The role of adjuvant chemotherapy in patients with H3K27 altered diffuse midline gliomas: a multicentric retrospective study.

PURPOSE: Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and chemotherapy even if only a few retrospective studies assessed the impact on overall survival (OS) of these approaches. METHODS: We carried out an Italian multicentric retrospective study of adult patients with H3K27-altered DMG to assess the effective role of systemic therapy in the treatment landscape of this rare tumor type. RESULTS: We evaluated 49 patients from 6 Institutions. The median age was 37.3 years (range 20.1-68.3). Most patients received biopsy as primary approach (n = 30, 61.2%) and radiation therapy after surgery (n = 39, 79.6%). 25 (51.0%) of patients received concurrent chemotherapy and 26 (53.1%) patients received adjuvant temozolomide. In univariate analysis, concurrent chemotherapy did not result in OS improvement while adjuvant temozolomide was associated with longer OS (21.2 vs. 9.0 months, HR 0.14, 0.05-0.41, p < 0.001). Multivariate analysis confirmed the role of adjuvant chemotherapy (HR 0.1, 95%CI: 0.03-0.34, p = 0.003). In patients who progressed after radiation and/or chemotherapy the administration of a second-line systemic treatment had a significantly favorable impact on survival (8.0 vs. 3.2 months, HR 0.2, 95%CI 0.1-0.65, p = 0.004). CONCLUSION: In our series, adjuvant treatment after radiotherapy can be useful in improving OS of patients with H3K27-altered DMG. When feasible another systemic treatment after treatment progression could be proposed.

The role of preoperative [11C]methionine PET in defining tumor-related epilepsy and predicting short-term postoperative seizure control in temporal lobe low-grade gliomas.

OBJECTIVE: Surgery is the mainstay of treatment for low-grade glioma (LGG)-related epilepsy. However, the goal of achieving both oncological radical resection and seizure freedom can be challenging. PET with [11C]methionine (MET) has been recently introduced in clinical practice for the management of patients with LGGs, not only to monitor the response to treatments, but also as a preoperative tool to define the metabolic tumor extent and to predict tumor grading, type, and prognosis. Still, its role in defining tumor-related epilepsy and postoperative seizure outcomes is limited. The aim of this preliminary study was to investigate the role of MET PET in defining preoperative seizure characteristics and short-term postoperative seizure control in a cohort of patients with newly diagnosed temporal lobe low-grade gliomas (tLGGs). METHODS: Patients with newly diagnosed and histologically proven temporal lobe grade 2/3 gliomas (2021 WHO CNS tumor classification) who underwent resection at the authors' institution between July 2011 and March 2021 were included in this retrospective study. MET PET images were acquired, fused with MRI scans, and qualitatively and semiquantitatively analyzed. Any eventual PET/MRI involvement of the temporomesial area, seizure characteristics, and 1-year seizure outcomes were reported. RESULTS: A total of 52 patients with tLGGs met the inclusion criteria. MET PET was positive in 41 (79%) patients, with a median metabolic tumor volume of 14.56 cm3 (interquartile range [IQR] 6.5-28.2 cm3). The median maximum and mean tumor-to-background ratio (TBRmax, TBRmean) were 2.24 (IQR 1.58-2.86) and 1.53 (IQR 1.37-1.70), respectively. The metabolic tumor volume was found to be related to the presence of seizures at disease onset, but only in noncodeleted tumors (p = 0.014). Regarding patients with uncontrolled seizures at surgery, only the temporomesial area PET involvement showed a statistical correlation both in the univariate (p = 0.058) and in the multivariate analysis (p = 0.030). At 1-year follow-up, seizure control was correlated with MET PET-derived semiquantitative data. Particularly, higher TBRmax (p = 0.0192) and TBRmean (p = 0.0128) values were statistically related to uncontrolled seizures 1 year after surgery. CONCLUSIONS: This preliminary study suggests that MET PET may be used as a preoperative tool to define seizure characteristics and outcomes in patients with tLGGs. These findings need to be further validated in larger series with longer epileptological follow-ups.

Supramaximal resection: retrospective study on IDH-wildtype Glioblastomas based on the new RANO-Resect classification.

BACKGROUND: The prognostic value of the extent of resection in the management of Glioblastoma is a long-debated topic, recently widened by the 2022 RANO-Resect Classification, which advocates for the resection of the non-enhancing disease surrounding the main core of tumors (supramaximal resection, SUPR) to achieve additional survival benefits. We conducted a retrospective analysis to corroborate the role of SUPR by the RANO-Resect Classification in a single center, homogenous cohort of patients. METHODS: Records of patients operated for WHO-2021 Glioblastomas at our institution between 2007 and 2018 were retrospectively reviewed; volumetric data of resected lesions were computed and classified by RANO-Resect criteria. Survival and correlation analyses were conducted excluding patients below near-total resection. RESULTS: 117 patients met the inclusion criteria, encompassing 45 near-total resections (NTR), 31 complete resections (CR), and 41 SUPR. Median progression-free and overall survival were 11 and 15 months for NTR, 13 and 17 months or CR, 20 and 24 months for SUPR, respectively (p < 0.001), with inverse correlation observed between survival and FLAIR residual volume (r -0.28). SUPR was not significantly associated with larger preoperative volumes or higher rates of postoperative deficits, although it was less associated with preoperative neurological deficits (OR 3.37, p = 0.003). The impact of SUPR on OS varied between MGMT unmethylated (HR 0.606, p = 0.044) and methylated (HR 0.273, p = 0.002) patient groups. CONCLUSIONS: Results of the present study support the validity of supramaximal resection by the new RANO-Resect classification, also highlighting a possible surgical difference between tumors with methylated and unmethylated MGMT promoter.

Quality of life of adult cancer survivors enrolled in Humanitas Research Hospital's survivorship care model.

INTRODUCTION: Clinicians should address the different health needs of cancer survivors (CS). We investigated concerns about physical/psychosocial symptoms and quality of life (QoL) of CS enrolled in our survivorship program. Our primary aim is to describe the CS population and their quality of life, considering both physical and psychosocial issues, with the intent to identify some possible association with the most frequently observed variables. METHODS: Adult patients, after ≥ 5 years from achieving complete hematologic or solid tumor remission, were included. The self-administered questionnaire used in the survey was based on the "Cancer Survivors Survey of Needs" (Mayo Clinic). RESULTS: We analyzed data from 191 CS. The median age was 63 years (53 years at diagnosis), and 70% of patients were females. A total of 93 patients (49%) reported a quality of life (QoL) score > 2. The most common psychosocial symptom concerns were fear of relapse (53%), genetic counseling (43%), living with uncertainty (35%), defining a new sense of normal (31%), and managing stress (28%). Females are more at risk to develop the following concerns compared with males: pain (40% vs 21%), sleep disturbance (54% vs 30%), weight gain (42% vs 21%), osteoporosis (41% vs 11%), body changes (45% vs 13%), hair or skincare issues (42% vs 16%), hot flashes (40% vs 11%), fear of recurrence (74% vs 54%), and living with a sense of uncertainty (53% vs 29%). Younger patients reported a higher score (> 2) for physical and psychological concerns compared with older patients. CONCLUSION: In this study, differences in physical and psychological symptoms/stressors among women and younger patients were identified. Female and younger patients appear to report physical and psychosocial concerns more frequently than other subgroups of patients. These observations should be validated and deepened in larger, prospective studies and considered during the long-term follow-up of these subgroups of patients.

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial.

BACKGROUND: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. METHODS: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). RESULTS: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

Prognostic relevance of temporal muscle thickness as a marker of sarcopenia in patients with glioblastoma at diagnosis.

OBJECTIVES: Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia, correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. We evaluated the prognostic relevance of TMT measured on brain MRIs acquired at diagnosis in patients affected by glioblastoma. METHODS: We retrospectively enrolled 51 patients in our Institution affected by methylated MGMT promoter, IDH1-2 wild-type glioblastoma, who underwent complete surgical resection and subsequent radiotherapy with concomitant and maintenance temozolomide, from January 1, 2015, to April 30, 2017. The last clinical/radiological follow-up date was set to September 3, 2019. TMT was measured bilaterally on reformatted post-contrast 3D MPRAGE images, acquired on our 3-T scanner no more than 2 days before surgery. The median, 25th, and 75th percentile TMT values were identified and population was subdivided accordingly; afterwards, statistical analyses were performed to verify the association among overall survival (OS) and TMT, sex, age, and ECOG performance status. RESULTS: In our cohort, the median OS was 20 months (range 3-51). Patients with a TMT ≥ 8.4 mm (median value) did not show a statistically significant increase in OS (Cox regression model: HR 1.34, 95% CI 0.68-2.63, p = 0.403). Similarly, patients with a TMT ≥ 9.85 mm (fourth quartile) did not differ in OS compared to those with TMT ≤ 7 mm (first quartile). The statistical analyses confirmed a significant association among TMT and sex (p = 0.0186), but none for age (p = 0.642) and performance status (p = 0.3982). CONCLUSIONS: In our homogeneous cohort of patients with glioblastoma at diagnosis, TMT was not associated with prognosis, age, or ECOG performance status. KEY POINTS: • Temporal muscle thickness (TMT) is a surrogate marker of sarcopenia and has been correlated with survival expectancy in patients suffering from brain metastases and recurrent or treated glioblastoma. • We appraised the correlation among TMT and survival, sex, age at surgery, and performance status, measured on brain MRIs of patients affected by glioblastoma at diagnosis. • TMT did not show any significant correlation with prognosis, age at surgery, or performance status, and its usefulness might be restricted only to patients with brain metastases and recurrent or treated glioblastoma.

Treatment of patients with glioma during the COVID-19 pandemic: what we learned and what we take home for the future.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has changed the way in which cancer is treated. Patients with high-grade glioma (HGG) are believed to be in a vulnerable category. The aim of this study was to describe the experience of a hub cancer center and the measures that were put in place for treatment of patients with newly diagnosed and recurrent glioma. METHODS: To prevent in-hospital contagion and preserve the safety of health professionals and patients, specific protocols and strict regulations were introduced. Physical distancing, use of surgical masks, and diligent hand hygiene were adopted. Each case was discussed in a multidisciplinary board meeting before treatment. All patient candidates for surgical procedures were tested for SARS-CoV-2 with a nasopharyngeal swab and a chest CT scan. Indications for surgery were the radiological suspicion of HGG in patients with a good performance status and/or the rapid and progressive occurrence of neurological deficits. Adjuvant treatments were performed only in cases of HGG. This therapy consisted of conventional fractional radiotherapy (RT; 60 Gy/30 fractions) with concomitant and adjuvant temozolomide chemotherapy (TMZCHT) in younger patients; in elderly patients, a short course of RT was employed (40.5 Gy/15 fractions). For recurrent HGG, treatments were assessed after a careful evaluation of the patient's general condition, neurological status, and risk of early impairment in neurological status if not treated. During simulation CT for the RT plan, each patient underwent a chest CT study. In cases in which an imaging study was suspicious for COVID-19 pneumonia, the patient was immediately isolated and rapidly underwent nasopharyngeal swab testing. RESULTS: Between March 1 and April 30, 2020, 23 HGGs were treated, and these cases are included in the present evaluation. Fifteen patients harboring newly diagnosed glioblastoma (GBM) underwent resection followed by a regimen of chemotherapy and RT, and 3 patients with newly diagnosed anaplastic oligodendroglioma underwent surgery followed by adjuvant RT. Five patients were treated for recurrent GBM, and they received surgery plus adjuvant RT. One patient in whom the simulation CT study was suspicious for COVID pneumonia was tested with a nasopharyngeal swab, which proved positive for SARS-CoV-2 infection. No patients contracted COVID-19 during hospitalization for surgery or during RT treatment. Corticosteroid therapy was administered to all patients beginning on the 1st day of RT. CONCLUSIONS: The authors' experience during the COVID-19 pandemic showed that patients with HGG can be treated in the most effective manner without a compromise in safety. Careful selection criteria and a multidisciplinary evaluation are pivotal to assessing the optimal therapeutic strategy.

Mismatch-Repair Protein Expression in High-Grade Gliomas: A Large Retrospective Multicenter Study.

BACKGROUND: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). MATERIALS AND METHODS: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. RESULTS: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. CONCLUSIONS: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients.

Is surgical resection useful in elderly newly diagnosed glioblastoma patients? Outcome evaluation and prognostic factors assessment.

ASTRACT: BACKGROUND: The incidence of glioblastoma among elderly patients is constantly increasing. The value of radiation therapy and concurrent/adjuvant chemotherapy has been widely assessed. So far, the role of surgery has not been thoroughly investigated. The study aimed to evaluate safety and impact of several entities of surgical resection on outcome of elderly patients with newly diagnosed glioblastoma treated by a multimodal approach. METHODS: Patients ≥ 65 years, underwent surgery were included. The extent of surgical resection (EOR) was defined as complete resection (CR = 100%), gross total resection (GTR = 90-99%), sub-total resection (STR = 78-90%), partial resection (PR = 30-78%), and biopsy. After surgery, all patients received adjuvant radiotherapy (60/2 Gy fraction) with concomitant/adjuvant temozolomide chemotherapy. RESULTS: From March 2004 to December 2015, 178 elderly with a median age of 71 years (range 65-83 years) were treated. CR was obtained in 8 (4.5%), GTR in 63 (35.4%), STR in 46 (25.8%), PR in 16 (9.0%), and biopsy in 45 (25.3%). RT was started in all patients, concurrent/adjuvant CHT in 149 (83.7%) and 132 (74.2%). The median follow-up time was 12.2 months (range 0.4-50.4 months). The median, 1- and 2-year progression-free survival was 8.9 months (95%CI 7.8-100 months), 32.0 ± 3.5%, and 12.9 ± 2.6%. The median, 1- and 2-year overall survival were 12.2 (95%CI 11.3-13.1 months), 51.1 ± 3.7%, and 16.3 ± 2.9%. Tumor location, extent of resection, and neurological status after surgery statistically affected survival (p ≪ 0.01). CONCLUSION: Maximal surgical resection is safe and feasible in elderly patients with influence on survival. A preoperative evaluation has to be carried out.

Prognostic value of molecular and imaging biomarkers in patients with supratentorial glioma.

PURPOSE: We evaluated the relationship between 11C-methionine PET (11C-METH PET) findings and molecular biomarkers in patients with supratentorial glioma who underwent surgery. METHODS: A consecutive series of 109 patients with pathologically proven glioma (64 men, 45 women; median age 43 years) referred to our Institution from March 2012 to January 2015 for tumour resection and who underwent preoperative 11C-METH PET were analysed. Semiquantitative evaluation of the 11C-METH PET images included SUVmax, region of interest-to-normal brain SUV ratio (SUVratio) and metabolic tumour volume (MTV). Imaging findings were correlated with disease outcome in terms of progression-free survival (PFS), and compared with other clinical biological data, including IDH1 mutation status, 1p/19q codeletion and MGMT promoter methylation. The patients were monitored for a mean period of 16.7 months (median 13 months). RESULTS: In all patients, the tumour was identified on 11C-METH PET. Significant differences in SUVmax, SUVratio and MTV were observed in relation to tumour grade (p < 0.001). IDH1 mutation was found in 49 patients, 1p/19q codeletion in 58 patients and MGMT promoter methylation in 74 patients. SUVmax and SUVratio were significantly inversely correlated with the presence of IDH1 mutation (p < 0.001). Using the 2016 WHO classification, SUVmax and SUVratio were significantly higher in patients with primary glioblastoma (IDH1-negative) than in those with other diffuse gliomas (p < 0.001). Relapse or progression was documented in 48 patients (median PFS 8.7 months). Cox regression analysis showed that SUVmax and SUVratio, tumour grade, tumour type on 2016 WHO classification, IDH1 mutation status, 1p/19q codeletion and MGMT promoter methylation were significantly associated with PFS. None of these factors was found to be an independent prognostic factor in multivariate analysis. CONCLUSION: 11C-METH PET parameters are significantly correlated with histological grade and IDH1 mutation status in patients with glioma. Grade, pathological classification, molecular biomarkers, SUVmax and SUVratio were prognostic factors for PFS in this cohort of patients. The trial was registered with ClinicalTrials.gov (registration: NCT02518061).

Maximize surgical resection beyond contrast-enhancing boundaries in newly diagnosed glioblastoma multiforme: is it useful and safe? A single institution retrospective experience.

The extent of surgical resection (EOR) has been recorded as conditioning outcome in glioblastoma multiforme (GBM) patients but no significant improvements were recorded in survival. The study aimed to evaluate the impact of EOR on survival, investigating the role of fluid-attenuated inversion recovery (FLAIR) abnormalities removal. 282 newly diagnosed GBM patients were treated with surgery followed by concurrent and adjuvant chemo-radiotherapy. The EOR was defined as: SUPr, in case of resection amounting to 100% of enhanced and FLAIR areas; gross total (GTR) in case of resection between 90 and 100% of enhanced areas with variable amount of FLAIR abnormalities; sub-total (STR), between 10 and 89%; biopsy (B) <10%. FLAIR-RTV was dichotomized in percentage values to identify the best separation threshold for progression free survival (PFS) and overall survival (OS). SUPr was obtained in 21 patients (7.4%), GTR in 60 (21.3%), STR in 143 (50.7%) and biopsy only in 58 (20.6%). The median, 1, 2-year PFS were 10.4 ± 0.4 months, 39.0 ± 3.0, and 17.0 ± 2.0%; the median, 1, 2-year OS were 14.5 ± 0.5 months, 63.3 ± 3.0, and 23.1 ± 3.1%. EOR was significantly influencing survival (p < 0.001). The median, 1, 2-year OS were 28.6 ± 5.2 months, 90.0 ± 6.0, 71.0 ± 10.0% for patients underwent SUPr vs. 16.2 ± 1.2 months, 81.0 ± 5.0, 24.0 ± 6.0% for GTR. The FLAIR removal threshold conditioning survival was 45%. Minor complications were recorded in 14 (5%) patients and major in 8 (2.8%). surgical resection beyond contrast-enhancing boundaries could represent a promising strategy to improve outcome in GBM patients. The identification of a FLAIR-RTV threshold can be useful in clinical practice and it was recorded as factor influencing survival.

Role of surgical resection in recurrent glioblastoma: prognostic factors and outcome evaluation in an observational study.

The role of surgical resection in progressive or recurrent glioblastoma multiforme (GBM) lack of high level of evidence. The aim of this evaluation was to assess the role of surgical resection in relapsing GBM, in relation to the extent of surgical resection (EOR) and the amount of residual tumor volume (RTV). Among patients treated for newly diagnosed GBM between September 2008-December 2014, 64 patients with recurrent GBM were included in this retrospective evaluation. All patients underwent surgical resection followed by adjuvant treatments, chemotherapy and/or radiotherapy Results were evaluated in terms of local control (LC) rate, progression free survival (PFS) and patients overall survival (OS). Gross total resection (GTR) (>90%) was achieved in 48 (75%) patients and subtotal resection (STR) in 16 (25%). RTV was 0 in 40 (62.5%) patients and >0 in 24 (37.5%). No severe postoperative morbidity occurred. The median LC time was 6.0 ± 0.1 months (95% CI 5.29-8.55), with a 1 and 2 years LC rate of 29.4 ± 6.9%. The median PFS time was 6.8 ± 0.8 months, with a 1 year PFS rate of 27.2 ± 7.2% (95% CI 14.2-41.9). The median OS time was 10.3 ± 0.5 months (95% CI 7.6-10.4) with a 1 and 2 years OS rate of 22.5 ± 6.7% (95% CI 10.9-36.6). On univariate analysis EOR and RTV were recorded as conditioning LC and survival. These data was confirmed also in multivariate analysis only for RTV (p < 0.01). Recurrent GBM can take advantage of repeated surgery in selected patients with younger age and good clinical status. The entity of surgical resection was confirmed as conditioning survival.

Value of Surgical Resection in Patients with Newly Diagnosed Grade III Glioma Treated in a Multimodal Approach: Surgery, Chemotherapy and Radiotherapy.

BACKGROUND: Current treatments in grade III gliomas include surgery, radiotherapy, and chemotherapy. The value of the entity of surgical resection remains an open question. The aim of this evaluation was to analyze the impact of extent of resection (EOR) and residual tumor volume (RTV) on progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed grade III gliomas. METHODS: Overall, 136 patients were included in this evaluation. EOR and RTV were defined in all patients on postoperative volumetric magnetic resonance imaging, with EOR being defined as the rate of surgical resection, and RTV as contrast-enhancing RTV (CE-RTV) and fluid-attenuated inversion recovery (FLAIR) RTV. A threshold of EOR and RTV was recorded using increments of 2 % and 1 cm(3). RESULTS: EOR and RTV were the only clinical variables influencing PFS and OS. The EOR cut-off value for conditioning survival was 76 %. For EOR ≥76 % or <76 %, the 5- to 10-year PFS was 57 % and 18 % versus 0 % (p = 0.03), and 5- to 10-year OS was 68 % and 42 % versus 0 % (p = 0.06), respectively. Additionally, the RTV cut-off value was 3 cm(3); for RTV <3 cm(3) or >3 cm(3), 5- to 10-year PFS was 64.3 % and 48.2 % versus 42 % and 0 % (p = 0.02), and 5- to 10-year OS was 66.8 % and 33.4 % versus 56 % and 0 % (p = 0.3), respectively. RTV was a more significant parameter conditioning PFS and OS than EOR (p = 0.04), and the presence of CE-RTV was an unfavorable prognostic factor compared with FLAIR-RTV. CONCLUSIONS: In heterogeneous lesions from a radiological point of view as WHO grade III gliomas if a complete removal is not possible, it would be advisable to maximize the removal of enhancing areas, possibly with an EOR >76 % and an RTV <3 cm(3).

Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors.

PURPOSE: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS: A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS: Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS: The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.

Imaging biomarkers in primary brain tumours.

We are getting used to referring to instrumentally detectable biological features in medical language as "imaging biomarkers". These two terms combined reflect the evolution of medical imaging during recent decades, and conceptually comprise the principle of noninvasive detection of internal processes that can become targets for supplementary therapeutic strategies. These targets in oncology include those biological pathways that are associated with several tumour features including independence from growth and growth-inhibitory signals, avoidance of apoptosis and immune system control, unlimited potential for replication, self-sufficiency in vascular supply and neoangiogenesis, acquired tissue invasiveness and metastatic diffusion. Concerning brain tumours, there have been major improvements in neurosurgical techniques and radiotherapy planning, and developments of novel target drugs, thus increasing the need for reproducible, noninvasive, quantitative imaging biomarkers. However, in this context, conventional radiological criteria may be inappropriate to determine the best therapeutic option and subsequently to assess response to therapy. Integration of molecular imaging for the evaluation of brain tumours has for this reason become necessary, and an important role in this setting is played by imaging biomarkers in PET and MRI. In the current review, we describe most relevant techniques and biomarkers used for imaging primary brain tumours in clinical practice, and discuss potential future developments from the experimental context.

Multimodality therapy approaches, local and systemic treatment, compared with chemotherapy alone in recurrent glioblastoma.

BACKGROUND: Long-term local control in Glioblastoma is rarely achieved and nearly all patients relapse. In this study we evaluated the clinical effect of different treatment approaches in recurrent patients. METHODS: Forty-three patients, with median age of 51 years were evaluated for salvage treatment: re-resection and/or re-irradiation plus chemotherapy or chemotherapy alone. Response was recorded using the Response Assessment in Neuro-Oncology criteria. Hematologic and non-hematologic toxicities were graded according to Common Terminology Criteria for Adverse Events 4.0. Twenty-one patients underwent chemotherapy combined with local treatment, surgery and/or radiation therapy, and 22 underwent chemotherapy only. RESULTS: The median follow up was 7 months (range 3-28 months). The 1 and 2-years Progression Free Survival was 65 and 10 % for combined treatment and 22 and 0 % for chemotherapy alone (p < 0.01). The 1 and 2-years overall survival was 69 and 29 % for combined and 26 and 0 % for chemotherapy alone (p < 0.01). No toxicity greater than grade 2 was recorded. CONCLUSION: These data showed that in glioblastoma recurrence the combination of several approaches in a limited group of patients is more effective than a single treatment alone. This stress the importance of multimodality treatment whenever clinically feasible.

Targeted therapy for thymic epithelial tumors: a new horizon? Review of the literature and two cases reports.

Surgical resection remains the cornerstone of therapy for early-stage thymic epithelial tumors (TETs), while in advanced or recurrent forms, a multimodality approach incorporating radiation and chemotherapy is required. Given the absence of effective treatment options for metastatic/refractory TETs and the poor related prognosis, there is a compelling need to identify promising 'drugable' molecular targets. Initial reports of activity from targeted agents in TETs derived from anecdotal cases have been often associated with specific activating mutations. Only in recent years, several agents have been formally investigated into prospective clinical trials, with varying success rates. We reviewed the literature on targeted therapy in TETs along with two cases of thymoma achieving striking responses to sorafenib in combination with lapatinib.

Brain metastases and next-generation anticancer therapies: a survival guide for clinicians.

Historically, patients with brain metastases (BMs) have been characterized by few systemic treatment options and poor prognosis. The recent introduction of next-generation anticancer therapies such as molecular targeted agents and immunotherapy have revolutionized the clinical decision-making process of this sub-population, posing new challenges to physicians. In this review, current evidence for the use of checkpoint inhibitors and targeted therapies in patients with BMs are discussed, with a focus on lung cancer, breast cancer, melanoma and renal cell carcinoma, providing suggestions and potential workflows for daily clinical practice. Several other on-going and future challenges, such as clinical trials design, ways to improve CNS penetration of novel drugs and unique molecular characteristics of BMs, are also discussed. The aim is producing an updated and easy-to-read guide for physicians, to improve decision-making in clinical practice.