Converging survival trends in non-small cell lung cancer patients with and without brain metastasis receiving state-of-the-art treatment.

INTRODUCTION: Historically, patients with brain metastasis (BM) have been excluded from clinical trials investigating treatments for non-small cell lung cancer (NSCLC) due to their unfavorable prognosis. Advanced treatments have increased survival prospects for NSCLC patients with BM. This study evaluated the life expectancy of NSCLC patients with and without BM in the context of contemporary treatments. METHODS: Outcome data were collected for patients with advanced NSCLC attending a tertiary medical center between 2015 and 2020. Patients were stratified according to BM status and compared for overall survival (OS) using log-rank and Cox regression analyses. RESULTS: The cohort included 360 patients with NSCLC of whom 134 (37.2%) had BM. Most (95%) of cases of BM developed within the first two years: 63% at diagnosis, 18% during the first year, 14% during the second year. There was no significant difference in OS between patients without BM and those with BM (median 23.7 vs. 22.3 months, HR = 0.97, p = 0.82); patients with BM and a targetable or non-targetable mutation (40.2 vs. 31.4 months, HR = 0.93, p = 0.84, and 20.7 vs. 19.87 months, HR = 0.95, p = 0.75, respectively); and patients with symptomatic BM (23.7 vs. 19.8 months, HR = 0.95, p = 0.78). Treatment for BM (95% of patients) consisted of stereotactic radiosurgery or tyrosine kinase inhibitors, with corresponding intracranial control rates of 90% and 86%. CONCLUSION: The results imply that the presence of BM has no impact on the prognosis of NSCLC. The practice of excluding NSCLC patients with BM from clinical trials warrants reconsideration.

Significant Systemic Insulin Resistance is Associated With Unique Glioblastoma Multiforme Phenotype.

Background: Some glioblastoma multiforme (GBM) are characterized by the presence of gemistocytes (GCs), a unique phenotype of reactive astrocytes. Certain GCs can be identified as neoplastic cells but these cells were also found to be associated with diabetes in non-neoplastic lesions of the central nervous system. Our aim was to find a correlation between insulin - resistance metabolic features and the presence of GCs in patients with newly diagnosed GBM. Methods: Medical records from histologically confirmed GBM patients were retrospectively extracted for different systemic metabolic variables. A statistic-based comparison was made between GBM, diabetic patients with and without GC. Patients with poorly controlled diabetes (ie, hemoglobin A1C ⩾ 8.0) were also compared between the 2 groups. Results: A total of 220 newly diagnosed GBM patients were included in our study. 58 (26.3%) patients had a history of diabetes mellitus type 2 (DM2) at the time of admission. The rate of poorly-controlled DM2 was nearly as twice in the GC-GBM group than in the non-GC GBM group (18.75% vs 9.5%; P = .130). In the DM2 cohort, the subgroup of GC-GBM was significantly associated with demographic and metabolic features related to insulin resistance such as male gender predominance (89% vs 50%, P = .073) and morbid obesity (weight ⩾85 kg: OR 6.16; P = .0019 and mean BMI: 34.1 ± 11.42 vs 28.7 ± 5.44; P = .034 for group with and without GCs, respectively). In the poorly-controlled DM2 group, none of the GC-GBM patients were using insulin prior to diagnosis, compared to 61.1% in the non-GC GBM patients (OR = 0.04, P = .045). Conclusion: Systemic metabolic factors related to marked insulin resistance (DM2, morbid obesity, male gender) are associated with a unique histologic phenotype of GBM, characterized by the presence of GCs. This feature is prominent in poorly-controlled DM2 GBM patients who are not using synthetic insulin. This novel finding may add to the growing data on the relevance of glucose metabolism in astrocytes and in astrocytes associated with high-grade gliomas. In GBM patients, a correlation between patients' metabolic status, tumor's histologic phenotype, tumor's molecular changes, use of anti-diabetic drugs and the respective impact of these factor on survival warrants further investigation.

[RAPIDLY PROGRESSING PARAPARESIS AND LOSS OF SENSATION BELOW T10 DURING NEOADJUVANT CHEMOTHERAPY FOR BREAST CANCER].

INTRODUCTION: A 35 years old woman was diagnosed with clinical stage 2, grade 3, hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative invasive ductal carcinoma, with ki-67 of 60%. She was treated with neoadjuvant chemotherapy with dose dense adriamycin and cyclophosphamide followed by paclitaxel. Six days following the third cycle of paclitaxel the patient presented with rapidly progressive weakness, proximal paresthesia and decreased sensation in both legs. Physical examination revealed hypoesthesia below level, proximal and distal weakness in both lower limbs and absence of reflexes. MRI of the spine demonstrated diffuse leptomeningeal enhancement from T11 to S1 including the cauda equina roots. The rapidly progressive neurological symptoms and the MRI findings were initially interpreted as leptomeningeal spread. High dose dexamethasone was promptly initiated and the patient was urgently planned for radiotherapy and received the first fraction of 3 Gy to level T11-S1. Further workup included lumbar puncture which showed elevated protein level (350 mg/dL), negative cytology for malignancy and EMG which demonstrated demyelinating injury compatible with Guillain-Barre syndrome (GBS). A diagnosis of GBS was made and treatment with intravenous immunoglobulins (IVIG) was initiated, followed by a gradual clinical improvement. Two months after the initial diagnosis, she had a near complete resolution of her neurological deficits. This case illustrates both the tendency to ascribe new symptoms and clinical findings in cancer patients to progressive disease, and the importance of keeping a wide differential diagnosis for non-cancer etiologies when treating our patients.

Immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients with primary brain tumors: a prospective cohort study.

PURPOSE: Immunogenicity of Covid-19 vaccines may be negatively impacted by anti-cancer treatment. The management of primary brain tumors (PBTs) routinely includes temozolomide and steroids, which are immune-suppressive. We aimed to determine the rate of seropositivity in PBT patients following receipt of two doses of the BNT162b2 vaccine. METHODS: We prospectively evaluated IgG levels against SARS-CoV-2 spike protein in 17 PBT patients following two doses of the BNT162b2 vaccine. IgG levels were collected at two time points: T1-after a median of 44 days from the second vaccine dose and T2-after a median of 130 days from the second dose. Titers were compared against a group of healthy controls (HC) comprised of patients' family members. RESULTS: At T1, 88.2% (15/17) of PBT patients achieved seroconversion, compared with 100% (12/12) of HCs. Median IgG titer was significantly lower in the PBT group (1908 AU/mL vs 8,198 AU/mL; p = 0.002). At T2, 80% (12/15) of PBT patients seroconverted, compared to 100% (10/10) of HCs. Median IgG titer remained significantly lower in the PBT group (410 AU/mLvs 1687 AU/mL; p = 0.002). During the peri-vaccination period, 15 patients received systemic treatment and 8 patients were treated with corticosteroids. All 3 patients who failed to seroconvert at T2 were treated with corticosteroids. In a univariate analysis, steroid use was negatively associated with antibody titer. CONCLUSION: Most PBT patients successfully seroconvert following two doses of the BNT162b2 vaccine, albeit with lower antibody titer compared to HCs. Steroid use during the vaccination period is associated with lower titer.

Neurologic complications of acute myeloid leukemia. Diagnostic approach and therapeutic modalities.

Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood malignancies that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. Neurologic manifestations of these malignancies are manifolds. AML is the most common form of acute leukemia in adults and this review describes the neurologic complications in this age group. Neurologic symptoms and signs may develop in AML either from a direct neoplastic involvement of the central or the peripheral nervous system or as an indirect effect of the disease process. Direct involvement of the nervous system includes invasion of the central or the peripheral nervous system (parenchymal and leptomeningeal dissemination, myeloid sarcoma, neuroleukemiosis). Thrombotic and hemorrhagic events are common manifestations of indirect involvement of the nervous system and they are the outcome of hyperleukocytosis, thrombocytopenia and coagulopathy. Many neurologic complications are iatrogenic and include diverse categories such as lumbar puncture and intrathecal or systemic chemotherapy and targeted therapies, radiotherapy and allogeneic stem cell transplantation. Most neurologic manifestations require urgent treatment and confer a poor prognosis. This review describes the neurologic complications of acute myeloid malignancies in the era of contemporary treatment. Those manifestations require expert consideration of their origin as they are being identified with increasing frequency as patients survive longer.

The Impact of Surgery on the Survival of Patients with Recurrent Glioblastoma.

OBJECTIVE: The purpose of this study was to investigate the possible benefit of repeat surgery on overall survival for patients with recurrent glioblastoma multiforme (GBM). METHODS: We performed a retrospective analysis of data from patients who presented with recurrent GBM over a 5-year period (n = 157), comparing baseline characteristics and survival for patients who had at least 1 new tumor resection followed by chemotherapy (reoperation group, n = 59) and those who received medical treatment only (no-reoperation group, n = 98) for recurrence. RESULTS: The baseline characteristics of the two groups differed in terms of WHO performance status (better in the reoperation group), mean age (60 years in the reoperation group vs. 65 years in the no-reoperation group), mean interval to recurrence (3 months later in the reoperation group than in the no-reoperation group) and more gross total resections in the reoperation group. Nevertheless, the patients in the reoperation group had a higher rate [32.8%] of sensorimotor deficits than those of the no-reoperation group [14.2]. There was no significant difference in sex; tumor localization, side, or extent; MGMT status; MIB-1 labeling index; or Karnofsky Performance Status [KPS] score. After adjustment for age, the WHO performance status, interval of recurrence, and extent of resection at the first operation, multivariate analysis showed that median survival was significantly better in the reoperation group than in the no-reoperation group (22.9 vs. 14.61 months, P < 0.05). After a total of 69 repeat operations in 59 patients (10 had 2 repeat surgeries), we noted 13 temporary and 20 permanent adverse postoperative events, yielding a permanent complication rate of 28.99% (20/69). There was also a statistically significant (P = 0.029, Student's t-test) decrease in the mean KPS score after reoperation (mean preoperative KPS score of 89.34 vs. mean postoperative score of 84.91). CONCLUSION: Our retrospective study suggests that repeat surgery may be beneficial for patients with GBM recurrence who have good functional status (WHO performance status 0 and 1), although the potential benefits must be weighed against the risk of permanent complications, which occurred in almost 30% of the patients who underwent repeat resection in this series.

Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer.

Importance: Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 vaccines is unclear. Objective: To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls. Design, Setting, and Participants: This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel). Interventions: Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL. Main Outcomes and Measures: The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses. Results: The analysis included 180 participants, which comprised 102 patients with cancer (median [interquartile range (IQR)] age, 66 [56-72] years; 58 men [57%]) and 78 healthy controls (median [IQR] age, 62 [49-70] years; 25 men [32%]). The most common tumor type was gastrointestinal (29 [28%]). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 [IQR, 509-4386] AU/mL vs 7160 [IQR, 3129-11 241] AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (ß, -3.5; 95% CI, -5.6 to -1.5). Conclusions and Relevance: In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.

Gemistocytes in newly diagnosed glioblastoma multiforme: Clinical significance and practical implications in the modern era.

BACKGROUND: Gemistocytes (GCs) in low grade gliomas are associated with rapid growth and worse prognosis. However, their clinical significance in glioblastomas (GBM) is a matter of debate. AIM OF STUDY: To investigate the clinical significance of the presence of GCs in newly-diagnosed GBM patients in the modern era. METHODS: Computerized medical records from newly diagnosed GBM patients were retrospectively reviewed and extracted for demographic, clinical, radiological and pathological variables. Patients with at least 5% GCs of neoplastic cells were considered GC-GBM (group 1). All other cases were considered non-GC GBM (group 2). Group 1 was further divided into two subgroups: Low percentage GCs (group 1a, ≤ 20% GCs) and high percentage GC (group 1b, >20% GCs). RESULTS: A total of 220 patients with newly diagnosed GBM were included. 14.5% were defined as GC-GBM (group I, n = 32) and 85.5% were defined as non-GC GBM (group 2, n = 188). 8.5% had ≤ 20% GCs (group 1a, n = 19) and 5.9% had > 20% GCs (group 1b, n = 13). Groups were similar for most epidemiological and clinical variables. There was a trend toward worse prognosis in group 1b. Several distinguished radiological and molecular features were observed in group 1. CONCLUSION: GCs are found in minority of naïve, newly diagnosed, GBM cases in adults. They seem to carry minimal implications on daily clinical practice. Higher percentage of GCs is associated with distinct radiological features such as multifocality that might be correlated with decreased OS. High-percentage GC-GBMs are also associated with increased prevalence of isocitrate dehydrogenase (IDH) mutations.

Height in adolescence as a risk factor for glioma subtypes: a nationwide retrospective cohort study of 2.2 million subjects.

BACKGROUND: Gliomas manifest in a variety of histological phenotypes with varying aggressiveness. The etiology of glioma remains largely unknown. Taller stature in adulthood has been linked with glioma risk. The aim of this study was to discern whether this association can be detected in adolescence. METHODS: The cohort included 2 223 168 adolescents between the ages of 16 and 19 years. Anthropometric measurements were collected at baseline. Incident cases of glioma were extracted from the Israel National Cancer Registry over a follow-up period spanning 47 635 745 person-years. Cox proportional hazard models were used to estimate the hazard ratio (HR) for glioma and glioma subtypes according to height, body mass index (BMI), and sex. RESULTS: A total of 1195 patients were diagnosed with glioma during the study period. Mean (SD) age at diagnosis was 38.1 (11.7) years. Taller adolescent height (per 10-cm increase) was positively associated with the risk for glioma of any type (HR: 1.15; P = .002). The association was retained in subgroup analyses for low-grade glioma (HR: 1.17; P = .031), high-grade glioma (HR: 1.15; P = .025), oligodendroglioma (HR: 1.31; P = .015), astrocytoma (HR: 1.12; P = .049), and a category of presumed IDH-mutated glioma (HR: 1.17; P = .013). There was a trend toward a positive association between height and glioblastoma, however this had borderline statistical significance (HR: 1.15; P = .07). After stratification of the cohort by sex, height remained a risk factor for men but not for women. CONCLUSIONS: The previously established association between taller stature in adulthood and glioma risk can be traced back to adolescence. The magnitude of association differs by glioma subtype.

Multicentric non-enhancing lesions in glioblastoma: A retrospective study.

Glioblastoma (GBM) typically presents as a single lesion. Multicentric GBM are defined as well separated lesions on MRI (enhancing and non-enhancing). Multicentric GBM with non-enhancing lesions (MNE-GBM) are rarely described in literature. We aimed at describing the radiologic characteristics, treatment, and clinical course of those patients. The institutional neuropathological database was searched for GBM patients diagnosed between 1/1/2015 and 31/05/2018. All pre-operative MRI brain scans were reviewed to identify patients with MNE-GBM. Electronic medical records and follow-up MRI scans were reviewed to assess progression-free survival (PFS) and overall survival (OS). Out of 149 adult patients with newly diagnosed GBM, 12 met the inclusion criteria of MNE-GBM, all of them presented at least one enhancing lesion. Median follow-up for the MNE-GBM patients was 16.1 months. At last follow-up, all patients had recurrence (median PFS 7.6 months) and eleven patients had deceased. Median OS was 16.2 months (95% CI, 4.1-27.5). Eleven patients received radiotherapy concomitant with temozolomide as initial treatment. Radiation field included all the disease foci (enhancing and non-enhancing lesions) in 8 patients, five of them progressed within the non-enhancing lesion. Three patients did not receive radiation for the entire non-enhancing lesions, and two of them progressed within the non-irradiated areas. In conclusion, MNE-GBM is not rare, and has high risk of aggressive progression within the separate non-enhancing lesion.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

PURPOSE: The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. METHODS: A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. RESULTS: Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. CONCLUSION: While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Height as a risk factor in meningioma: a study of 2 million Israeli adolescents.

BACKGROUND: Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults. METHODS: The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease. RESULTS: A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4-62.6). On univariate analysis, female sex (p < 0.01) and height (p < 0.01) were associated with risk of meningioma. When the data were stratified by sex, height remained a significant factor only in men. Spline analysis of the male subjects showed that a height of 1.62 m was associated with a minimum disease risk and a height of 1.85+ meters, with a significant risk. CONCLUSIONS: This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG).

LESSONS LEARNED: Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status.Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study. BACKGROUND: The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70. MATERIALS AND METHODS: Patients aged ≥70 years with a KPS <70 and biopsy-proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130-150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks. RESULTS: The trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval [CI], 19-27.6), and the median progression-free survival (PFS) was 15.3 weeks (95% CI, 12.9-19.3). Twenty-two (33%) patients became transiently capable of self-care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%). CONCLUSION: This study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level.

Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma.

We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with ≥18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: -7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields.

Do perfusion and diffusion MRI predict glioblastoma relapse sites following chemoradiation?

To assess the value of T2* dynamic-susceptibility contrast MRI (DSC-MRI) and diffusion-weighted imaging (DWI) to predict the glioblastoma relapse sites after chemoradiation. From a cohort of 44 patients, primarily treated with radiotherapy (60 Gy) and concomitant temozolomide for glioblastoma, who were included in the reference arm of a prospective clinical trial (NCT01507506), 15 patients relapsed and their imaging data were analyzed. All patients underwent anatomical MRI, DSC-MRI and DWI before radiotherapy and every 2 months thereafter until relapse. Voxels within the sites of relapse were correlated with their perfusion and/or diffusion abnormality (PDA) pretreatment status after rigid co-registration. The relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were used as biomarkers. Several PDA areas were thresholded: hyperperfused voxels using a 1.75 fixed rCBV threshold (HPt); hypoperfused (hPg) and hyperperfused (HPg) voxels using a histogram-based Gaussian method; diffusion-restricted voxels (DRg); and HPg voxels with diffusion restriction (HPg&DRg). Two sets of voxels (2,459,483 and 2,073,880) were analyzed according to these thresholding methods. Positive predictive values (PPV) of PDA voxels were low (between 9.5 and 31.9 %). The best PPV was obtained with HPg&DRg voxels within the FLAIR hyperintensity, as 18.3 % of voxels without initial PDA were within relapse sites, versus 31.9 % with initial PDA (p < 0.0001). This prospective study suggests that DSC and/or DWI-MRI do not predict the glioblastoma relapse sites. However, further investigations with new methodological approaches are needed to better understand the role of these modalities in the prediction of glioblastoma relapse sites.

Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network.

BACKGROUND: Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort. METHODS: We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014. RESULTS: Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival. CONCLUSIONS: About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial.

BACKGROUND: No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. METHODS: In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. FINDINGS: Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. INTERPRETATION: In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. FUNDING: Schering-Plough/Merck and French Government.

αvß3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I-II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma.

BACKGROUND: Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway. PATIENTS AND METHODS: Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvß3, αvß5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome. RESULTS: For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvß3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS. CONCLUSION: Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvß3 integrin are independent bad prognostic factors of OS and TTP.

SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas.

Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.