6-month Progression Research Articles

G.P.392 - Five-year longitudinal UC Davis CINRG Duchenne Natural History Study (DNHS) data show mobility-focused POSNA PODCI items are sensitive to 12-month disease progression across all stages of DMD functional ability

G.P.392 - Five-year longitudinal UC Davis CINRG Duchenne Natural History Study (DNHS) data show mobility-focused POSNA PODCI items are sensitive to 12-month disease progression across all stages of DMD functional ability

IDH1 mutation status and outcome in clinical trials for recurrent glioblastoma.

2073 Background: IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. Clinical trials for recurrent GB currently do not stratify patients (pts) based upon IDH status. It is not known if pts with IDH1 mutated GB on clinical trials are more likely to have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate. Methods: A retrospective review of GB pts treated at MD Anderson Cancer Center between 2006-2012 identified 330 pts enrolled in recurrent GB trials. 93 pts (28%) either had PFS6 or a complete or partial RR per RANO criteria. 49/93(53%) pts with PFS6 or a complete or partial RR were found to have tumor tissue available for IDH1 testing. A matched cohort of pts on the same recurrent GB clinical trials with tissue for IDH1 testing but no PFS6 or RR was identified based on the specific clinical trial, age and KPS. 49 pts were identified for comparison resulting in a total of 98 patients. Results: IDH1 status was obtained in 92 (94%) pts of which 17 (18...

Early Cerebral Blood Volume Changes Predict Progression After Convection-Enhanced Delivery of Topotecan for Recurrent Malignant Glioma

To assess whether early changes in enhancing tumor volume (eTV) and relative cerebral blood volume (rCBV) 1 month after convection-enhanced delivery of topotecan in patients with recurrent malignant glioma correlated with 6-month disease progression status. Sixteen patients were enrolled in a Phase Ib trial of convection-enhanced delivery of topotecan for recurrent malignant glioma. Each patient was evaluated with serial follow-up magnetic resonance imaging at baseline and at 4- to 8-week intervals. Changes at 1 month compared with baseline in eTV and rCBV were evaluated as potential predictors of 6-month progression status, classified as either progressive disease or nonprogressive disease. Relationships between percent changes in eTV and rCBV at 1 month with the probability of progressive disease at 6 months were estimated by the use of logistic regression analysis. Receiver operating characteristic curves for varying percent change thresholds in eTV and rCBV were evaluated by the use of 6-month progressive disease as the reference. There was a significant difference in the percent change in rCBV at 1 month in patients with progressive disease compared with those with nonprogressive disease at 6 months (+12% vs. -29%, P = 0.02). Logistic regression analysis demonstrated on average that a 10% increase in rCBV at 1 month after convection-enhanced delivery of topotecan was associated with 1.7 times the odds of developing progressive disease at 6 months (95% confidence interval [CI] 1.0-2.9 P = 0.05). Receiver operating characteristic analysis for determining progressive disease at 6 months showed a greater area under the curve with rCBV (0.867; 95% CI 0.66-1.00) than with change in enhancing tumor volume (0.767; 95% CI 0.51-1.00). In this selected population of patients with recurrent malignant glioma treated with convection-enhanced delivery of topotecan, early changes in rCBV at 4 weeks after therapy may help predict progression status at 6 months.

The development and utility of a novel scale that quantifies the glycemic progression toward type 1 diabetes over 6 months.

We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers.

Percutaneous radiofrequency ablation with internally cooled wet electrodes versus cluster electrodes for the treatment of single medium-sized hepatocellular carcinoma

BackgroundTo compare the effectiveness and complications of radiofrequency ablation (RFA) using cluster electrodes or internally cooled wet (ICW) electrodes in patients with medium-sized hepatocellular carcinomas (HCCs). MethodsBetween February 2008 and September 2013, 40 patients (31 men and 9 women; mean age, 61.2 years) with a single medium-sized HCC (mean size, 3.5 ± 0.5 cm; range, 3.1–5.0 cm) underwent percutaneous RFA with cluster electrodes (n = 19) or ICW electrodes (n = 21). Technical success, technical effectiveness, ablation volume, major complications, and local tumor progression were compared. ResultsAfter the initial RFA, technical success was achieved in 84% of patients and 90% of patients treated by cluster electrodes and ICW electrodes, respectively (P = 0.654). At 1 month, technical effectiveness was achieved by cluster electrodes and ICW electrodes in 84% and 100% of patients, respectively (P = 0.098). During follow-up period (mean, 17.8 months; range, 0–67 months), the median local tumor progression rates were 21.3 months in the cluster group and 31.0 months in the ICW group. The 6-month, 1-, 2-, and 4-year local tumor progression rates were significantly lower after RFA with ICW electrodes (0%, 7%, 25%, and 57%, respectively) than after RFA with cluster electrodes (26%, 33%, 53%, and 68%, respectively; P = 0.036). Major complications occurred in 15.8% of patients treated with cluster electrodes and in 4.8% of patients treated with ICW electrodes (P = 0.331). ConclusionFor the treatment of medium-sized HCCs, percutaneous RFA using ICW electrodes results in lower rate of local tumor progression and fewer serious complications, compared to cluster electrodes.

Open, Single Arm Trial of Erlotinib As the 2Nd/3Rd Line Treatment in Advanced or Recurrent Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Wild Type and C-Met Negative Expression (Ml28941, C-Tong 1306)

ABSTRACT Background: Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations show excellent clinical benefit to Erlotinib. Since EGFR wild type constitutes approximately 70% NSCLC, it is also important to evaluatethe efficacy of Erlotinib in this group of patients. Preclinical study shows that c-Met over-expression could be the cause of EGFR-TKI primary and secondary resistance, which gives us a hint, that c-Met negative expression maybe feasible to exclude the purely resistant to EGFR TKIs,which could be considered as 2nd biomarker, as so called “bi-biomarker”.This concept is supported by a phase II study (OAM4558g, ASCO2011), which showed in patients withEGFR wild type and c-met negative expression population treated with Erlotinib had a longer duration of PFS versus Erlotinib plus Onartuzumab (2.7 vs. 1.4 months, stratified HR = 1.82; 95% CI: 0.99, 3.32). The aim of this study is to evaluate the efficacy and safety of erlotinib as the 2nd/3rd line treatment in stage IV NSCLC with EGFR wild type and c-met negative expression. Trial design: This is a multicenter, single arm phase II study. Stage IV NSCLC patients (aged ≥18 yand ≤75 y, ECOG PS ≤ 2) with EGFR wild type and c-met negative expression on Ventana benchmark instrument(≥50% of the cells do not stain or stain with weak intensity, clinical score 0 or 1+) were eligible if they have had at least one prior platinum-based chemotherapy regimen.The primary objective of the study was 6-month progression free survival (PFS) rate. Secondary end-point include overall survival (OS), objective response rate (ORR), PFSand health-related quality of life (HRQoL). We estimated 6months PFS rate of experimental arm was 35% (OAM4558g, 2011ASCO), and historical control is estimated to be 20% (BR.21 and TAILOR), considering 10% total dropout rate, adjusting two-sided a = 0.05, power 80%. A total of 54 enrollments will be needed. All patients will receive once-daily oral Erlotinib (150mg) until disease progression or intolerable toxicities.The study has been registered on the ClinicalTrials.gov (NCT02006043) and the recruitment has begun in January 2014. Up to now, one patient has been recruited. The trial will be finished at July 2016 (12months recruitment and 18 months follow-up). Disclosure: Z. Li: The research is sponsored by the Roche. All other authors have declared no conflicts of interest.

Tumor testicular bilateral, tipo linfoma no Hodgkin de células T/NK extranasal

Lymphoma is a malignant neoplasia characterized by the proliferation of cells native to the lymphatic system. It makes up 1 % to 9 % of testicular neoplasia. Bilateral testicular tumor presentation was first described by Aberhouse in 1955. Extranodal nasal-type natural killer (NK) lymphoma is the most frequent variant of non-Hodgkin's tumors and presents with extensive vascular destruction and necrosis; the most common extranodal site is the upper respiratory system. It is characterized by poor outcome and systemic dissemination and does not respond well to current treatments.A 45-year-old man presented with bilateral increased testicular volume of 6-month progression, having received multiple treatments. Testicular ultrasound and abdominal computed tomography scan revealed increased testicular volume, retroperitoneal metastasis, and metastasis to the subcutaneous cell tissue. Tumor markers were negative. Right radical orchiectomy and biopsy of the left testis were performed. The definitive histopathologic diagnosis was extranasal- type NK/T-cell non-Hodgkin's lymphoma. The patient was referred to the Hematology Service and chemotherapy and hormone replacement treatment were begun.This tumor represents 1 % of all non-Hodgkin's lymphomas and 5 % of testicular masses. Mean presentation age is 50 years and there is a higher incidence in Asia and South America. Twenty percent of the cases affect areas outside of the nasal cavity. There is no staging classification for this disease. Five-year survival is 60 % and 17 % for disseminated disease. None of the current treatments (orchiectomy, chemotherapy and/or chemo-radiotherapy) are considered the criterion standard.

Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab.

Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen. In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment. Forty-two patients were identified (28 males) with a median age of 49 years (range, 24-78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3-4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen. The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.

AB0466 Glucocorticoid Effect on Radiographic Progression in Rheumatoid Arthritis BIOLOGICS Trials

BackgroundIn most registration trials of antirheumatic agents co-medication with a stable low dose of glucocorticoids (GC; usually up to 10 mg/d of prednisolone equivalents) is allowed. GC are known inhibitors...

Sorafenib enhances effects of transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis.

Combination therapy of sorafenib and transarterial chemoembolization (TACE) showed benefits for hepatocellular carcinoma (HCC). This systematic review aims for evaluation of efficacy and safety between sorafenib plus TACE and TACE alone for HCC. We systematically searched multi-databases to identify eligible studies. Studies comparing sorafenib combined with TACE and TACE alone for HCC were included. Nine studies with 900 patients (sorafenib + TACE = 446, TACE = 454) were finally included. Sorafenib combined with TACE significantly reduced 6-month mortality [OR 0.24, 95 % confidential interval (CI) 0.09-0.68, P = 0.007] and 1-year mortality (OR 0.35, 95 % CI 0.21-0.56, P < 0.0001), but did not decrease 2-year mortality (OR 0.58, 95 % CI 0.14-2.46, P = 0.46). Although combination therapy tend to reduce 3-month (OR 0.76, 95 % CI 0.52-1.10, P = 0.15) and 6-month progression free rate (OR 0.27, 95 % CI 0.07-1.05, P = 0.06), the changes were not significant. Additionally, objective response ratio (OR 0.39, 95 % CI 0.19-0.78, P = 0.008) and clinical benefit ratio (OR 0.27, 95 % CI 0.15-0.50, P < 0.0001) also favored for combination therapy, which, however, caused higher morbidity, especially hand-foot skin reaction (OR 53.71, 95 % CI 28.86-99.93, P < 0.00001), hematological events (OR 14.8, 95 % CI 6.07-36.07, P < 0.00001), diarrhea (OR 6.62, 95 % CI 3.82-11.45, P < 0.00001), hypertension (OR 5.03, 95 % CI 3.02-8.38, P < 0.00001), rash/desquamation (OR 5.67, 95 % CI 3.58-8.99, P < 0.00001), and fatigue (OR 2.5, 95 % CI 1.09-5.72, P = 0.03). Combination of sorafenib and TACE showed survival and clinical benefits in patients with HCC, though enhanced morbidity.

Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event

ObjectiveTo report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria.MethodsRetrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model.ResultsData were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11–74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01–21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96–0.99); p = 0.03], sex (male) [HR: 1.93 (1.24–2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06–4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event.InterpretationThese data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

Double‐blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma

Angiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC. Patients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6-month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor-2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05). A total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6-month progression rate was 72% versus 64%. The median progression-free survival (PFS) was 2.9 months (range, 0.5 months-32.5 months) versus 2.7 months (range, 0.8 months -65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P < .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months-22 months). The current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6-month progression rate. Open-label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib.

Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study

The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients.

Intraoperative Fluorescence-Guided Resection of High-Grade Malignant Gliomas Using 5-Aminolevulinic Acid–Induced Porphyrins: A Systematic Review and Meta-Analysis of Prospective Studies

BackgroundWe performed a systematic review and meta-analysis to address the (added) value of intraoperative 5-aminolevulinic acid (5-ALA)-guided resection of high-grade malignant gliomas compared with conventional neuronavigation-guided resection, with respect to diagnostic accuracy, extent of tumor resection, safety, and survival.Methods and FindingsAn electronic database search of Medline, Embase, and the Cochrane Library was undertaken. The review process followed the guidelines of the Cochrane Collaboration. 10 studies matched all selection criteria, and were thus used for qualitative synthesis. 5-ALA-guided resection demonstrated an overall sensitivity of 0.87 (95% confidence interval [CI], 0.81–0.92), specificity of 0.89 (95% CI, 0.79–0.94), positive likelihood ratio (LR) of 7.62 (95% CI, 3.87–15.01), negative LR of 0.14 (95% CI, 0.09–0.23), and diagnostic odds ratio (OR) of 53.06 (95% CI, 18.70–150.51). Summary receiver operating characteristic curves (SROC) showed an area under curve (AUC) of 94%. Contrast-enhancing tumor was completely resected in patients assigned 5-ALA as compared with patients assigned white light. Patients in the 5-ALA group had higher 6-month progression free survival and overall survival than those in the white light group.ConclusionBased on available literature, there is level 2 evidence that 5-ALA-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing diagnostic accuracy and extent of tumor resection, enhancing quality of life, or prolonging survival in patients with high-grade malignant gliomas.

A phase I study of the combination of sorafenib (Sor) and bortezomib (Bor) in patients (pts) with metastatic melanoma (MM).

9076 Background: Sor is a small molecule tyrosine kinase inhibitor that has many targets and previously was developed for the treatment of MM. Bor is a proteasome inhibitor widely used to treat multiple myeloma and other malignancies. In preclinical studies, the combination of Sor and Bor has been shown to modulate expression of BCL-family members and augment cytotoxicity in MM cell lines. Methods: Pts with MM were enrolled in cohorts of 3 during dose escalation to determine the maximum tolerated dose (MTD) of Sor twice daily (BID) in combination with Bor given days 1, 8, 15 of a 28 day cycle. The MTD was defined as the highest dose level at which less than 33% of pts exhibited a dose limiting toxicity (DLT). Efficacy, as measured by 6-month progression free survival (PFS) and response rate (RR) per RECIST, was documented. Results: Eleven pts were enrolled in 3 dose levels. DLTs (fatigue and rash respectively) were seen in 2 of 3 patients enrolled at the highest dose level (Sor 400 mg and Bor 1.3 mg/m2). The next lowest dose level (Sor 400 BID and Bor 1.0) enrolled 5 pts and none had DLTs. Thus, this dose level was defined as the MTD. Toxicities seen in &gt;20% of pts included hypertension, pruritus, hand-foot syndrome, mucositis, nausea, vomiting, rash, constipation, abdominal pain, anorexia and fatigue. Of 9 response evaluable pts, none had radiographic evidence of tumor response. Two of 11 (18%) pts remained progression free for greater than 6 months. Conclusions: The combination of Sor and Bor is safe, but minimally active in pts with MM. In the absence of tumor response at or above the MTD, the study was closed with only 5 pts treated at the provisional MTD and enrollment to a planned dose expansion cohort will not occur. Clinical trial information: NCT01078961.

Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199)

ObjectiveHPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix. MethodsTemsirolimus 25mg i.v. was administered weekly in 4week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue. ResultsThirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5months (range 2.4–12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14–43%). The median progression free survival was 3.52months [95% CI (1.81–4.70)]. Adverse effects were mild–moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability. ConclusionSingle agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified.

Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma

Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m² daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.

Efficacy and safety of second-line fotemustine in elderly patients with recurrent glioblastoma

Fotemustine (FTM) is a common treatment option for glioblastoma patients refractory to temozolomide (TMZ). Although elderly patients represent a large component of glioblastoma population, the feasibility and the efficacy of second-line FTM are not available in those patients.We retrospectively analyzed the records of glioblastoma patients older than 65 years, receiving FTM at a dose of 70–100 mg/m2 of FTM every week for 3 consecutive weeks (induction phase) and then every 3 weeks (70–100 mg/m2), as second-line treatment.Between January 2004 and December 2011, 65 glioblastoma patients (median age, 70 years; range, 65–79 years) were eligible for this analysis. Sixty-five patients received a total of 364 FTM cycles, with a median of 4 cycles for each patient. After induction, we observed 1 complete response (1.5 %), 12 partial responses (18.5 %), 18 stable diseases (27.7 %), and 34 patients’ progressions (47.7 %). Disease control rate was 43.1 %. Median survival from the beginning of FTM therapy was 7.1 months, while the median progression-free survival was 4.2 months, and the 6-months progression free survival rate was 35.4 %. The most relevant grade 3–4 toxicity events were thrombocytopenia (15.3 %) and neutropenia (9.2 %). In the univariate and multivariate analysis, time from radiotherapy to FTM, number of TMZ and FTM cycles and disease control resulted independent prognostic factors.This study showed that FTM is a valuable therapeutic option for elderly glioblastoma patients, with a safe toxicity profile.

Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials

There remain some key questions regarding the adoptive infusion of chimeric antigen receptor (CAR) transduced T-cells in the clinical setting. This article systematically reviews the phase I clinical trials using CARs targeting CD19 in B-lineage malignancies. Twenty-nine patients were enrolled and the 6-month progression free survival for this cohort was 50.0 ± 9.9%. Univariate analysis showed that patients benefited from lymphodepletion before CAR+T-cell infusion and the administration of interleukin-2 (IL-2). Longer-term persistence (≥ 4 weeks) and stronger expansion of CAR+ T-cells in the blood and higher peak serum interferon-γ (IFN-γ) level (≥ 200 pg/mL) were also related to superior outcome. Regarding treatment-related adverse events, the most prominent toxicities were fever, rigors, chills, acute renal failure, hypotension and capillary leak syndrome. In conclusion, anti-CD19 CAR+ T-cells have shown some benefits in patients with B-lineage malignancies and are well tolerated in most patients. Preconditioning and cytokine supplement are required to improve the clinical outcome.

Myopia Progression in Chinese Children is Slower in Summer Than in Winter

To characterize seasonal variation in the myopic progression of Chinese children. Myopia progression data are presented for a total of 85 Chinese children, aged 6 to 12 years, with baseline myopia of -0.75 D to -3.50 D sphere and astigmatism ≤-1.50 D, who wore traditional single-vision spectacles in two clinical trials (trial A: n = 37, trial B: n = 48). Refractive error and axial length data were obtained at 6-month intervals using cycloplegic autorefraction and partial coherence interferometry, respectively. Progression rates for right eyes were defined for the first and second 6 months of the studies and classified in terms of "summer," "autumn," "winter," or "spring" based on the mid-point of the 6-month period between visits. The mean 6-month spherical equivalent progression was -0.31 ± 0.25 D for summer, -0.40 ± 0.27 D for autumn, -0.53 ± 0.29 D for winter, and -0.42 ± 0.20 D for spring (p < 0.001). Mean axial elongation was 0.17 ± 0.10 mm for summer, 0.24 ± 0.09 mm for autumn, 0.24 ± 0.09 mm for winter, and 0.15 ± 0.08 mm for spring (p < 0.001). Post hoc analysis indicated that data for summer and winter were different from each other at p < 0.05 for both myopia progression and axial elongation after adjusting for age. Myopia progression in summer months was approximately 60% of that seen in winter, and axial elongation was likewise significantly less in summer. It is unclear whether more time spent outdoors in summer vs. winter is a contributing factor, or the difference in progression rates is a result of "seasonal" variations in the intensity or amount of close work performed. These results indicate that studies of potential myopia treatment strategies should be at least 12 months in duration to take seasonal variations into account.