Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Delay in starting radiotherapy due to neoadjuvant therapy does not worsen survival in unresected glioblastoma patients.

PURPOSE: We retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients. PATIENTS AND METHODS: We compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy. RESULTS: OS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13 weeks for the NA group and 4.2 weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12 weeks and the shortest by patients who started radiotherapy within 4 weeks (12.3 vs 6.6 months) (P = 0.05). OS was 6.6 months for patients who started radiotherapy before the optimal cutoff of 6.43 weeks and 19.1 months for those who started after this time (P = 0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P = 0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor. CONCLUSION: In our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

Correction to: SEOM clinical guideline of diagnosis and management of low-grade glioma (2017).

The original version of this article unfortunately contained a mistake. Figure 3 was incorrect.

SEOM clinical guideline of diagnosis and management of low-grade glioma (2017).

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk-benefit ratio of adjuvant treatment must be weighed for each individual.

The usefulness of 18F-fluorocholine PET/CT in the detection of recurrence of central nervous system primary neoplasms. / Valor de la PET/TC cerebral con 18F-fluorocolina en la detección de recurrencias de neoplasias primarias del sistema nervioso central.

AIM: To study the usefulness of 18F-fluorocholine (FCH) in detecting the recurrence of primary brain tumours. MATERIAL AND METHODS: A prospective study was conducted on brain PET/CT with FCH for compassionate use in 21 patients with suspected recurrence of a primary brain tumour. The distribution by pathology was: three grade ii astrocytomas, three grade iii astrocytomas, one grade ii oligodendroglioma, three grade iii oligodendrogliomas, one grade iii oligoastrocytoma, four glioblastoma multiform, one gliomatosis cerebri, and five meningiomas. Studies in which there was a visually significant uptake in the brain parenchyma were classified as positive. RESULTS: A total of 17 patients were classified as positive, with the results being confirmed by histology (10 cases) or clinical follow-up and imaging, with no false positives or negatives. The mean SUVmax for positive patients was 8.02 and 0.94 for the negative ones, which was significantly different (P=.003) CONCLUSION: PET/CT with FCH shows encouraging results in the evaluation of patients with suspected recurrence of primary brain neoplasms.

Nasopharyngeal carcinoma: 30-year experience of a single institution in a non-endemic area.

PURPOSE: Over the past years, radiotherapy techniques have changed significantly. The impact of these changes in the management of nasopharyngeal carcinoma (NPC) has not been fully evaluated. METHODS/PATIENTS: Between 1984 and 2014, 223 NPC were diagnosed in our hospital. Prior to 2000, patients were treated with 2D treatment plan (RT2D) that evolved to 3D schemes thereafter (RT3D). RESULTS: Tumors in the RT3D period showed significantly lower stages than those in the RT2D period. 5-year cause-specific survival improved from 55.7% (95% CI: 46.7-64.7%) in the RT2D period to 78.7% (95% CI: 68.7-88.7%) in the RT3D period (P = 0.006). This difference was greater for non-keratinizing NPC, where specific survival went from 63.2% (95% CI: 52.2-74.2%) to 84.4% (95% CI: 74.4-94.4%) (P = 0.014). CONCLUSION: Recent changes in treatment strategies including concurrent chemoradiation and 3D radiotherapy may have impacted in better survival for NPC. Improved imaging techniques may have contributed by earlier detection and better treatment planning.

Nonsurgical treatment of recurrent glioblastoma.

Standard treatment for glioblastoma multiforme is surgery followed by radiotherapy and chemotherapy, generally with temozolomide. However, disease recurs in almost all patients. Diagnosis of progression is complex given the possibility of pseudoprogression. The Response Assessment in Neuro-Oncology criteria increase the sensitivity for detecting progression. Most patients will not be candidates for new surgery or re-irradiation, and anticancer drugs are the most common approach for second-line treatment, if the patient's condition allows. Antiangiogenics, inhibitors of the epidermal growth factor receptor, nitrosoureas, and re-treatment with temozolomide have been studied in the second line, but a standard therapy has not yet been established. This review considers currently available medical treatment options for patients with glioblastoma recurrence.

A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma.

PURPOSE: The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. PATIENTS AND METHODS: Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m(2) days 1-7 and 15-21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. RESULTS: Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44%) had gross total resection. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9% (95% CI 9.3-40.0%). The median PFS and overall survival (OS) were 4.2 months (95% CI 3.6-5.4 months) and 7.3 months (95% CI 5.8-8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19%; 95% CI 7.2-36.4) were long-term survivors, with a median PFS and OS (50% events) of 9.5 months (95% CI 7.9-23.6) and 15.4 (95% CI 8.9-NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. CONCLUSIONS: This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy.

[Microwave ablation of a sarcoma lung metastasis in a patient with a pacemaker]. / Ablación mediante microondas de metástasis pulmonar de sarcoma en paciente portador de marcapasos.

We present the case of a patient with a pacemaker and a sarcoma lung metastasis treated with microwave ablation. Although the treatment of tumours with microwave ablation is a successful and minimally invasive approach, there are concerns about the safety of this procedure for patients with implanted cardiac devices, such as a pacemaker. After careful planning between radiology and cardiology, microwave ablation was indicated in the patient since it is safer and shorter than the radiofrequency technique. The lesion was treated without complications. It is important to communicate the procedures performed, as well as any complications in order to formulate guidelines for the use of microwave ablation in patients with pacemakers.

Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: a Spanish group for research on sarcomas (GEIS) study.

BACKGROUND: This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma. METHODS: Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m(2) respectively). A 3 + 3 dose escalation design with cohorts of 3-6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted. RESULTS: Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m(2) and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m(2). Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro. CONCLUSIONS: RD was sorafenib 400 mg bid plus ifosfamide 6 g/m(2), allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing.

Optimization of the crossflow microfiltration of arazá juice (Eugenia stipitata) under different operation modes / Optimización del proceso de microfiltración tangencial de jugo dearazá (Eugenia stipitata) a diferentes modos de operación

This study analyzed the effects of temperature and transmembrane pressure on the crossflow microfiltration process of arazá (Eugenia stipitata) juice treated with a commercial pectic enzyme preparation, thus finding the appropriate operation values of the process. Clarified arazá juice was obtained with a crossflow microfiltration pilot plant equipped with ceramic membranes with a 0.48 m2 total effective filtration area and mean pore diameter of 0.2 µm. The juice was evaluated at transmembrane pressures 1.5,3.0 and 4.5 bar, and at temperatures of 30, 35 and 40ºC at different volumetric reduction factors. The tests were carried out using three systems (total recirculation, concentration, and continuous mode). In total recirculation, it was found that the most influential variable was the transmembrane pressures, and that the partial enzymatic liquefaction of the arazá juice, prior to microfiltration, produced an unusual pattern of permeate flux, characterized by an increase following an abrupt decrease at 4.5 bar and 6.5 m/s. In this case, the highest values of the flux were obtained when compared with those obtained during the crossflow microfiltration in concentration mode. After reaching the value of volumetric reduction factor (3.2), during the crossflow microfiltration in continuous mode, it was not necessary to stop the process as the volumetric reduction factor remained constant for the continuous removal of retained, achieving a high permeate fluxin a short period of time 319 L/(h m2), thus adding to the economic viability of the process.

En este trabajo se analizaron los efectos de la temperatura y la presión transmembrana sobre el proceso de microfiltración tangencial de jugo de arazá (Eugenia stipitata) tratado con una preparación comercial de enzimas pectolíticas, encontrando los valores adecuados de operación. Se obtuvo un jugo clarificado de arazá con un equipo piloto de microfiltración tangencial provisto de membranas cerámicas de 0,48 m2 de área total efectiva de filtración, diámetro promedio de poro de 0,2 µm, evaluado a diferentes presionestransmembrana de 1,5; 3,0 y 4,5 bar y temperaturas de 30, 35 y 40ºC, a diferentes factores de reducciónvolumétrica. Las pruebas fueron llevadas a cabo utilizando tres modos de operación: recirculación total,concentración y continuo. En recirculación total, se encontró que la variable más influyente sobre el proceso fue la presión transmembrana y que la licuefacción enzimática parcial realizada al jugo de arazá, previo a la microfiltración, produjo un patrón inusual del flux de permeado, caracterizado por un incremento después de una disminución abrupta cuando se trabajó a 4,5 bar y 6,5 m/s. En este caso se encontraron los valores más altos del flux al compararse con los obtenidos durante la microfiltración tangencial en modo de concentración. Una vez alcanzado el valor de factor de reducción volumétrica (3,2) durantela microfiltración tangencial en modo continuo no fue necesario detener el proceso, ya que el factor de reducción volumétrica se mantuvo constante durante la eliminación continua de retenido, lográndose altos flujos de permeado en corto tiempo (319 L/(h m2)), facilitando la viabilidad económica del proceso.

Extended-schedule dose-dense temozolomide in refractory gliomas.

This multicenter phase II study conducted by the Spanish Neuro-Oncology Group evaluated the activity of an extended, dose-dense temozolomide regimen in patients with temozolomide-refractory malignant glioma. Adult patients (at least 18 years of age) with WHO grade III or IV glioma and a Karnofsky Performance Status of 60 or higher were treated with temozolomide (85 mg/m(2)/day) for 21 consecutive days every 28-day cycle until disease progression or unacceptable toxicity. All patients had developed progressive disease either during or less than 3 months after completing previous temozolomide treatment. Forty-seven patients were treated with a median of 2 (range, 1-13) cycles of temozolomide. Before study entry, patients had received a median of 6 cycles of temozolomide: 39 (83%) as part of initial therapy and 23 (49%) as second-line therapy. Three patients (6.4%) had a partial response with durations of 8.0, 3.5, and 3.2 months; 15 patients (31.9%) had stable disease with a median duration of 2.1 months, including 2 patients with stable disease (SD) for greater than 6 months (14 and 16 months). Median time to progression was 2 months, and median overall survival from study entry was 5.1 months. The 6-month progression-free survival rate was 16.7%. The most common hematologic toxicities were lymphopenia, thrombocytopenia, and leukopenia. Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no opportunistic infections occurred. In conclusion, this extended dose-dense schedule of temozolomide appears to have modest activity in patients refractory to previous treatment with temozolomide and is associated with manageable toxicity.

Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism.

The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2 (ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined K(m) values ranged from 0.05 to 0.3 microM and k(cat) values from 2.3 to 17.6 min(-1), while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup. This mutation increased the retinoid activity up to 100-fold. The K(m) values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic retinol oxidation at physiological concentrations.

Changes in the rate of genotypic resistance to antiretroviral drugs in Spain.

Genotypic resistance to antiretroviral drugs was examined in 684 individuals attending 18 outpatient clinics distributed across Spain in June 2000. Compared with similar surveys conducted before 1998, the prevalence of resistance to nucleosides has declined significantly among naive chronic HIV carriers. In contrast, resistance among pre-treated patients has increased; resistance to all three drug families having been recognized in nearly a quarter of patients.

Drug resistance in patients experiencing early virological failure under a triple combination including indinavir.

OBJECTIVE: To assess the pattern of drug resistance mutations selected in HIV-1-infected patients failing a first line triple combination therapy including indinavir. PATIENTS AND METHODS: Plasma samples from 87 patients collected at the time of the first virological rebound (> 50 HIV-RNA copies/ml) were examined for the presence of drug-resistant genotypes. RESULTS: The mean level of plasma viraemia at rebound was 7824 HIV-1 RNA copies/ml in 73 subjects with good compliance, whereas it was 359,460 HIV-1 RNA copies/ml in 14 patients who admitted to poor adherence. Genetic sequence analysis yielded results for 51 (70%) of the patients having good adherence. More than half of them (26/51, 51%) carried primary mutations associated with resistance to nucleoside analogues. In contrast, primary protease inhibitor resistance mutations were recognized less frequently (14/51, 27%; P < 0.05). Moreover, in 23 (45%) patients there was no evidence of drug-resistant viruses at all. The most frequent drug-resistant genotypes in the reverse transcriptase gene were at codons 184 (n = 19), 215 (n = 14) and 41 (n = 8), whereas for the protease they were at codons 46 (n = 10), 82 (n = 9) and 90 (n = 7). No resistance genotypes were found among non-compliant patients. CONCLUSION: The overall rate of drug-resistant HIV genotypes was 38% (28/73) in patients with good adherence and who were experiencing a first virological failure under a triple combination regimen including indinavir; resistance to nucleoside analogues was more frequent than resistance to indinavir. Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified.