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M Milella

Publications and source records attributed to M Milella.

At least 19 recordsLinked to original sources
PubMed2006

Second- and third-generation aromatase inhibitors as first-line endocrine therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised trials.

The purpose of this study was to estimate in all randomised trials the relative risk of overall response rate (ORR), clinical benefit (CB), time to progression (TTP), overall survival (OS), and toxicity of aromatase inhibitors (AI), compared with tamoxifen (Tam) as first-line endocrine therapy in postmenopausal metastatic breast cancer (PMBC) women. Prospective randomised studies were searched through computerised queries of MEDLINE, EMBASE, and the American Society of Clinical Oncology (ASCO) abstract database. Relative risk, 95% confidence interval, and heterogeneity were derived according to the inverse variance and Mantel-Haenszel method and Q statistics. Six phase III prospective randomised trials including 2787 women were gathered. A significant advantage in ORR (P = 0.042), TTP (P = 0.007), and CB (P = 0.001) in favour of AI over Tam was detected at the fixed effects model. These results were not significant at the random effects model, owing to the significant heterogeneity. On the contrary, no difference was registered for OS (P = 0.743) with no significant heterogeneity. Regarding toxicity, Tam caused more frequently thromboembolic events (P = 0.005) and vaginal bleeding (P = 0.001) compared with AI. Aromatase inhibitors appear to be superior to Tam as first-line endocrine option in PMBC women. Owing to a component of variability between the six studies analysed, the random effects estimates differed from corresponding fixed ones. Investigators should assess heterogeneity of trial results before deriving summary estimates of treatment effect.

Aromatase Inhibitors↗
PubMed2005

Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia.

We investigated the constitutive activation of the MEK/ERK pathway in acute myelogenous leukemia (AML) via a flow cytometric technique to quantitate expression of phosphorylated ERK (p-ERK). A total of 42 AML samples (16 newly diagnosed, 26 relapsed/refractory) were analyzed. Normal bone marrow CD34+ cells (n = 10) had little or no expression of p-ERK, while G-CSF-mobilized CD34+ cells exhibited enhanced p-ERK levels. Markedly elevated p-ERK levels were found in 83.3% of the AML samples, with no differences observed between the newly diagnosed and relapsed/refractory samples. Treatment with a MEK inhibitor resulted in significantly decreased p-ERK levels in both the newly diagnosed and relapsed/refractory samples, which was associated with growth arrest, but not apoptosis induction. In summary, we defined conditions for the analysis of MAPK signaling in primary AML samples. Normal CD34+ cells expressed very low levels of p-ERK, and increased p-ERK levels were found in normal G-CSF-stimulated circulating CD34+ cells. Constitutively high p-ERK levels observed in the majority of AML samples suggest deregulation of this pathway that appears to be independent of disease status. The ability of ERK inhibition to promote growth arrest rather than apoptosis suggests that clinical trials of MEK/ERK inhibitors may be more effective when combined with chemotherapy.

Acute Disease↗
PubMed2005

Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects.

The MEK/MAPK signaling module is a key integration point along signal transduction cascades that regulate cell growth, survival, and differentiation, and is aberrantly activated in many human tumors. In tumor cells, constitutive MAPK activation affords increased proliferation and resistance to apoptotic stimuli, including classical cytotoxic drugs. In most instances, however, MAPK inhibition has cytostatic rather than cytotoxic effects, which may explain the lack of objective responses observed in early clinical trials of MEK inhibitors. Nevertheless, amenability of the MAPK pathway to pharmacodynamic evaluation and negligible clinical toxicity make MEK inhibitors an ideal platform to build pharmacological combinations with synergistic antitumor activity. In AML, the MEK/MAPK pathway is constitutively activated in the majority of cases (75%), conferring a uniformly poor prognosis; in preclinical models of AML, MEK blockade profoundly inhibits cell growth and proliferation and downregulates the expression of several anti-apoptotic players, thereby lowering the apoptotic threshold. Apoptosis induction, however, requires concentrations of MEK inhibitors much higher than those required to inhibit proliferation. Nevertheless, MEK blockade efficiently and selectively sensitizes leukemic cells to sub-optimal doses of other apoptotic stimuli, including classical cytotoxics (nucleoside analogs, microtubule-targeted drugs, gamma-irradiation), biologicals (retinoids, interferons, arsenic trioxide), and, most interestingly, other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists). In most instances, these MEK inhibition-based combinations result in a striking pro-apoptotic synergism in preclinical models. Here we briefly discuss evidence suggesting that MAPK pathway inhibition could play a prominent role in the development of integrated therapeutic strategies aimed at synergistic anti-leukemic effects.

Animals↗
PubMed2004

Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias.

The phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathway is involved in cell growth, proliferation, and apoptosis. The functional activation of PI3K/AKT provides survival signals and blockade of this pathway may facilitate cell death. Downstream targets of PI3K-AKT include the proapoptotic protein BAD, caspase-9, NF-kappaB, and Forkhead. We have previously reported that BAD is constitutively phosphorylated in primary acute myeloid leukemia (AML) cells, a post-transcriptional modification, which inactivates its proapoptotic function. In this study, we tested the hypothesis that the inhibition of PI3K by LY294002 results in the dephosphorylation of AKT and BAD, and thus promote leukemia cell apoptosis. We investigated the effects of LY294002 in megakaryocytic leukemia-derived MO7E cells, primary AML and normal bone marrow progenitor cells. In MO7E cells, LY294002 reduced AKT kinase activity, induced dephosphorylation of AKT and BAD, and increased apoptosis. Concomitant inhibition of mitogen-activated protein kinase signaling or combination with all-trans retinoic acid further enhanced apoptosis of leukemic cells. In primary AML samples, clonogenic cell growth was significantly reduced. Normal hematopoietic progenitors were less affected, suggesting preferential targeting of leukemia cells. In conclusion, the data suggest that the inhibition of the PI3K/AKT signaling pathway restores apoptosis in AML and may be explored as a novel target for molecular therapeutics in AML.

Apoptosis↗
PubMed2004

Incidence of chemotherapy-induced amenorrhea depending on the timing of treatment by menstrual cycle phase in women with early breast cancer.

BACKGROUND: The aim of this study was to characterize the factors associated with chemotherapy-induced amenorrhea (CIA) and to examine whether the phase of the menstrual cycle at chemotherapy start could affect the rate of CIA in premenopausal women with early breast cancer. METHODS: CIA was defined as the cessation of menses for at least 3 months during or after chemotherapy. Menstrual phase was defined as days 1-6, follicular phase as days 7-14, luteal phase as days 15-20 and premenstrual phase as days 21-28. Univariate and multivariate predictors of CIA were examined. RESULTS: Among 111 premenopausal women, univariate analysis showed a higher incidence of CIA in patients treated in the follicular phase rather than in other menstrual cycle phases (67.6% compared with 45.5%; P=0.03). The rate of CIA increased with age: 65.2% and 45.8% in patients aged >42 and </=42 years, respectively (P=0.05). Upon multivariate analysis these differences remained statistically significant and duration of chemotherapy of more than six cycles correlated significantly with the incidence of CIA (P=0.03). CONCLUSIONS: The major implication of this analysis is that the timing of treatment within the menstrual cycle may potentially modulate the onset of CIA. This work and its future confirmation using prospective randomized trials would be useful in predicting the likelihood of CIA and in counseling breast cancer patients, especially those with a good prognosis who benefit less from chemical castration.

Adult↗
PubMed2004

[Preclinical and clinical results with the epidermal growth factor receptor inhibitor Gefitinib (ZD1839, Iressa)].

Since epidermal growth factor receptor (EGFR) is involved in tumor proliferation and angiogenesis, and in the mechanisms of resistance to chemo- and hormono-therapy, it represents a unique promising target for anticancer treatment. Gefinitib (Iressa, ZD1839), an inhibitor of the EGFR tyrosine kinase activity able to bind the intracellular domain of the receptor, is at present in clinical development. In preclinical models Gefitinib induced a dose-dependent response rate in tumor xenografts obtained from different human cancer cells lines. The expression of EGFR in the prior tumor did not appear to be a predictive marker for Gefitinib sensitivity. Furthermore, long-term drug use was well tolerated in mice without inducing resistance. However, tumors started to grow again after treatment interruption. Laboratory findings and in vivo data have prompted the evaluation of Gefitinib administered as a single oral daily dose alone or in combination with conventional anticancer treatment.

Animals↗
PubMed2004

Single-agent vinorelbine in pretreated breast cancer patients: comparison of two different schedules.

This retrospective study compared toxicity and activity of vinorelbine according to two schedules with different projected dose intensities in heavily pretreated breast cancer patients. Forty patients were assessable for toxicity and activity in each group; group A received vinorelbine 25 mg/m2 week + lenograstim (150 microg/m2 s.c. on day 3); group B received 25 mg/m2 on days 1 and 8 every 3 weeks. The projected dose intensity was 25 mg/m2/week and 16.6 mg/m2/week, and delivered dose intensity 95.2% and 94.5% in group A and B, respectively. Grade 3-4 afebrile neutropenia was recorded in 25% and 37.5% of patients in A and B, respectively. Overall response rate, 52.5% and 35%; no change, 35% and 40%; progression of disease, 12.5% and 25% in A and B, respectively. Median duration of the response was 10 months for group A and 7 months for B. Median time to progression: 9.0 months and 4.0 months for A and B, respectively. At a median follow-up of 45 months for group A and 19 months for group B, median overall survival was 19 months and 16, respectively. In conclusion the results of the study showed that dose intensity of vinorelbine could have an improvement in terms of time to progression in pretreated advanced breast cancer.

Adjuvants, Immunologic↗
PubMed2004

[Diagnostic modalities in patients affected by differentiated thyroid carcinoma with high thyroglobulin levels and total body Iodium-131 negative: PET/CT use after recTSH].

In the follow-up of differentiated thyroid carcinoma (DTC), after total thyroidectomy and Iodine-131 therapy, thyroglobulin (Tg) levels and Iodine-131 total body have particular importance. The Tg level becomes a specific and very sensitive marker of DTC recurrence: it is usually evaluated after eradication of thyroid residual tissue (by thyroidectomy and radiometabolic therapy), in presence of high level of TSH (>35 microU/ml) obtained with the suspension of therapy or after rec-TSH administration and in absence of anti-Tg antibodies. Usually, to solve diagnostic problems in patients with negative total body Iodine-131 and high levels of thyroglobulin, we consider one or more of the following investigations, on the basis of prognostic factors: radiological examinations (neck US, skeletal X-ray, CT chest and abdomen, MRI) and scintigraphy (bone scintigraphy, Tc-MIBI or Tl-201 scintigraphy, octreoscan, PET/CT). The use of PET is well known in patients in whom carcinoma metastases are strongly suspected and who are unable of concentrating Iodine-131. In order to increase the PET sensitivity, scintigraphy is performed with high TSH levels obtained through a rec-TSH injection on the 1st and 2nd day, PET/CT scan and blood withdrawal (for Tg level evaluation) on the 3rd day. Considering the hypothesis of a recurrence with lesion size below the resolution power of the diagnostic equipment (5 mm), if PET/CT results are negative, the patients are strictly followed-up and Tg is monitored every 4-6 months. An alternative hypothesis might be not to consider the negative-PET patients as sick persons, but to attribute high Tg levels to illegitimate transcription of mRNA for Tg by the non-thyroid cells or to ectopic thyroid tissue (e.g. intrathymus). Positive PET/CT patients are evaluated for a possible surgical removal of the lesions or alternative appropriate therapies.

Antineoplastic Agents, Hormonal↗
PubMed2003

Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia.

XIAP is a member of the inhibitors-of-apoptosis family of proteins, which inhibit caspases and block cell death, with prognostic importance in AML. Here we demonstrate that cytokines regulate the expression of XIAP in leukemic cell lines and primary AML blasts. Inhibition of phosphatidylinositol-3 kinase (PI3K) with LY294002 and of the mitogen-activated protein kinase (MAPK) cascade by PD98059 resulted in decreased XIAP levels (34+/-8.7 and 23+/-5.7%, respectively). We then generated OCI-AML3 cells with constitutively phosphorylated Akt (p473-Akt) by retroviral gene transfer. Neither these nor Akt inhibitor-treated OCI-AML3 cells showed changes in XIAP levels, suggesting that XIAP expression is regulated by PI3K downstream effectors other than Akt. The induction of XIAP expression by cytokines through PI3K/MAPK pathways is consistent with its role in cell survival. Exposure of leukemic cells to chemotherapeutic agents decreased XIAP protein levels by caspase-dependent XIAP cleavage. Targeting XIAP by XIAP antisense oligonucleotide resulted in downregulation of XIAP, activation of caspases and cell death, and sensitized HL-60 cells to Ara-C. Our results suggest that XIAP is regulated by cytokines through PI3K, and to a lesser degree through MAPK pathways. Selective downregulation of XIAP expression might be of therapeutic benefit to leukemic patients.

Base Sequence↗
PubMed2003

Long-term results of balloon dilation of benign bile duct strictures.

PURPOSE: To evaluate the results of percutaneous balloon dilation of benign bile duct strictures in a series of patients with a long follow-up period. MATERIAL AND METHODS: 56 patients with benign bile duct strictures underwent balloon catheter dilation. These patients had strictures of various origins: postsurgical, postlocal not surgical treatments, associated with gallstones, due to primary sclerosing cholangitis and to Mirizzi's syndrome. In 41 cases the diagnosis was made on the basis of radiological findings and history and in 15 cases on the basis of transluminal biopsy. RESULTS: In 87.5% of cases the treatment was immediately successful. There were no early recurrences, but 7 (21%) recurrences were seen over 1 year after treatment; of these, 57% underwent another balloon dilation procedure with a positive long-term outcome. CONCLUSION: The long-term success rate obtained in 72% of this series confirms that percutaneous bile duct dilation is a valid alternative to surgery without being burdened by complications; the procedure is also a valid alternative to the approach using endoscopic stents.

Adult↗
PubMed2003

Clinically meaningful response to the EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in non small cell lung cancer.

Preclinical research and ongoing clinical trials are validating epidermal growth factor receptor (EGFR) as a suitable molecular target in cancer therapy. Here we report the case of a 39-year-old non-smoking man with heavily pretreated stage IV bronchioloalveolar NSCLC who was treated with gefitinib ('Iressa', ZD1839) at the dose of 250 mg/day, orally. Symptomatic relief was already detectable after 2 weeks of gefitinib therapy, pulmonary function tests readily improved, performance status went from 2 to 0 within 8 weeks, CT scan performed after 10 weeks of treatment showed nearly complete resolution of the clinical picture, and clinical remission was maintained up to 32 weeks. This case-report illustrates the potential of EGFR tyrosine kinase inhibition to induce clinically meaningful responses in heavily pretreated, advanced NSCLC patients and suggests that participation of such patients into clinical trials of signal transduction inhibitors should be encouraged.

Adult↗
PubMed2001

Cytokine-regulated expression of survivin in myeloid leukemia.

Survivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle-dependent manner in all the most common cancers but not in normal differentiated adult tissues. Survivin expression and regulation were examined in acute myeloid leukemia (AML). Survivin was detected by Western blot analysis in all myeloid leukemia cell lines and in 16 of 18 primary AML samples tested. In contrast, normal CD34(+) cells and normal peripheral blood mononuclear cells expressed no or very low levels of survivin. Cytokine stimulation increased survivin expression in leukemic cell lines and in primary AML samples. In cultured primary samples, single-cytokine stimulation substantially increased survivin expression in comparison with control cells, and the combination of G-CSF, GM-CSF, and SCF increased survivin levels even further. Conversely, all-trans retinoic acid significantly decreased survivin protein levels in HL-60, OCI-AML3, and NB-4 cells within 96 hours, parallel to the induction of myelomonocytic differentiation. Using selective pharmacologic inhibitors, the differential involvement of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol-3 kinase (PI3K) pathways were demonstrated in the regulation of survivin expression. The MEK inhibitor PD98059 down-regulated survivin expression in both resting and GM-CSF-stimulated OCI-AML3 cells, whereas the PI3K inhibitor LY294002 inhibited survivin expression only on GM-CSF stimulation. In conclusion, these results demonstrate that survivin is highly expressed and cytokine-regulated in myeloid leukemias and suggest that hematopoietic cytokines exert their antiapoptotic and mitogenic effects, at least in part, by increasing survivin levels.

Acute Disease↗
PubMed2001

Changes of gallbladder and gastric dynamics in patients with acute hepatitis A.

Transient alterations of gallbladder morphology and dynamics have been reported in patients with during acute hepatitis A. The presence of dyspepsia also suggests involvement of gastric motility. During a 60-day follow-up, we investigated gallbladder and gastric motility in relation to dyspepsia in acute viral hepatitis A patients. Twenty patients were assessed at referral (day 0) and at days 7, 21, 42 and 60 and compared with 20 healthy volunteers. Gallbladder morphology and motility and gastric motility were assessed in the fasting and postprandial period by functional ultrasonography using a liquid test meal. Dyspeptic symptoms were scored. At day 0, fasting gallbladder volume was 5.9 +/- 1.3 mL, 32.6 +/- 4.6 mL, and 21.5 +/- 1.9 mL (mean +/- SE) in patients with gallbladder sludge (n = 7), without sludge (n = 13) and controls, respectively (P < 0.05 in sludge vs. no sludge and controls; P < 0.05 in no sludge vs. controls, ANOVA). Small fasting gallbladder volume in patients with sludge increased and sludge disappeared within 7 days. At day 0, patients with sludge also had increased thickness of fasting gallbladder wall and increased serum transaminase levels compared with patients without sludge and controls. Gallbladder contraction was similar in patients and controls. However, patients had delayed gastric emptying, which positively correlated with dyspepsia score. Gallbladder morphological changes observed in the acute phase of hepatitis A are transient and are associated with hepatocellular damage. Gastric emptying is delayed during the first week of disease and is associated with dyspeptic symptoms.

Acute Disease↗
PubMed2001

Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.

Apoptosis↗
PubMed2001

Ultrasonography of arm edema after axillary dissection for breast cancer: a preliminary study.

This work examined whether ultrasonography (US) provides detailed information about physical characteristics of lymphedema and whether there is agreement between imaging and clinical data. The study population included 46 women with chronic arm edema after axillary dissection for breast cancer. US showed in each patient an increase of subcutaneous tissue thickness compared with the contralateral arm. Fluid accumulation was seen in 16 patients (34.7%), fibrosis in 12 (26.0%), and a mixed picture (fibrosis and fluid) in 18 (39.1%). Correlation with clinical information ("soft," "medium," "hard, "and "pitting" edema) demonstrated that US documented interstitial fluid in 68.4% of soft edema, mixed fluid and fibrosis in 64.2% of medium edema, and fibrosis in 76.9% of hard edema. Ultrasonography also showed that in soft and medium edema, fibrosis may already have formed. US is useful to follow progression, composition, and management of arm lymphedema after axillary dissection.

Adult↗