Adjuvant chemotherapy in average-risk adult medulloblastoma patients improves survival: a long term study.

BACKGROUND: Medulloblastoma is extremely rare in adults. The role of chemotherapy for average-risk adult patients remains controversial. Surgery and radiotherapy provide a significant disease control and a good prognosis, but about 25% of average-risk patients have a relapse and die because of disease progression. No data in average-risk adult patients are available to compareradiotherapy alone and radiotherapyfollowed byadjuvant chemotherapy. METHODS: We analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016. RESULTS: Median age was 29 years (range 16-61). Based on histological subtypes, 15 patients (31.3%) had classic, 15 patients (31.3%) had desmoplastic, 5 patients (10.4%) had extensive nodularity and 2 patients (4.2%) had large cells/anaplastic medulloblastoma. Twenty-four patients (50%) received adjuvant radiotherapy alone and 24 (50%) received radiotherapy and chemotherapy. After a median follow-up of 12.5 years, we found that chemotherapyincreases progression-free survival (PFS-15 82.3 ± 8.0% in patients treated with radiotherapy and chemotherapyvs. 38.5% ± 13.0% in patients treated with radiotherapy alone p = 0.05) and overall survival (OS-15 89.3% ± 7.2% vs. 52.0% ± 13.1%, p = 0.02). Among patients receiving chemotherapy, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia (6 cases of G3 neutropenia [25%] and 3 cases of G4 neutropenia [13%]), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%). CONCLUSIONS: Our study with a long follow up period suggests that adding adjuvant chemotherapy to radiotherapy might improve PFS and OS in average-risk adult medulloblastoma patients.

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Adjuvant chemotherapy in adult medulloblastoma: is it an option for average-risk patients?

The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or ≤1.5 cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age >16 years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide ± cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9 %) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if ≤1.5 cm) and delay in RT. After a median follow up time of 10 years (range: 8-13), median survival was 18 years (95 % CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15 years were 100 %, 78.6 % (95 % CI 60.0-97.2 %) and 60.2 % (95 % CI 36.9-83.5 %), in patients treated with RT alone, and 100, 100 and 100 %, in patients treated with RT plus chemotherapy (p = 0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group).

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

BACKGROUND: The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. PATIENTS AND METHODS: This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. RESULTS: From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. CONCLUSIONS: The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EUDRACT NUMBER: 2012-003505-10.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Relationship between prognostic factors of breast cancer and 99mTc-sestamibi uptake in patients who underwent scintimammography: Multivariate analysis of causes of false-negative results.

The complementary role of sestamibi scintimammography (SSM) in patients with breast cancer (BC) is well established. The aim of this study was to establish whether a relationship exists between sestamibi uptake, evaluated as a tumour-to-background ratio (TBR), and the main prognostic factors of BC. SSM with the measurement of TBR was performed preoperatively in 102 women (median age 57 years, range 32-81 years) who underwent curative surgery for primary BC. Final pathology showed 4 (3.9%) with pT1a, 17 (16.7%) with pT1b, 44 (43.1%) with pT1c and 37 (36.3%) with pT2 breast carcinomas. The overall sensitivity of SSM was 80.4%. An ANOVA showed significant (P<0.01) differences between the TBR of patients with G1 vs. G3 tumours, and between the TBR of those with G2 vs. G3 breast carcinomas. Moreover, there was a difference (P=0.021) between the TBR of patients (n=12, 11.8%) with CEA serum levels >10 ng/ml (2.031+/-0.420), and those with normal (n=90, 88.2%) CEA values (1.713+/-0.446), whilst no difference (P=NS) was found between patients (n=27, 26.5%) with CA 15-3 >30 U/ml (1.893+/-0.401) and those with normal (n=75, 73.5%) CA 15-3 values (1.699+/-0.462). There was a mild inverse correlation between TBR and both the oestrogen (R=0.25, P=0.011) and the progesterone receptor (R=0.23, P=0.02) rate. The logistic regression analysis showed that only size and CA 15-3 serum levels represent true independent parameters, but the function was able to predict only 11 out of 21 (52.4%) patients with false-negative SSM. TBR is independent of age and mainly correlates with the size of the tumour. There are no reliable preoperative prognostic factors that are really useful for improving SSM sensitivity in patients with small breast carcinomas.

Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study.

PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). PATIENTS AND METHODS: Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. RESULTS: The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). CONCLUSION: Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.

PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

The treatment of cranial germ cell tumours.

Germ cell tumours of the central nervous system (CNS) include many subtypes whose response to treatment varies, even though the symptoms and radiological appearances are similar. Five-year survival rates are 96% for germinomas, 100% for mature teratomas, 67% for immature teratomas and 69% for immature teratomas mixed with germinomas; for beta-HCG secreting germinomas the rate is only 38%. Patients with choriocarcinoma, embryonal carcinoma, or yolk sac tumour have the lowest survival rates; patients with germinoma or mature teratoma have longer survival rates. Although a wider resection is associated with a higher rate of survival for patients with non-germinomatous germ cell (NGGC) tumours, to date an aggressive surgical approach has been advocated only for pineal region tumours, but not for hypothalamic/neurohypophyseal tumours. Beside the delayed injury induced by radiotherapy, the late injury induced by chemotherapy is becoming increasingly evident. Cisplatin is considered an indispensable drug, but it may cause renal damage, ototoxicity, peripheral neuropathy and sterility, while etoposide is associated with an excess frequency of second neoplasms. Taking into account all of the published literature, the following therapeutic options are suggested: in pure germinoma tumours (GT) radiotherapy alone will usually ensure adequate control of the disease, and the long-term sequelae may be limited by reducing the dose delivered, as was proposed for germ cell testicular tumours, to 30 Gy to limited fields plus 25-30 Gy to the spinal axis if there is disseminated disease. In cases of recurrence, which should be uncommon, patients may be rescued with both radiotherapy and chemotherapy. In NGGC tumours, the prognosis is more unfavourable and there is often dissemination to the spine at diagnosis; however, the tumour's high chemosensitivity suggests neoadjuvant treatment chemotherapy with cisplatin and etoposide for three cycles followed by consolidation radiotherapy with 40 Gy to the limited fields plus 30 Gy to the spinal axis if disseminated. In our opinion, a higher dose of radiotherapy in cases in which chemotherapy does not achieve a radiological complete remission is not advisable, because very often the residual radiological abnormality does not represent biologically active tumour but differentiated forms such as mature teratoma. The challenge for 2000 is to both cure these patients, and avoid the late and permanent sequelae of radiation and/or chemotherapy that may subsequently impair quality of life.

Medulloblastoma in adults: clinical characteristics and treatment.

Long-term survival is possible in adults with medulloblastoma with rates of approximately 50-60% at 5 years, and 40-50% at 10 years. As the literature data are based on retrospective studies, treatments are neither randomized nor uniform, however, some treatment cornerstones have been identified. The first step is surgery, which should be as radical as possible; adjuvant radiotherapy must be 55 Gy on the posterior fossa, and 36 Gy on the remaining cranial-spinal axis; adjuvant chemotherapy may be useful in patients at high risk of recurrence provided it is administered before radiotherapy in moderate-high dosages and includes cisplatin, etoposide and cyclophosphamide. This chemotherapy program should not overly delay the start of radiotherapy, be recycled as soon as blood count permits and not exceed two or three cycles. Adjuvant chemotherapy after radiotherapy, even if indicated in cases with persistent tumour, may have an adverse effect due to the poor marrow reserves of these patients. At recurrence the prospects of cure are very poor due to the deficient hematopoietic reserve, but in very young patients high dose chemotherapy with marrow rescue might be usefully employed.

Temozolomide chemotherapy in recurrent oligodendroglioma.

The authors determined the tolerance, response rate, and duration of recurrent anaplastic oligodendroglioma in 30 patients to temozolomide given orally at 150 to 200 mg/m2 on days 1 through 5 in cycles of 28 days. Nine patients responded: 7 of 27 patients (26%) treated with temozolomide after prior PCV chemotherapy and 2 of 3 chemotherapy-naive patients (both complete response). Median time to progression in responding patients was 13 months. Temozolomide shows promise and has an acceptable safety profile in recurrent anaplastic oligodendroglial tumors. Patients not responding to PCV may respond to temozolomide.

A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme.

BACKGROUND: Nitrosoureas constitute the main resource of chemotherapy for glioblastoma. However, because of chemoresistance, which is intrinsic or rapidly acquired after the first administration of chemotherapy, there have been few improvements in survival. Because O(6)-alkylguanine-DNA alkyltransferase (AGT) is the main target for increasing cell sensitivity to the nitrosoureas, we postulated that preexposure to other alkylating agents might increase the therapeutic index of the nitrosoureas by saturating all the copies of AGT present in the tumor cells. OBJECTIVE: To investigate the response rate, toxic effects, time from start of chemotherapy to progression of disease or exit from the study for any reason (TTP), and progression-free survival at 6 months (PFS-6) associated with a multidrug combination that could reverse resistance to carmustine (BCNU) through AGT depletion. METHODS: We conducted a phase 2 study of patients with glioblastoma at first relapse or progression after surgery and standard radiotherapy. Patients were treated with 100 mg/m(2) of procarbazine on days 1 to 5, 80 mg/m(2) of BCNU on days 3 to 5, and 1.4 mg/m(2) of vincristine on day 3 every 8 weeks. RESULTS: Fifty-eight patients were enrolled in the study, and all were assessable for response and toxic effects. Six patients (10.3%) had a complete response, 11 (19%) had a partial response, and 17 (29.3%) had stable disease. The median TTP was 4.8 months; 42.3% of patients had PFS-6, and 15.4% had PFS at 12 months. Response to chemotherapy was the only significant prognostic factor for TTP. Neutropenia was grade 3 in 8.6% of patients and grade 4 in 5.2% of patients, and thrombocytopenia was grade 3 in 17.2% of patients and grade 4 in 12% of patients; hepatic and pulmonary toxic effects were grade 3 in 5.2% and 8.6% of patients, respectively. CONCLUSION: This regimen proved active in chemotherapy-naive patients with recurrent glioblastoma even though toxic effects were substantial.

New strategy developments in brain tumor therapy.

BACKGROUND: The incidence of brain and other central nervous system malignant neoplasias is 6.5 cases per 100,000 inhabitants-years, and appears to increase with increasing age (1.2 % per year), with the greatest rate of increase in the population over age 70 years. MATERIAL AND METHODS: Chemotherapy remains part of the treatment that includes surgery and radiation therapy for the management of malignant gliomas. This article reviews the new drugs that have been introduced in the treatment of these patients in the latest years, their specific cellular targets, the objective response, the TTP and the MST. RESULTS: The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years, and from clinical trials of CPT11. CONCLUSIONS: New approaches to chemotherapy treatment are necessary. Enrollment of patients into rigorous, well conducted, clinical trials, both at tumor diagnosis and recurrence, will generate new information regarding investigational therapies, and may offer improved therapies for patients with malignant gliomas.

Diagnostic advances and new trends for the treatment of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma arising in the brain. Recent increase in its incidence has been noted both in immunocompetent individuals and patients with immunodeficiency. This review will focus on the epidemiology, pathogenesis, diagnosis and treatment of this aggressive extranodal lymphoma in immunocompetent patients. Stereotactic biopsy is usually required for diagnosis, while molecular biology and/or cytofluorimetric analysis may confirm the presence of clonal proliferation in the cerebrospinal fluid (CSF). Methotrexate-based chemotherapy plus whole-brain radiotherapy are the standard treatment for PCNSL and achieve a high rate of complete remissions (CR), but long-term neurotoxicity may heavily compromise the patient's quality of life. The metabolic rate of controversial gadolinium-enhancing lesions on magnetic resonance (MR) scans may be assessed with positron emission tomography (PET), which discriminates radiation necrosis from true recurrence. Withholding radiotherapy in patients achieving CR after first-line chemotherapy is a new and interesting treatment option, while the role of high-dose chemotherapy with stem cell rescue is still uncertain.

Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study.

A prospective study of a series of 77 patients on adjuvant radiochemotherapy following surgery for high-grade gliomas was conducted to evaluate the risk of deep vein thrombosis and identify risk factors. We found a 20.8% risk of deep vein thrombosis at 12 months (standard error = 4.8%) and a 31.7% risk (standard error = 7.4%) at 24 months (Kaplan-Meier method). Twenty patients (26%) developed deep vein thrombosis with a maximum incidence within the first 7 months after surgery when chemotherapy was still being administered, often with corticosteroids. The risk factors identified were histology (glioblastoma versus anaplastic astrocytoma, P = 0.032, log rank test; 0.0485 L-ratio) and the presence of paresis (P = 0.010, log rank test; 0.0161 L-ratio). A borderline tendency was found for an association between the deep vein thrombosis site and the side of paresis (P = 0.103, Fisher's exact test). Four patients (5%) had massive pulmonary embolism, which was fatal in 3 (4%).

Changing boundaries in the treatment of malignant gliomas.

Malignant gliomas are still among the most lethal and difficult tumors to treat; even the most intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on survival for most of these patients, as long-term survivors are less than 10%. There is a major need for new chemotherapeutic drugs and alternative therapeutic modalities. This review aims to define the best standard treatment in the common clinical practice and also summarizes the most promising lines of investigational research in the field of neuro-oncology, which will probably offer new and long-awaited valid therapy options for brain tumor patients.

Seroma prevention following axillary dissection in patients with breast cancer by using ultrasound scissors: a prospective clinical study.

AIMS: Seroma formation following axillary dissection is a common complication of breast surgery. The aims of this study were (1) to analyse the risk factors of seroma formation, and (2) to evaluate the role of ultrasound scissors in performing axillary dissection in patients with primary breast cancer undergoing mastectomy and breast-conserving surgery. METHODS: Ninety-two women (median age 55 years, range 33-73 years) requiring surgery for known unilateral primary breast cancer (pT1a=1, pT1b=20, pT1c=43, pT2=25, pT3=3) were prospectively randomised to undergo axillary dissection by either using (Group A, 45 patients) or not using (Group B, 47 patients) ultrasound scissors (US). Thirty-eight (41.3%) patients underwent modified radical mastectomy, while 54 (58.7%) underwent breast-conserving surgery. RESULTS: Twenty-eight (30.4%) patients (Group A=9 out of 45, 20%; Group B=19 out of 47, 42%; P=NS) developed a wound seroma. Multivariate analysis using a logistic regression model showed that surgical procedure (RR=8.9; 95% CI: 3.2-25.3), total amount of drainage (RR=7.8; 95% CI: 2.8-22.0), and size of the tumour (RR=6.0; 95% CI: 2.2-16.5) independently correlated with seroma formation. The logistic regression function (RR=19.4; 95% CI: 6-62) correctly allocated 75 out of 92 (81.5%) patients. CONCLUSIONS: Size of the tumour, and total amount of drainage represent the principal factors of seroma formation following axillary dissection in patients undergoing surgery for breast cancer. Although the use of ultrasound cutting devices may reduce the risk of seroma formation, further studies are need to verify the real impact on long-term morbidity of such technique.

Usefulness of 99m-Tc-sestamibi scintimammography in suspected breast cancer and in axillary lymph node metastases detection.

AIMS: To evaluate the usefulness of 99m-Tc-sestamibi scintimammography (SSM) in the detection of T1-2, N0-1, M0 breast cancer (BC) and axillary node (AN) metastases. PATIENTS AND METHODS: A series of 239 women (median age 55 years) who had already been selected for breast biopsy underwent both mammography (MG) and SSM before surgery. The final diagnosis confirmed in 207 (86.6%) patients, and benign breast lesions in 32 (13.4%). RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MG and SSM in BC detection were 88.9% vs 87.9%, 62.5% vs 93.8% (P<0.01), 93.9% vs 98.9%, 46.5% vs 54.5%, and 85.4% vs 88.7%, respectively. Age did not affect (P=NS) SSM sensitivity, and in premenopausal patients (n=80 (33.5%)) its specificity was 100%. Overall sensitivity and specificity of SSM for assessing AN involvement were 82.3% and 94.1%, respectively. In patients with <3 AN metastases (n=33 (53.2%)) SSM sensitivity was 69.7%, and only one out of six patients with a single AN metastasis had a positive scan. CONCLUSIONS: In patients with suspicious MG undergoing biopsy, SSM should be considered before surgery because of its high specificity, especially in younger patients. At present, its usefulness in detection of AN metastases is still modest and does not allow a correct pre-operative staging of patients with BC.