. Immunotherapy (IT) was IL2 3MU subcutaneously daily for 5 days a week or Alfa-INF 3MU three days a week, chronically given. Results: We enrolled 23 pts; 5 female; median age 59 years (29–75), all stage IV disease, all nephrectomized with histologically confirmed clear cell carcinoma; median Fhurman’s grade was 3 (1–4); median PS was 2 (0–3); 9 pts had bone mets; prior treatments: IT, mostly low doses IL2, in 12 pts; chemotherapy in 7 pts and palliative radiotherapy in 9 pts. 125 cycles (median of 5, range 1–35) were administered with a median G dose of 1050 mg/m
2
over 105’. 13 Pts received IT (11 pts were IT naïve and received IL2 and 2 pts previously treated with IL2 received Alfa-INF). In the 22 pts valuable for toxicity grade 1–2/#pts was: granulocytopenia/5, anemia/2, nausea/5, vomiting/2, constipation/1, mucositis/1, fever/1, infection/1, fatigue/2, cutaneous/5, peripheral edema/4; grade 3–4 was: anemia/3, nausea/1, fatigue/3, cutaneous/1, vascular venous/1, peripheral edema/1. 26 cycles had to be delayed due to side effects. In the 22 valuable pts we reported 3 PR with a RR of 14% and 11 pts (50%) had SD. All pts were valuable for TTP with a median of 5.6 months (1–35). Data on OS are still immature with a median of 15+ (3–55+). Conclusions: FIR-G ± IT is safe and moderately effective against ARCC. Due to the small number of pts no separate analysis is possible between G ± IT or prognostic factors groups. Nevertheless our TTP and OS data are promising considering the detrimental prognostic factors in the treated population. Present work was part of studies program of, and partly supported by, AOI (Associazione Oncologia Italiana), Padova, Italy.
No significant financial relationships to disclose.
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