Outcomes from the use of computerized neurocognitive testing in a recurrent glioblastoma clinical trial.

Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.

Identification and quantification of nuisance odors at a trash transfer station.

The objective of this study was to evaluate the effectiveness of a modified Odor Profile Method (OPM) at a trash transfer station (TTS). An updated Landfill Odor Wheel was used to define odor character and distinguish among odor sources. The Flavor Profile Analysis (FPA) intensity scale was used to rank the relative intensity of the various odor characters defined by the odor wheel and to understand how each odor profile changed off site. Finally, the odor wheel was used to select the appropriate chemical analysis to identify the odorants causing the odors identified by the human panelists. The OPM was demonstrated as an effective tool for characterizing and distinguishing odor sources at a TTS. Municipal solid waste (MSW) odors were characterized as rancid, sulfur, and fragrant; rancid odors were dominant in the odor profile on-site, while sulfur odors dominated off-site. Targeted chemical analysis was used to identify odorants potentially responsible for odors at the site. Methyl mercaptan (rotten vegetable) and hydrogen sulfide (rotten egg) were identified as the odorants most likely to be responsible for the sulfur odors at the site. Acetaldehyde (sweet, fruity), acetic acid (vinegar), and butyric acid (rancid) were identified as the odorants mostly likely to be causing the rancid and sour odors. Terpenes/pine odors were observed near the greenwaste pile. Results confirm that the OPM, together with properly selected chemical analyses, can be a useful tool for identifying and quantifying the sources of odors.

Prolonged disease control with MEK inhibitor in neurofibromatosis type I-associated glioblastoma.

WHAT IS KNOWN AND OBJECTIVE: Neurofibromatosis is associated with overactivation of the RAS-MAPK pathway. MEK inhibitors have been shown to be an effective treatment modality in other malignancies. CASE SUMMARY: We present a 24-year-old male with treatment-refractory neurofibromatosis-associated glioblastoma, who experienced clinical and radiological benefit from the MEK inhibitor, trametinib. WHAT IS NEW AND CONCLUSION: This case highlights the therapeutic success of a MEK inhibitor in neurofibromatosis-associated glioblastoma. As a corollary, this should prompt evaluation of MEK inhibitors in tumours associated with neurofibromatosis. It remains to be elucidated if tumours with somatic NF1 mutations may also benefit from therapy targeting the RAS-MAPK pathway.

Local perspective on a rare brain tumour: adult medulloblastoma.

BACKGROUND: Little contemporary data are available regarding Australian patterns of care in adult medulloblastoma. It is unclear whether treatment, extrapolated from paediatric protocols despite known differences between the two groups, results in comparable efficacy. AIM: To perform a retrospective review of patterns of care in adult medulloblastoma, especially with respect to adjuvant chemotherapy, in Australian patients. METHODS: All medulloblastoma patients aged 15 years or older at two neuro-oncology institutions were identified from January 1995-May 2011. Patients with supratentorial or peripheral tumours were excluded. Standardised data were extracted from each institution regarding symptoms, disease staging, treatments received, toxicities and survival outcomes. RESULTS: Seventeen eligible patients were identified. Median age was 37 years (range 20-67 years). All had good performance status (Eastern Cooperative Oncology Group 0-1). There were 11 standard-risk de novo patients, three high-risk de novo patients and three patients with recurrent disease. Median overall survival (OS) had not been reached for standard-risk patients with median follow up of 58 months. The median OS for high-risk de novo patients was 21 months, while the median OS was 15 months for patients with recurrent disease. Treatment was well tolerated, with haematological toxicities being most common. CONCLUSIONS: Combined modality therapy (surgery followed by postoperative radiotherapy and adjuvant chemotherapy) was well tolerated and associated with good outcomes in standard-risk de novo patients. High-risk and recurrent disease patients do extremely poorly regardless of treatment and better treatment strategies are needed in these patients.

A single centre study of the treatment of relapsed primary central nervous system lymphoma (PCNSL) with single agent temozolomide.

Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. Although recommendations for first-line treatment usually incorporate high-dose methotrexate, there is substantial heterogeneity in the types of salvage therapies used at relapse. Phase II data supported the use of temozolomide as a well-tolerated treatment modality in this setting. Therefore, we reviewed the treatment and outcomes of patients with relapsed PCNSL who were treated with salvage temozolomide at our institution. Seven patients were treated with salvage temozolomide between January 2000 and May 2011. The objective response rate was 14%. Progression-free survival was 2 months (95% confidence interval [CI]: 0-5.9) and median overall survival was 4 months (95% CI: 0-13). Toxicity was mild, with one episode of grade 3 neutropenia during 25 cycles of chemotherapy. Although these results are consistent with previous phase II results, the outcomes for these patients remain extremely poor. The low toxicity of temozolomide raises the possibility of combining temozolomide with other chemotherapeutic agents or targeted agents in future clinical trials.

Primary anaplastic pilocytic astrocytoma.

We report two adult patients with pilocytic astrocytomas with anaplastic features at initial diagnosis. Pilocytic astrocytomas are low-grade astrocytomas that occur rarely in adults. Initial presentation of a pilocytic astrocytoma with anaplastic features is particularly uncommon and making a definitive diagnosis of pilocytic astrocytoma with anaplastic features can be challenging. It is critical to differentiate glioblastoma (World Health Organization [WHO] grade 4) and pilocytic astrocytoma with anaplastic features (WHO grade 3) from pilocytic astrocytoma (WHO grade 1) as there are significant therapeutic and prognostic implications. Improved therapeutic strategies are required for pilocytic astrocytomas with anaplastic features.

Radiotherapy management of patients diagnosed with glioma in Victoria (1998-2000): a retrospective cohort study.

This study aimed to describe the radiotherapy (RT) management and subsequent outcome in a cohort of patients with newly diagnosed glioma. Treatment details were obtained via a questionnaire completed by neurosurgeons, radiation and medical oncologists who treated patients diagnosed with glioma in Victoria during 1998-2000. Patients were identified by using the population-based Victorian Cancer Registry. Over the study period, data on 828 patients were obtained, of whom 612 (74%) were referred for consideration of RT. Radiotherapy was given to 496 patients as part of their initial treatment and to an additional 10 patients at the time of tumour recurrence or progression. The median age was 72 (16-85) years. Median overall survival (OS) was 9.2 (standard error (SE) 0.6) months for the entire group. Median OS was 29.1 (SE 8.0) and 7.4 (SE 0.4) months for all patients with histological confirmation of World Health Organization Grades III (anaplastic astrocytoma) and IV (glioblastoma multiforme) histology, respectively. A total of 47 different RT dose fractionation schedules were identified. This is the largest survey detailing management of glioma with RT, published to date. A marked variation in dose fractionation schemes was evident. While current best practice involves the use of chemotherapy in conjunction with RT for glioblastoma multiforme, advances in patient care may be undermined by this variation in the use of RT. Clinical trials relevant to an ageing population and evidence-based national clinical guidelines are required to define best practice.

Temozolomide-induced flare in high-grade gliomas: a new clinical entity.

A transient deterioration in neurological status following commencement of chemotherapy for high-grade gliomas has not been previously described. We report eight cases of transient deterioration following administration of temozolomide, a relatively new cytotoxic agent used in the treatment of high-grade gliomas. We believe this represents the novel clinical entity of temozolomide-induced tumour flare.

Cancer and the nervous system.

Brain tumours should be considered when patients present with headache with diurnal variation, seizures, or progressive neurological symptoms. Spinal cord compression by tumour is a medical emergency. Prognosis for patients with glioma is better in those with tumours of low grade, and in patients younger than 50 years and with higher functional levels. Surgery, radiotherapy and chemotherapy can improve survival for patients. Anticancer therapies can have neurotoxic side effects.

An Australian experience with temozolomide for the treatment of recurrent high grade gliomas.

Temozolomide has an evolving role in the treatment of high grade gliomas. Recent studies suggest that temozolomide is well tolerated and efficacious. This study retrospectively analysed the activity and toxicity associated with temozolomide at two Australian centres over a 24 month period. Fifty-six patients with recurrent high grade gliomas were treated with temozolomide. Patients received temozolomide orally at 150-200mg/m(2)daily, days 1-5, every 4 weeks. The median number of treatment cycles was 4 (1-12). Of the 56 patients, 15 (27%) achieved complete or partial response and 18 (32%) achieved minor response or stable disease. There were no episodes of febrile neutropenia and temozolomide was generally well tolerated. In conclusion, temozolomide is an active therapy in patients with recurrent high grade glioma and our results concord with published studies.

L-dopa-resistant parkinsonism syndrome following cerebral radiation therapy for neoplasm.

A bradykinetic form of parkinsonism, unresponsive to levo-dopa therapy developed in four patients two to eight weeks after completion of external beam irradiation (39.2 Gy to 59.4 Gy) of their intracranial neoplasm. In the absence of other causative factors, we relate the movement disorder to radiation-induced changes within the basal ganglia. At post-mortem examination one patient had putamenal gliosis and thickened vessels with loss of nigral neurons.

High-dose methotrexate for primary CNS lymphoma in the elderly.

Primary central nervous system lymphoma (PCNSL) in the immunocompetent patient reaches a peak incidence in the sixth and seventh decades of life. This retrospective study reviewed the efficacy and tolerability of high-dose methotrexate (HDMTX) in an elderly patient population. Between May 1995 and September 1998, ten consecutive elderly patients with histologically proven PCNSL were treated with HDMTX. The median age was 72.5 years and eight patients (80%) were older than 70 years. HDMTX was well tolerated with no episodes of grade 4 toxicity nor febrile neutropenia. Toxicity included grade 3 nausea (1), grade 2 mucositis (2), and grade 2 asymptomatic elevation of liver transaminases (2). Grade 1 toxicity occurred in three patients with nausea, diarrhea, and mild reversible elevation in serum creatinine in one patient each. Six patients had a complete response and three patients achieved a partial response, giving an overall response rate of 90% (95% confidence interval, 56%-100%). The median overall survival for the cohort was 36 months (range 4-43 months). In summary, HDMTX is well tolerated in this elderly population with PCNSL and achieves response rates and median survival comparable with other chemotherapy or radiotherapy regimens.

KRN8602 (MX2-hydrochloride): an active new agent for the treatment of recurrent high-grade glioma.

PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma. PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score < or = 2) were treated with an intravenous bolus of 40 mg/m(2) KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles. RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting. CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

Cancer associated retinopathy and non-small cell lung cancer.

The syndrome of cancer associated retinopathy is a relatively recently described entity that has characteristic clinical and electrophysiological features. It is most closely associated with small cell carcinoma and a specific antibody against a retinal protein. We present a patient with cancer associated retinopathy and a non-small cell lung cancer. The diagnosis of the clinical syndrome led to the discovery of the tumour. The antibody was not present. Therapy with chemotherapy, corticosteroids and plasma exhange did not improve the retinopathy. Earlier recognition of the syndrome may be important in detecting malignancy and attempting treatment of the retinopathy before irreversible damage is done.

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD).

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results.

Disease-free survival in primary CNS lymphoma has improved with the advent of methotrexate-based pre-irradiation chemotherapy. Prolonged response durations have been noted in six of eight patients refusing radiation therapy in two of our prior series. We have treated an additional 11 patients with methotrexate-based chemotherapy without subsequent planned irradiation. Some received maintenance chemotherapy. Most have had durable responses with little or no toxicity. Prolonged responses can be maintained without radiation therapy, thus avoiding potential long-term radiation toxicity.

Echo-planar MR determination of relative cerebral blood volume in human brain tumors: T1 versus T2 weighting.

PURPOSE: Maps related to relative cerebral blood volume (rCBV) were generated with the use of the T1 effects produced by a low-dose bolus passage of gadopentetate dimeglumine. The T1 maps were evaluated in a tumor population and compared with rCBV maps obtained with T2-weighted measurements. METHODS: Imaging was performed in 19 patients with suspected intraaxial brain tumors. For the T1 rCBV maps, a low-dose bolus of contrast material was given during T1-weighted interleaved spin-echo echo-planar MR imaging. This was followed by a second injection during serial T2-weighted imaging for generation of the T2 rCBV maps. RESULTS: Among patients with low-grade lesions (n = 9), T1-based and T2-based rCBV maps showed comparably low rCBV in 7 subjects. In the other 2 patients, with confirmed tumor dedifferentiation, elevation of rCBV values was seen on maps obtained with both techniques. Among patients with high-grade tumors (n = 10), 4 had no evidence of recurrence and 6 did have tumor recurrence (confirmed by follow-up and positron emission tomography). In patients with the high-grade lesions exhibiting conventional contrast enhancement, lesions tended to have higher estimated values on T1 rCBV maps than on the T2 rCBV maps. CONCLUSION: Although the T1 rCBV maps showed less contrast as compared with the T2 rCBV maps, they provided diagnostic information that was comparable to the T2 rCBV maps in our series of 19 patients with primary brain tumors.

Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption.

BACKGROUND: Paraneoplastic neurologic syndromes, although rare, cause significant morbidity and mortality. They are thought to be immunologically mediated, but to date those involving the central nervous system (CNS) have not been particularly responsive to immunologic therapy. The use of the novel immunomodulator, protein A immunoadsorption, was explored to address this question. METHODS: Six patients with neurologic paraneoplastic syndromes were treated with this technique, using the "off line" method. Two hundred fifty ml of plasma was perfused through a column containing protein A covalently attached to a silica matrix. The plasma was then returned to the patient. RESULTS: Five of the patients responded to the therapy, with complete and durable responses in three patients with opsoclonus-myoclonus, objective, though transient, improvement in one patient with paraneoplastic brainstem encephalitis associated with a Merkel cell tumor, and stabilization and partial improvement in one patient with paraneoplastic limbic encephalitis. The patient without response developed a cutaneous vasculitis after the second treatment, and therapy was discontinued. CONCLUSIONS: This therapy appears beneficial for a number of paraneoplastic syndromes, most dramatically in the opsoclonus/myoclonus syndrome.