Impact of IDH1 mutation status on outcome in clinical trials for recurrent glioblastoma

IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. However, it remains unknown whether patients (pts) with IDH1 mutated GB have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate on clinical trials for recurrence. Retrospective review of GB pts at MDACC between 2006 and 2012 identified 330 patients in recurrent GB trials. 93 patients (28?%) had either PFS6 or a complete/partial RR per RANO criteria. 49/93 (53?%) patients with PFS6 or a complete/partial RR had tumor tissue for IDH1 testing. A matched cohort of 49 patients on recurrent GB clinical trials that failed to achieve PFS6 or RR (also with tissue for IDH1 testing) was identified for comparison. IDH1 status was obtained in 92/98 (94?%) patients of which 17 (18?%) had an IDH1 mutation. PFS6 was seen in 26/49 (53?%) patients. IDH status was unknown in two of these patients. 5/24 (21?%) were IDH1 mutated compared to 5/24 (21?%) of their matched cohort without PFS6. RR was found in 47/49 (94?%) patients. IDH status was unknown in four of these patients. IDH1 mutation was present in 7/43 (16?%) patients with RR compared to 10/43 (23?%) in the matched cohort without RR (p?=?0.48). Median OS for trials at first recurrence was 9.8 months for IDH1 wildtype GB vs. 19.32 months for IDH1 mutated GB (p?=?0.14). IDH1 mutation status was not predictive of PFS6 or RR in recurrent GB trials for this data set. However, further examination in larger randomized prospective studies is needed.     

Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation

The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity‐modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLT_{pre‐chemoRT,} Hgb_{pre‐chemoRT}) before start of treatment were identified. Patients were risk‐stratified using Dahlstrom–Sturgis criteria and were tested for association with survival and disease‐control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLT_{pre‐chemoRT} value of ≥350 × 10⁹/L. Actuarial 5‐year locoregional control (LRC) and FDM were 83 and 85% for non‐thrombocythemic patients while patient with high platelets had 5‐year LRC and FDM of 73 and 74%, respectively. Likewise, 5‐year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLT_{pre‐chemoRT} was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3‐, 5‐ and 10‐year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients.     

Inhibition of the p38 MAPK pathway sensitises human colon cancer cells to 5-fluorouracil treatment

Colorectal cancer is the third most common cause of cancer-related deaths in the Western world. 5-Fluorouracil (5-FU) based chemotherapeutic regimes have been the mainstay of systemic treatment for disseminated colorectal cancer for many years. However, it only produces a 25% response rate due to the drug-resistance. The mitogen-activated protein kinase (MAPK) pathway is involved in the anti-apoptotic process; its activation provides cancer cells with a survival advantage to escape the apoptotic challenge. This study assessed whether the p38 MAPK pathway is involved in 5-FU resistance in colorectal cancer cells. 5-FU only or 5-FU combined with a p38 MAPK pathway inhibitor (SB203580) was used to treat 5-FU-resistant colorectal cancer cells. The effect of the treatment on cell viability, death and caspase activities was assessed. Western blotting was used to investigate the responses of apoptosis-related proteins following the treatment. Results showed that p38 MAPK inhibitor significantly increased colorectal cancer cell sensitivity to 5-FU. SB203580 in combination with 5-FU significantly reduced cell viability (P<0.01), and increased cell death and cellular caspase activity (P<0.01). Western blotting data revealed that SB203580 sensitises cancer cells to 5-FU due to an increase in Bax expression. These findings suggest that p38 MAPK is involved in cancer cell survival, and that the inhibition of p38 MAPK can enhance 5-FU to kill colorectal cancer cells.     

Parasuicide in central London 1984-1988.

Experience of a central London unit dedicated to the care of patients following parasuicide between 1984 and 1988 is reviewed. There were 1160 admissions, which accounted for 11% of all acute adult medical admissions. The female to male ratio was 1.3, with a peak rate for females below 25 years and for males between 20 and 35. Unemployment was found to be a risk factor for parasuicide in men. Benzodiazepines were the most frequently used drug in parasuicide (35%), followed by paracetamol (13%) and aspirin (9%).     

Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials

Purpose

The effectiveness of stereotactic body radiotherapy (SBRT) for localized prostate cancer is tested.

Methods and materials

A total of 1100 patients with clinically localized prostate cancer were enrolled in separate prospective phase 2 clinical trials of SBRT from 8 institutions during 2003–11 and pooled for analysis. SBRT using the CyberKnife delivered a median dose of 36.25 Gy in 4–5 fractions. Patients were low-risk (58%), intermediate-risk (30%) and high-risk (11%). A short-course of androgen deprivation therapy (ADT) was given to 14%. PSA relapse defined as a rise >2 ng/ml above nadir was analyzed with the Kaplan Meier method.

Results

With a median follow-up of 36 months there were 49 patients with PSA failure (4.5%), 9 of whom were subsequently determined to be benign PSA bounces. The 5-year biochemical relapse free survival (bRFS) rate was 93% for all patients; 95%, 83% and 78% for GS ?6, 7 and ?8, respectively (p = 0.001), and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively (p < 0.001). No differences were observed with ADT (p = 0.71) or as a function of total dose (p = 0.17). A PSA bounce of >0.2 ng/ml was noted among 16% of patients. For 135 patients possessing a minimum of 5 years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively.

Conclusion

PSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients. The current evidence supports consideration of SBRT among the therapeutic options for these patients.     

Clinical and prognostic features of adult patients with gangliogliomas

Background

Gangliogliomas (GGs) represent <1% of primary brain tumors in adults. Little is known regarding prognostic features, clinical characteristics, or the impact of treatment on patient outcomes.

Methods

Our neuro-oncology longitudinal database was screened for patients with GG from 1992 to 2012. Sixty-seven patients (age >18 y) were identified.

Results

Sixty-two patients presented with low-grade GG and 5 with anaplastic GG. The median age at diagnosis was 29 years. With a median follow-up of 4.7 years after the initial diagnosis, 23 patients had progressive disease. Range of time to progression was 0.2–20 years. Nine patients with low-grade GG progressed to a malignant tumor. The median overall survival (OS) for all patients was not reached. The 2-, 5-, and 10-year OS for patients with low-grade GG were 100%, 88% (95% confidence interval [CI]: 73%, 95%), and 84% (95% CI: 67%, 93%), respectively.Factors identified by univariate analysis that were significantly associated with OS were age, KPS, extent of resection (EOR), and grade. Factors on univariate analysis that were significantly associated with progression-free survival were grade and EOR. On multicovariate Cox regression, lower tumor grade and younger age were significant factors for longer OS. EOR is a significant factor for progression-free survival.

Conclusions

While GG has excellent prognosis, malignant histologic grade, older age, and diagnosis with biopsy could indicate worse prognosis. The late nature and high rate of progression emphasize the importance of long-term follow-up. The role of chemotherapy and radiation therapy for incompletely resected low-grade GG remains unclear.     

Selection of tumor-binding ligands in cancer patients with phage display libraries

Phage display has been used extensively in vitro and in animal models to generate ligands and to identify cancer-relevant targets. We report here the use of phage-display libraries in cancer patients to identify tumor-targeting ligands. Eight patients with stage IV cancer, including breast, melanoma, and pancreas, had phage-displayed random peptide or scFv library (1.6 x 10(8)-1 x 10(11) transducing units/kg) administered i.v.; tumors were excised after 30 minutes; and tumor-homing phage were recovered. In three patients, repeat panning was possible using phage recovered and amplified from that same patient's tumor. No serious side effects, including allergic reactions, were observed with up to three infusions. Patients developed antiphage antibodies that reached a submaximal level within the 10-day protocol window for serial phage administration. Tumor phage were recoverable from all the patients. Using a filter-based ELISA, several clones from a subset of the patients were identified that bound to a tumor from the same patient in which clones were recovered. The clone-binding to tumor was confirmed by immunostaining, bioassay, and real-time PCR-based methods. Binding studies with noncancer and cancer cell lines of the same histology showed specificity of the tumor-binding clones. Analysis of insert sequences of tumor-homing peptide clones showed several motifs, indicating nonrandom accumulation of clones in human tumors. This is the first reported series of cancer patients to receive phage library for serial panning of tumor targeting ligands. The lack of toxicity and the ability to recover clones with favorable characteristics are a first step for further research with this technology in cancer patients.     

USE OF COMMUNITY HEALTH NEEDS ASSESSMENT FOR REGIONAL PLANNING IN COUNTRY SOUTH AUSTRALIA

ABSTRACT: This study examined the impact of community health needs assessments used in country South Australian health service planning between 1995 and 1999. Data were collected from regional health planning officers during a Search Conference and a series of Delphi rounds. The needs assessments were found to vary from regionally to locally driven approaches. Locally driven approaches ensured local involvement but the process was slower and required more effort from the planner. It was also felt that locally driven approaches could exacerbate tension between a community's imperatives and the regional focus of regional decision-makers. In the overall regional budgets, the reallocation of health service funds according to the needs assessment findings was only small because of difficulties in refocusing from traditional clinical services in the short term. In contrast, the impact on health service thinking about population health issues was thought to have been more significant, for example, in the development of regional women's health plans. The use of community health needs assessments was useful, but for greater impact these should not now be so 'broad-brushed', but be more focused on feasible changes that health services could support. Other priority-setting techniques, such as marginal analysis, should also be used to determine where maximum health gains can be obtained.