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Biomedical subjects

M Aglietta

Publications and source records attributed to M Aglietta.

At least 19 recordsLinked to original sources
PubMed2007

Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer.

Trastuzumab is a humanized mAb directed against the extracellular domain of the tyrosine kinase receptor HER2. Trastuzumab has shown clinical activity in HER2-overexpressing breast cancers and, at present, is currently approved for patients whose tumours have this abnormality, in both the metastatic and the adjuvant setting. Several issues about its optimal use, however, are still unresolved. One of the reasons for these uncertainties lies in the absence of conclusive data about its mechanism of action and possible primary or acquired resistance mechanisms. Therefore, clinical questions such as how to optimize patient selection, how to prevent resistance to trastuzumab, or what is the optimal management of those patients whose tumours progress during treatment still await convincing answers. This review summarises the current knowledge on the preclinical and clinical evidence about the mechanism of action of trastuzumab and on the mechanisms underlying the development of resistance and also briefly discusses their possible clinical implications.

Antibodies, Monoclonal↗
PubMed2006

The role of haemoglobin level in predicting the response to first-line chemotherapy in advanced colorectal cancer patients.

The purpose of the study was to evaluate the influence of baseline haemoglobin level in predicting response to 5-fluorouracil (5FU)-based first-line chemotherapy in advanced colorectal cancer patients. Data from 631 patients were collected from three different institutions. Globally, overall response rate was 35.8% (226 out of 631). Factors influencing response rate were 5FU dose intensity (high: 43.1%, low: 34.0%, P = 0.03); oxaliplatin (yes: 45.8%, no: 22.9%, P < 0.0001), performance status (PS 0: 46.1%, 1: 28.8%, 2: 26.7%, P < 0.0001), and haemoglobin levels (> or = 12 g dl(-1): 40.4%, < 12 g dl(-1): 29.2%, P = 0.004). In subgroup analysis significant differences in response rate between anaemic and nonanaemic patients were recorded in those patients treated with infusional chemotherapies (45.7 vs 25.5%, P < 0.0001), with high 5FU dose intensity (50.3 vs 32.7%, P = 0.005), with PS = 0 (49.8 vs 37.9%, P = 0.03), and with liver metastases (44.8 vs 33.8%, P = 0.002), whereas no difference was evident in those subjects treated with bolus schedules or according to gender. Anaemia was a strong predictor for activity of first-line 5FU-based chemotherapy especially in those groups that showed the best responses, for example high performance status, infusionally treated, higher 5FU dose and those with liver secondaries. Patients with higher haemoglobin levels recorded a greater response rate and a longer time to progression and survival than anaemic subjects. Prospective evaluation of role of correcting anaemia on response to therapy is justified by these results.

Adult↗
PubMed2006

High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

Adult↗
PubMed2006

Neoadjuvant chemotherapy and resection for initially irresectable colorectal liver metastases.

BACKGROUND: Hepatic surgery is the treatment of choice for resectable colorectal liver metastases. Neoadjuvant chemotherapy can downstage the tumour and enable surgery in up to 38 per cent of patients whose tumours were initially considered irresectable. METHODS: This prospective study included 150 patients who underwent hepatic resection over a 4-year period. One hundred and sixteen patients had resection without neoadjuvant chemotherapy (group 1) and 34 had chemotherapy before liver surgery (group 2). Perioperative features, survival and pattern of recurrence were compared. RESULTS: Median follow-up was 35.1 months. The in-hospital mortality rate was zero. Three-year overall survival in the two groups was comparable (P = 0.232). The 3-year disease-free survival rate was 21 per cent in the neoadjuvant group compared with 50.5 per cent in the immediate resection group (P < 0.001). Recurrence rates were 94 per cent (32 of 34) in group 1 and 66.4 per cent in group 2 (P = 0.001); extrahepatic recurrence, alone or associated with recurrence in the liver, was significantly more common in group 2 than in group 1 (78 versus 55 per cent; P = 0.016). Multivariate analysis revealed that resection of the recurrence was the most important independent prognostic factor for improved disease-free survival (relative risk 0.2; P < 0.001). Patients in group 2 had reduced disease-free survival (RR 1.8; P = 0.012). CONCLUSION: The recurrence rate among patients who had neoadjuvant chemotherapy and surgery for initially irresectable liver metastases was extremely high. Re-resection should be attempted whenever feasible.

Adult↗
PubMed2006

Diagnostic accuracy of portal-phase CT and MRI with mangafodipir trisodium in detecting liver metastases from colorectal carcinoma.

AIM: To compare the diagnostic accuracy of single section spiral computed tomography (CT) and magnetic resonance imaging (MRI) with tissue-specific contrast agent mangafodipir trisodium (MnDPDP) in the detection of colorectal liver metastases. MATERIAL AND METHODS: One hundred and twenty-five consecutive patients undergoing surgery for primary and/or metastatic disease were evaluated using CT (5 mm collimation and reconstruction interval, pitch 2), two-dimensional fast spoiled gradient echo (2D FSPGR) T1 and single shot fast-spin echo (SSFSE) T2 weighted breath-hold MRI sequences, performed before and after intravenous administration of MnDPDP. The reference standards were intraoperative ultrasound and histology. RESULTS: The per-patient accuracy of CT was 72.8 versus 78.4% for unenhanced MRI (p = 0.071) and 82.4% for MnDPDP-enhanced MRI (p = 0.005). MnDPDP-enhanced MRI appeared to be more accurate than unenhanced MRI but this was not significant (p = 0.059). The sensitivity of CT was 48.4% versus 58.1% for unenhanced MRI (p = 0.083) and 66.1% for MnDPDP-enhanced MRI (p = 0.004). The difference in specificity between procedures was not significant. The per-lesion sensitivity was 71.7, 74.9 and 82.7% for CT, unenhanced MRI, and MnDPDP-enhanced MRI, respectively; the positive predictive value of the procedures was respectively 84.0, 96.0 and 95.8%. MnDPDP-enhanced MRI provided a high level diagnostic confidence in 92.5% of the cases versus 82.5% for both unenhanced MRI and CT. The kappa value for inter-observer variability was >0.75 for all procedures. CONCLUSIONS: The diagnostic accuracy and sensitivity of MnDPDP-enhanced MRI is significantly higher than single section spiral CT in the detection of colorectal cancer liver metastases; no significant difference in diagnostic accuracy was observed between unenhanced MRI and MnDPDP-enhanced MRI.

Adult↗
PubMed2006

Concurrent radiotherapy does not affect adjuvant CMF delivery but is associated with increased toxicity in women with early breast cancer.

We evaluated whether concurrent radiotherapy (RT) affected delivery and toxicity of adjuvant intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) in women with operable breast cancer. The medical charts of 321 consecutive breast cancer patients who received CMF either alone for 6 cycles, or for 4 cycles following of an anthracycline (A-CMF) were reviewed. One hundred forty-four women underwent radiotherapy concurrently with CMF. Optimal CMF delivery (success as opposite to failure) was defined as the combined achievement of an average relative dose intensity (aRDI) > or = 85% and an average percent of the total dose (aPTD) > or = 90% for the three drugs in the CMF regimen. Multivariate logistic regression analysis showed that concurrent-RT did not affect CMF delivery (OR for success 1.391 p=0.230). The sequential A-CMF regimen (OR for success 0.208, 95% C.I. 0.120-0.360, p<0.001) and age > or = 56 (OR for success 0.351, 95% C.I. 0.200-0.161, p<0.001) were independently associated with suboptimal CMF delivery. Moreover, concurrent RT was independently associated with increased leukopenia, thrombocytopenia, upper abdominal pain, mucositis and fatigue. Our retrospective analysis suggests that concurrent-RT has no impact on optimal CMF delivery, but it increases the burden of CMF-related toxicity.

Adult↗
PubMed2005

Phase II trial of primary radiation therapy and concurrent chemotherapy for patients with locally advanced pancreatic cancer.

OBJECTIVES: Primary chemoradiotherapy for locally advanced pancreatic cancer (LAPC) may improve local control, curative resection rate and long-term survival. We performed a phase II study to evaluate toxicity and activity of primary radiation therapy and concurrent chemotherapy with gemcitabine (GEM) twice weekly in patients (pts) with LAPC. METHODS: From 6/1999 to 6/2003, 23 LAPC pts received GEM 100 mg/m2 twice weekly in the first 15 pts and 50 mg/m2 in the last 8 pts, concurrently with radiotherapy (1.8 Gy/day for a total dose of 45 Gy). RESULTS: The treatment was completed in 19/23 pts. Toxicities: G3-4 hematological toxicity occurred in 35 and 4% respectively; G3 nausea and vomiting and gastrointestinal toxicity in 30%. Clinical benefit was found in 10/18 pts (55%). Overall response: partial response rate 4/18 (22%); stable disease 13/18 (72%); progressive disease 1/18 (6%). Six pts underwent pancreaticoduodenectomy with extended lymphadenectomy (5/6 pts pT3, 1/6 pts microscopic cancer foci, 1/6 N+, 5/6 negative retroperitoneal margin). MEDIAN SURVIVAL: 14 months for the entire group, 12 months for unresected pts, 20 months for resected pts. CONCLUSIONS: The treatment with GEM twice weekly at 50 mg/m2 associated with radiotherapy (45 Gy) is feasible and permits to obtain clinical benefit in a good percentage of pts. Objective response, median survival, and local and systemic control are similar to other studies and need further improvement.

Adolescent↗
PubMed2005

A modified Trastuzumab antibody for the immunohistochemical detection of HER-2 overexpression in breast cancer.

The immunohistochemical determination of HER-2 to identify patients with advanced breast cancer candidates for Trastuzumab treatment proved neither accurate nor fully reliable, possibly because none of the current reagents detects the specific antigenic site target of Trastuzumab. To circumvent this problem, we conjugated the NH2 groups of Trastuzumab with biotin, and the compound obtained, designated BiotHER, was added directly to tissue sections. Biotin-labelling was revealed with horseradish peroxidase-conjugated streptavidin. Specificity and sensitivity of BiotHER immunostaining with respect to HER-2 amplification were tested on 164 breast carcinoma samples. BiotHER staining was detected on the tumour cell membrane of 12% of all specimens and in 49% specimens with gene amplification, while absent in nonamplified tumours. Predictivity of BiotHER status with respect to the clinical outcome was analysed in 54 patients with HER-2 amplified advanced breast cancer treated with Trastuzumab plus chemotherapy. BiotHER staining, detected in 50% of tumours with HER-2 amplification, was an independent predictor of clinical outcome. In fact, BiotHER positivity was independently associated with increased likelihood of tumour response and reduced risk of tumour progression and death. Biotinylated Trastuzumab can thus be used for immunohistochemical detection of HER-2 overexpression in breast cancer, and has the potential to identify patients likely to benefit from Trastuzumab treatment.

Adult↗
PubMed2004

Dynamic contrast enhanced magnetic resonance imaging in monitoring bone metastases in breast cancer patients receiving bisphosphonates and endocrine therapy.

PURPOSE: To study the role of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in monitoring the response of bone metastases to endocrine therapy combined with bisphosphonates in patients with breast cancer. MATERIAL AND METHODS: Ten breast cancer patients with bone metastases who were to receive endocrine therapy and bisphosphonates were investigated prospectively by DCE-MRI. We chose a reference lesion for each patient who was studied at baseline, within 3 weeks from the second administration of bisphosphonates, and after 4 and 8 months from the initiation of medical treatment. Time/intensity curves, representing temporal changes of signal intensity in areas of interest in the context of the target lesions (ROI), were obtained for each DCE-MRI. RESULTS: Changes in the shape of the T/I curves suggesting tumor regression were seen shortly after the initiation of medical treatment in the three patients who had the most durable responses. CONCLUSION: DCE-MRI has the potential to detect early changes related to medical treatment in bone metastases from breast cancer. If confirmed in larger series, these data identify DCE-MRI as a diagnostic tool for evaluating new bone targeting antineoplastic agents.

Adult↗
PubMed2003

ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells.

Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT-PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker.

Adolescent↗
PubMed2002

High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study.

PURPOSE: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse. PATIENTS AND METHODS: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT. RESULTS: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%. CONCLUSION: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.

Adolescent↗
PubMed2002

Role of different medium and growth factors on placental blood stem cell expansion: an in vitro and in vivo study.

Expansion of haemopoietic stem cells from placental blood has been obtained with a combination of flt3 ligand (FL), thrombopoietin (TPO), kit-ligand (KL) with or without interleukin-6 (IL6) in serum-replete medium. For clinical use, cell expansion in the absence of serum is a clear advantage. Therefore, stem cell expansion in serum-free (SF) medium with a combination of three (FL, TPO, KL) or four (FL, TPO, KL, IL6) growth factors was compared with the results obtained using fetal calf serum (FCS) or human serum (HS). Human CD34(+) placental blood cells were cultured in the presence of FL, TPO, KL +/- IL6 with SF medium, HS and FCS for up to 8 weeks. CD34(+), CFC, LTC-IC content was measured at intervals. To determine the in vivo repopulating capacity of expanded cells, CD34(+) expanded cells were transplanted in sublethally irradiated NOD/SCID mice. With the three growth factor combination the CD34(+) cell number increased steadily up to the 8 weeks of culture. CD34(+) cells were expanded 67.5-fold with SF, 11.7 with HS and 49.2 with FCS. However, when CFCs and LTC-ICs were considered, a continuous expansion was observed only with HS and FCS, whereas in SF medium after 6 weeks their number started to decline. The addition of IL-6 did not change the expansion significantly. Cells grown ex vivo for 14 days were transplanted into NOD/SCID mice. The engraftment of human cells in mice was higher for serum-replete than for SF expanded cells. Nevertheless, SF cultured cells were also able to engraft both marrow and spleen in all animals. In addition, engrafted human cells still maintained clonogenic ability. With KL, FL, TPO +/- IL6 it is possible to expand haemopoietic progenitor cells in a SF medium. Compared with serum-replete cultures, the absolute number of clonogenic cells and in vivo repopulating cells is lower. Although the degree of expansion remains significant, a clinical trial still needs to be carried out to address the question of whether this expansion might be useful in reducing post-transplant aplasia.

Animals↗
PubMed2001

Detection of breast cancer cell contamination in leukapheresis product by real-time quantitative polymerase chain reaction.

Identification of sensitive techniques for breast cancer cell detection might be relevant for high-dose chemotherapy programs with autologous stem cell transplantation. We investigated the feasibility of Maspin, Mammaglobin and c-ErbB-2 amplification by real-time quantitative polymerase chain reaction (RQ-PCR) for the detection of breast cancer cells in leukaphereses. Expression of the three markers was determined in primary breast cancers and cell lines. Peripheral blood (PB), bone marrow (BM), and leukapheresis samples from patients with malignancies other than breast cancer were used as controls. Sensitivity was evaluated by dilution of primary tumors and cell lines with mononuclear blood cells. We found expression of the three markers in all primary tumors and most cell lines. No blood specimen from control patients had the Maspin transcript, while only one was positive for Mammaglobin. Weak c-ErbB-2 expression was detectable in most PB, all BM and all leukapheresis samples from controls. We observed a low sensitivity of Maspin RQ-PCR and a sensitivity of Mammaglobin RQ-PCR up to one tumor cell in 10(6) mononuclear cells. One out of 18 leukaphereses from breast cancer patients screened for the presence of Mammaglobin mRNA was positive. We conclude that Mammaglobin RQ-PCR might be a useful tool for detection of leukapheresis contamination.

Blood↗
PubMed2001

[Prevalence of anemia in oncologic patients treated with chemotherapy. Italian survey at the national level].

UNLABELLED: In Italy the prevalence of anemia in cancer patients has only been indirectly drawn from clinical studies, and a direct estimation has never been made. METHODS: This is the first nation-wide survey on the prevalence of anemia in cancer patients in Italy. In 193 Centres, clinical data were collected on consecutive patients with non-myeloid malignancies entering a new cycle of chemotherapy during a reference week in 1997. RESULTS: A total of 1763 patients has been recruited. At the time of enrollment grade I-II anemia was observed in 56% of patients, although only 1% showed severe anemia. Most of the patients (73%) experienced a decrease of haemoglobin level following treatment completion. Drop of haemoglobin correlated with a more advanced stage of the disease and with a lower performance status at baseline. CONCLUSION: Anemia is an increasingly common complication in cancer patients undergoing chemotherapy. Improving our knowledge on occurrence of anemia and the type of neoplasms and chemotherapies which are more likely to be associated with this complication may allow the adoption of specific measures to prevent the development of anemia and to avoid the need of blood transfusion in these patients.

Anemia↗
PubMed2000

Short term treatment with Escherichia coli recombinant human granulocyte-macrophage-colony stimulating factor prior to chemotherapy for Hodgkin disease.

BACKGROUND: Granulocyte-macrophage-colony stimulating factor (GM-CSF) administration stimulates the proliferation of hemopoietic progenitors. Shortly (48-96 hours) after its discontinuation, feedback phenomena occur and the progenitor proliferation rate drops below baseline levels. As the quiescence of hyperplastic bone marrow suggests that hemopoietic cells may be refractory to the toxic effects of cytostatic drugs, the decision was made to test the hypothesis that GM-CSF given before chemotherapy may be myeloprotective. METHODS: Fifty-six patients with newly diagnosed Stage II-IV Hodgkin disease, ages 18-77 years, were randomized to receive GM-CSF (5 microg/kg subcutaneously) or placebo from Day 7 to Day 4 before each chemotherapy administration (6 cycles of a hybrid of mechlorethamine, vincristine, procarbazine, and prednisone with doxorubicin, bleomycin, vinblastine, and dacarbazine). The treatment was considered a success if the delivery rate of chemotherapy was >90% after 3 cycles and >80% after 6 cycles. RESULTS: Thirty patients received GM-CSF and 26 placebo. The dose intensity (85.2% vs. 79.6%) and the overall success in terms of delivery rate (56.7% vs. 50%) were higher in the GM-CSF group, although these differences were not statistically significant. The neutrophil nadirs were higher in the GM-CSF group during the first three cycles and subsequently similar in both groups. CONCLUSIONS: No significant differences in terms of myelotoxicity or drug delivery were observed between the two treatment arms. Although the myeloprotective effect of the prechemotherapy administration of GM-CSF seems to be minimal, the data indicate a safe timing between GM-CSF discontinuation and further chemotherapy. Because cumulative myelotoxicity has been observed with other growth factors, given in the interval between the chemotherapy cycles, this may be relevant to the planning of rapid cycling.

Adolescent↗
PubMed2000

The involvement of human-nuc gene in polyploidization of K562 cell line.

During megakaryocyte differentiation, the immature megakaryocyte increases its ploidy to a 2(x) DNA content by a process called endomitosis. This leads to the formation of a giant cell, the mature megakaryocyte, which gives rise to platelets. We investigated the role of human-nuc (h-nuc), a gene involved in septum formation in karyokynesis in yeast, during megakaryocytic polyploidization. Nocodazole and 12-O-tetradecanoylphorbol-13-acetate (TPA) were used to induce megakaryocytic differentiation in K562 cell line. The ploidy distribution and CD41 expression of treated K562 cells were evaluated by flow cytometry. Using quantitative reverse transcriptase polymerase chain reaction (RT-PCR), we analyzed the h-nuc mRNA expression on treated K562 cells. Mature megakaryocyte-like polyploid cells were detected at day 5-7 of treatment with nocodazole. TPA also had a similar effect on K562 cells, but it was much weaker than that of nocodazole. The analysis of ploidy of nocodazole-treated K562 cells showed that nocodazole preferentially induced polyploidization of K562 cell line with a pronounced increase of the cells 8N at day 7 of culture. Expression of CD41, a differentiation-related phenotype, was significantly induced by TPA after 7 days of treatment, showing that functional maturation was mainly induced by TPA. In contrast, there was no significant increase in CD41 expression in nocodazole-treated K562 cells, suggesting that polyploidization and functional maturation are separately regulated during megakaryocytopoiesis. RT-PCR analysis indicated that h-nuc mRNA increased after 72 hours in the presence of nocodazole, preceding the induction of polyploidization. Our data indicate that h-nuc might play a role in polyploidization during megakaryocytic differentiation via inhibition of septum formation.

Apoptosis↗