Umberto Basso

Second-Line Chemotherapy With Irinotecan Plus Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

PURPOSE Glioblastoma multiforme (GBM), the most frequent brain tumor in adults, is not considered chemosensitive. Nevertheless, there is widespread use of first-line chemotherapy, often with temozolomide, as a therapeutic option in patients with progressive disease after surgery and radiotherapy. However, at the time of second recurrence and/or progression, active and noncross-resistant chemotherapy regimens are required. The aim of the present multicenter phase II trial, therefore, was to ascertain the efficacy of second-line carmustine (BCNU) and irinotecan chemotherapy. PATIENTS AND METHODS Patients with histologically confirmed GBM, recurring or progressing after surgery, standard radiotherapy and a first-line temozolomide-based chemotherapy, were considered eligible. The primary end-point was progression-free survival at 6 months (PFS-6), and secondary end-points included response rate, toxicity, and survival. All patients were on enzyme-inducing antiepileptic prophylaxis. Chemotherapy consisted of BCNU (100 mg/m2 on day 1) plus irinotecan (175 mg/m2/weekly for 4 weeks), every 6 weeks, for a maximum of eight cycles. In the absence of grade 2 toxicity, the irinotecan dose was increased to 200 mg/m2. RESULTS A total of 42 patients (median age, 53.4 years; median Karnofsky performance status, 80; range, 60 to 90) were included in the study. PFS-6 was 30.3% (95% CI, 18.5% to 49.7%). Median time to progression was 17 weeks (95% CI, 11.9 to 23.9). Nine partial responses (21.4%; 95% CI, 9% to 34%) were obtained. Toxicity was manageable. CONCLUSION The BCNU plus irinotecan regimen seems active and non-cross-resistant in patients with GBM with recurrence after temozolomide-based chemotherapy.

First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia

PURPOSE Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. PATIENTS AND METHODS Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. RESULTS A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%). CONCLUSION The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

M30 Neoepitope Expression in Epithelial Cancer: Quantification of Apoptosis in Circulating Tumor Cells by CellSearch Analysis

Purpose: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment. Experimental Design: An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer. Results: M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings. Conclusions: M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers. Clin Cancer Res; 16(21); 5233–43. ©2010 AACR.

Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: A phase II study

BACKGROUND To investigate the efficacy of temozolomide in relation to response rate, toxicity, time to progression. and median survival time, a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea, procarbazine and vincristine. PATIENTS AND METHODS Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. RESULTS Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%-35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. CONCLUSIONS On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). Temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma.

Endocrine Therapy of Breast Cancer

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.

Treatment of Estrogen Receptor-Positive Breast Cancer

Estrogen receptor (ER) expression is the main indicator of potential responses to endocrine therapy (ET), and approximately 70% of human breast cancers (BCs) are hormone-dependent and ER-positive. The introduction of adjuvant systemic therapy led to a significant improvement in post-surgical survival and a reduction in disease relapse, especially in women with early BC and those with ER+ tumors, who may receive ET alone or in combination with cytotoxic therapy. Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor modulators (SERMs) and down-regulators, and (iii) aromatase inhibitors (AIs). In patients with ER+ tumors pharmacologic ovary suppression with gonadotropin-releasing hormone agonists in combination with standard adjuvant therapy is generally more effective than adjuvant chemotherapy alone. Tamoxifen is the best established SERM, has favorable effects on BC control and bone metabolism, but also has adverse effects due to its estrogenic activity in other tissues. For these reasons, other SERMs have been developed. Fulvestrant is an ER down-regulator with several potential advantages over SERMs, including a 100-fold increase in its affinity for ER compared with tamoxifen and no estrogen-like activity in the uterus. The inhibition of the aromatase system with third-generation AIs is associated with improved survival in patients with advanced BC compared with SERMs. In postmenopausal patients with ER+ BC adjuvant treatment with AIs should be performed, either as sequential treatment after tamoxifen or as upfront therapy. Studies evaluating the role of AIs as first-line therapy are ongoing and the results are encouraging.

Temozolomide in Patients with Glioblastoma at Second Relapse after First Line Nitrosourea-Procarbazine Failure: A Phase II Study

Objectives: To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Methods: Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m2/daily for 5 days every 4 weeks. Results: The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14–42%) and 8% (CI = 2–27%), respectively, with a median TTP of 11.7 weeks (CI = 9–22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7–31%). Conclusion: TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM.

Telomerase activity in chronic lymphoproliferative disorders of B-cell lineage

The progressive shortening of telomeres at each cell division is a key mechanism in controlling cell proliferative capacity. The activation of telomerase, a reverse transcriptase that extends telomere length, potentially leads to unlimited cell proliferation, and is believed to play a critical role in the neoplastic process. High levels of telomerase activity have been demonstrated in almost all solid tumours; however, little data is available concerning its expression in chronic B‐cell neoplasms. By using a quantitative polymerase chain reaction‐based method we quantified telomerase activity in normal B lymphocytes, and in various B‐cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and hairy cell leukaemia (HCL). Compared to normal B cells, which expressed very low levels of telomerase activity, malignant cells from most of the patients showed a significant increase in telomerase activity, with highest values observed in HCL samples. Moreover, among the CLL and HCL cases, significantly higher levels of telomerase activity were found in patients with progressive disease at 1 year follow‐up versus patients with stable disease. These data suggest that telomerase activity might correlate with disease progression.

Cells and Molecules Involved in the Development of Sarcoid Granuloma

Although the etiology of sarcoidosis is still unknown, characteristic morphologic aspects and immunohistological patterns of sarcoid granulomatous lesions suggest that they are the consequence of an exaggerated immunological response against an undefined antigen which persists at different sites of disease involvement. This article reviews the newly emerging hypothesis regarding the molecular bases which drive the development of sarcoid granulomas. The accumulation of Th1 cells represents the pivotal step along the series of events that lead to the formation of granuloma; furthermore, a set of biological mediators of the immune response define immune regulatory networks that may contribute to tissue damage. It is also thought that shifts of the Th1/Th2 networks and alterations in the complex networks between immunocompetent cells and mesenchymal cells may set the stage for the remodeling of tissues surrounding granulomatous lesions.

Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST.

Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. In this study, we simultaneously sequenced the genome of all subunits, SDHA, SDHB, SDHC, and SDHD in a larger series of KIT/PDGFRA wild-type GIST in order to evaluate the frequency of the mutations and explore their biological role. SDHA, SDHB, SDHC, and SDHD were sequenced on the available samples obtained from 34 KIT/PDGFRA wild-type GISTs. Of these, in 10 cases, both tumor and peripheral blood (PB) were available, in 19 cases only tumor, and in 5 cases only PB. Overall, 9 of the 34 patients with KIT/PDGFRA wild-type GIST carried mutations in one of the four subunits of the SDH complex (six patients in SDHA, two in SDHB, one in SDHC). WB and immunohistochemistry analysis showed that patients with KIT/PDGFRA wild-type GIST who harbored SDHA mutations exhibited a significant downregulation of both SDHA and SDHB protein expression, with respect to the other GIST lacking SDH mutations and to KIT/PDGFRA-mutated GIST. Clinically, four out of six patients with SDHA mutations presented with metastatic disease at diagnosis with a very slow, indolent course. Patients with KIT/PDGFRA wild-type GIST may harbor germline and/or de novo mutations of SDH complex with prevalence for mutations within SDHA, which is associated with a downregulation of SDHA and SDHB protein expression. The presence of germline mutations may suggest that these patients should be followed up for the risk of development of other cancers.