Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.

BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Large Collective Lamb Shift of Two Distant Superconducting Artificial Atoms.

Virtual photons can mediate interaction between atoms, resulting in an energy shift known as a collective Lamb shift. Observing the collective Lamb shift is challenging, since it can be obscured by radiative decay and direct atom-atom interactions. Here, we place two superconducting qubits in a transmission line terminated by a mirror, which suppresses decay. We measure a collective Lamb shift reaching 0.8% of the qubit transition frequency and twice the transition linewidth. We also show that the qubits can interact via the transmission line even if one of them does not decay into it.

Reflective Amplification without Population Inversion from a Strongly Driven Superconducting Qubit.

Amplification of optical or microwave fields is often achieved by strongly driving a medium to induce population inversion such that a weak probe can be amplified through stimulated emission. Here we strongly couple a superconducting qubit, an artificial atom, to the field in a semi-infinite waveguide. When driving the qubit strongly on resonance such that a Mollow triplet appears, we observe a 7% amplitude gain for a weak probe at frequencies in between the triplet. This amplification is not due to population inversion, neither in the bare qubit basis nor in the dressed-state basis, but instead results from a four-photon process that converts energy from the strong drive to the weak probe. We find excellent agreement between the experimental results and numerical simulations without any free fitting parameters. Since our device consists of a single two-level artificial atom, the simplest possible quantum system, it can be viewed as the most fundamental version of a four-wave-mixing parametric amplifier.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Global Burden and Inequality of Dental Caries, 1990 to 2019.

Previous studies on the global burden of caries primarily focused on simple descriptive statistics. We aimed to characterize the burden, trends, and inequalities of untreated caries of permanent and deciduous teeth from 1990 to 2019 at the global, regional, and national levels through an array of analytic approaches. Estimates of caries burden were extracted from the Global Burden of Disease Study 2019. Decomposition analysis was performed to examine the contribution of demographic and epidemiologic factors to the evolving number of prevalent caries cases. In portfolio analysis, the caries epidemiologic profile of each country was categorized by terciles of age-standardized prevalence in 2019 and average annual percentage change from 1990 to 2019. Sociodemographic attribution analysis was performed to reveal the scale of inequality in burden of caries. Age-standardized prevalence of caries in permanent and deciduous teeth decreased 3.6% (95% uncertainty interval, 2.6% to 4.5%) and 3.0% (1.3% to 4.9%), respectively. Population growth was the key driver of the changes in the number of caries cases, especially in sub-Saharan Africa (percentage contribution: 126.6%, permanent teeth; 103.0%, deciduous teeth). Caries prevalence in the permanent dentition was lower in more developed countries, whereas a reverse trend was noted in the deciduous dentition, except for the highest sociodemographic quintile where caries prevalence was the lowest. Globally, 64.6 million (95% CI, 64.4 to 64.9 million) and 62.9 million (62.8 to 63.1 million) prevalent cases of caries in permanent and deciduous teeth were attributable to sociodemographic inequality in 2019. This amounted to 3.2% (3.2% to 3.2%) and 12.1% (12.1% to 12.1%) of the global number of prevalent cases of caries in permanent and deciduous teeth. Burden of dental caries remains a global public health challenge. A systemwide reform of the global oral health care system is needed to tackle the causes of the burden and inequality of dental caries.

Increased mobilisation of circulating endothelial progenitors in von Hippel-Lindau disease and renal cell carcinoma.

BACKGROUND: Circulating endothelial cells (CECs) are a candidate biomarker for monitoring angiogenesis in cancer. Circulating endothelial cell subsets are mobilised by angiogenic mediators. Because of the highly angiogenic phenotype of renal cell carcinoma (RCC), we sought to assess the potential of CECs as a marker of RCC in patients with von Hippel-Lindau (VHL) disease and those with sporadic RCC. METHODS: We performed multicolour flow cytometry to enumerate CECs in patients with RCC, patients with VHL disease with and without RCC, and normal subjects. Two subsets of CECs were evaluated: mature CECs (mCECs) and circulating endothelial progenitors (CEPs). RESULTS: In patients with VHL disease and RCC and those with sporadic RCC (N=10), CEPs and the CEP:mCEC ratio were higher than in normal subjects (N=17) (median CEPs: 0.97 vs 0.19 cells µl(-1), respectively, P<0.01; median CEP:mCEC: 0.92 vs 0.58, respectively, P=0.04). However, in patients with VHL without RCC, CECs were not increased. In paired pre- and post-nephrectomy RCC patient samples (N=20), CEPs decreased after surgery (median difference 0.02 cells µl(-1), -0.06 to 1.2; P=0.05). CONCLUSION: Circulating endothelial progenitors were elevated in RCC, but not in patients with VHL without RCC. Circulating endothelial progenitor enumeration merits further investigation as a monitoring strategy for patients with VHL.

Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure.

There is no effective treatment for recurrent glioblastoma (GBM) after bevacizumab failure. Putative mechanisms of resistance to bevacizumab include increased pericyte coverage, mediated partly by platelet-derived growth factor receptor (PDGFR) signaling, and an infiltrative tumor growth pattern potentially dependent on SRC. We explored the efficacy of dasatinib, a SRC, BCR-ABL, c-KIT, EPHA2, and PDGFRß inhibitor, in patients with recurrent GBM after bevacizumab failure. Adult patients with histologically confirmed GBM who failed bevacizumab therapy were treated with dasatinib 70-100 mg twice daily in combination with bevacizumab (n = 14), until tumor progression or unacceptable toxicity. Fourteen patients were treated. Median age was 55 years (range 32-66) and median KPS was 80 (range 50-90). All patients (100%) had glioblastomas. The median number of prior regimens was 4 (range from 2 to 6). Of the thirteen evaluable patients, none had a complete or partial response. Only one patient had stable disease after an 8 week interval. Median progression-free survival (PFS) was 28 days (95% confidence interval [CI] 26-35 days). Six month progression-free survival (PFS6) was 0%. Median overall survival (OS) was 78 days (95% CI 41-137 days). Treatment was moderately well-tolerated, although one patient sustained a grade 4 intracerebral hemorrhage. Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM.

Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo.

Cytosine arabinoside (ara-C) is a cytidine analog that incorporates into replicating DNA and induces lethal DNA strand breaks. Although ara-C is a potent antitumor agent for hematologic malignancies, it has only minimal activity against most solid tumors. The rate-limiting step in intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cells lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment of established intradermal and intracerebral gliomas transduced with dCK results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gene therapy.

[The status quo of amphetamine type stimulants use among residents aged 15-64 in a border city of Yunnan province, 2014].

Objective: To understand status of amphetaminetype stimulants (ATS) use among residents aged 15-64 in a border city of Yunnan province. Methods: Using the stratified cluster random sampling method, a total of 3 130 residents were recruited through both anonymous questionnaire and interview, regarding their health-related behaviour and ATS use. Results: Among 3 130 residents aged 15-64 years in this city, the overall prevalence rates of ATS use were 4.0% (126/3 130) in the lifetime and 2.6% (82/3 130) in the past one year, while the prevalence of ATS use disorder in the past year was 2.3% (73/3 130). The prevalence rates of lifetime ATS use and in the past year were 7.5% (108/1 443) and 5.1% (73/1 443) in the high epidemic area, 7.3% (122/1 682) and 4.8%(80/1 682) in males, 5.2% (118/2 260) and 3.4% (77/2 260) in 18-45 age group, 4.6%(63/1 361) and 3.4% (46/1 361) in the ones having had elementary school education, 10.3% (50/487) and 8.6% (42/487) in unmarried group, 17.1% (19/111) and 12.6% (14/111) in either divorced, widowed or separated group, 4.8% (108/2 256) and 3.2% (72/2 256) in the farmers group, 6.0% (99/1 643) and 4.4% (73/1 643) in the non-religious groups (neither Buddhism nor Christianity), 15.2% (97/639) and 11.9% (76/639) in groups with negative hobbies which were 1.3% (29/2 314) and 0.3%(6/2 314) higher than the ones with positive hobbies, 8.5% (84/992) and 6.3% (62/992) in the ones negatively managing the stress which were 2.0% (42/2 138) and 0.9% (20/2 138) higher than the ones that treating the stress in a positive way. Conclusions: The prevalence rates of ATS use and ATS use disorder in the past one year appeared high among those residents aged 15-64 years in the border city of Yunnan province. Prevention and intervention programs should be carried out for the target groups as soon as possible.

Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases.

BACKGROUND: The spread of systemic cancer to the brain is a common complication for cancer patients. Conventional radiotherapy offers modest palliation, and surgery is helpful only for the patient with a single metastasis in an accessible location. Stereotactic radiosurgery, a technique that permits the precise delivery of a high dose of radiation to a small intracranial target while sparing the surrounding normal brain, has been used as an alternative treatment for brain metastases. PURPOSE: Our medical center's 7-year experience with radiosurgery for metastases was reviewed to establish the effectiveness of the treatment and to understand the prognoses in patients so treated. METHODS: Retrospective analysis of hospital records, from 248 consecutive patients (421 lesions) that were treated with radiosurgery between May 1986 and May 1993, was performed. Patients were only excluded for a Karnofsky performance score of less than 70, evidence of acute neurologic deterioration, or tumor diameter more than 4 cm. Median follow-up was 26.2 months. Seventy-six percent of patients had recurrent disease, 69% had evidence of systemic disease, 69% had a single metastasis. Treatment was performed using a 6-MeV linear accelerator. The median tumor volume was 3 cm3. The median treatment dose was 1500 cGy. Whole brain radiotherapy was given to all newly diagnosed patients. Patients were followed by neurological examination and neuroimaging at regular intervals. Local control of disease was defined as a lack of progression of solid-contrast enhancement on computed tomography scan or magnetic resonance imaging. RESULTS: Median overall survival from radiosurgery was 9.4 months. The absence of active systemic disease, younger than 60 years of age, two or fewer lesions, and female sex were significantly associated with increased survival (two-sided P < .05). Actuarial local control rates were approximately 85% at 1 year and 65% at 2 years. Factors associated with a significantly decreased local control rate were location below the tentorium, recurrent tumor, and larger tumor volume (two-sided P < .05). Radioresponsive and radioresistant tumor types had similar control rates. The median drop in Karnofsky performance score at 1 year was 10%. CONCLUSIONS: The results of this retrospective analysis show that radiosurgery is an effective, minimally invasive outpatient treatment option for small intracranial metastases. Results of this study also indicate that radiosurgery not only provides local control rates equivalent to those from surgical series but is also effective in treating patients with surgically inaccessible lesions, with multiple lesions, or with tumor types that are resistant to conventional treatment.

Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma.

Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results, we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated, supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery, partial brain external-beam radiotherapy (59.4 Gy in 33 fractions), and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group, we identified 40 patients with glioblastoma treated with surgery and external radiotherapy, with or without chemotherapy, between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%, respectively, for patients receiving brachytherapy versus 40% and 12.5%, respectively, for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately, only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation.

Specific uptake of the auger electron-emitting thymidine analogue 5-[123I/125I]iodo-2'-deoxyuridine in rat brain tumors: diagnostic and therapeutic implications in humans.

Glial neoplasms of the human central nervous system are malignancies that have defied treatment. Part of the problem lies in the limitations of current diagnostic techniques which are unable to identify small collections of neoplastic glia within normal parenchyma and in the difficulty of sterilizing these tumors because of limited selectivity of the cytotoxic agents available. The thymidine analogue 5-iodo-2'-deoxyuridine (IdUrd) radiolabeled with 123I and 125I was injected directly into an intracerebral rat 9L gliosarcoma and found to be a sensitive and specific agent for the detection of this neoplasm in rats. External gamma camera imaging (123I) visualized tumors as small as 0.5 mm in diameter. Autoradiography (125I) indicated that IdUrd was incorporated into the DNA of neoplastic glia only. Since 123I emits gamma-photons suitable for scintigraphy, [123I]IdUrd holds promise for the diagnosis of brain tumors in humans as well. Furthermore, since 123I and 125I are Auger electron emitters that have demonstrated antineoplastic effects, direct administration of [123I]IdUrd or [125I]IdUrd into tumors may also have potential for the treatment of central nervous system malignancies.

The treatment of recurrent brain metastases with stereotactic radiosurgery.

Between May 1986 and August 1989, we treated 18 patients with 21 recurrent or persistent brain metastases with stereotactic radiosurgery using a modified linear accelerator. To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of (or stable) systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. The most common histology of the metastatic lesion was carcinoma of the lung (seven patients), followed by carcinoma of the breast (four patients), and melanoma (four patients). With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy.

Radiosurgery as part of the initial management of patients with malignant gliomas.

PURPOSE: Between May 1988 and May 1991, 41 patients with malignant gliomas were enrolled onto a prospective study designed to evaluate the role of radiosurgery as a component of initial management. PATIENTS AND METHODS: Thirty-seven patients underwent radiosurgery according to the protocol and were assessable for survival and complications of treatment. Diagnoses included glioblastoma multiforme (GBM) in 23 (62%) cases and anaplastic astrocytoma in 14 (38%) cases. In 20 (54%) cases, surgical resection was attempted initially, whereas 17 (46%) patients underwent biopsy only. Patients in the study group received external-beam radiotherapy that consisted of 5,940 cGy given in 33 fractions to partial brain fields that encompassed the primary tumor with a 3 to 4 cm margin. Radiosurgery, used as a technique for boosting the dose to any residual contrast-enhancing mass lesion, was given 2 to 4 weeks after the completion of conventional radiotherapy. Minimum radiosurgical doses ranged from 1,000 to 2,000 cGy (median, 1,200 cGy), whereas maximum doses ranged from 1,250 to 2,500 cGy (median, 1,500 cGy). The median tumor volume at the time of radiosurgery was 4.8 cm3 (range, 1.2 to 72 cm3). Adjuvant chemotherapy was not given. RESULTS: After a median follow-up of 19 months, only nine of 37 (24%) patients have died. Six patients (all glioblastoma multiforme) died of recurrent tumor, whereas death was attributable to complications of treatment in two cases and intercurrent disease in one case. Four patients with recurrent tumor failed at the margins of the radiosurgical treatment volume, whereas two patients progressed locally. One patient is alive with local and marginal failure. Seven (19%) patients underwent reoperation at a median time of 5 months (range, 1 to 14 months) after radiosurgery. CONCLUSION: We conclude that radiosurgery is a useful adjunct to other modalities in the initial management of patients with small, radiographically well-defined malignant gliomas.

Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

A phase I trial of a new recombinant human beta-interferon (BG9015) for the treatment of patients with recurrent gliomas.

Primary brain tumors represent an important cause of cancer-related morbidity and mortality in the United States. Despite advances in neurosurgery and radiotherapy, the median survival of patients with malignant gliomas remains less than 1 year. A contributing factor to the poor prognoses of these patients is the diffuse, infiltrative nature of these tumors, which limits the effectiveness of focal therapies (i.e., surgery and radiation). Unfortunately, standard chemotherapy has been of limited benefit in the treatment of malignant gliomas, underlying the necessity for new drugs with novel mechanisms of action. On the basis of promising in vitro and clinical data demonstrating significant antiglioma activity of purified IFN-beta and a synthetic IFN-beta (Betaseron), we conducted a Phase I trial of a new, nonmutated, glycosylated recombinant human IFN-beta (BG9015) in patients with recurrent, high-grade astrocytomas. In this trial, we demonstrate that the maximally tolerated dose of BG9015 is 6 million units/m2 delivered by intramuscular injection three times per week. Dose-limiting neurotoxicity was seen in both patients treated at 8 million units/m2. Additionally, we demonstrate that high BG9015 serum levels are associated with a fall in natural killer cell number, radiographic response, and prolonged survival. We conclude that BG9015 has activity in patients with malignant gliomas, although the therapeutic index may be narrow. Future studies will be needed to confirm the observation that natural killer cell number and activity as well as BG9015 serum levels are important markers of antitumor activity.

Deceptively normal ventricular fluid in lymphomatous meningitis.

The diagnosis of leptomeningeal cancer ultimately depends on the finding of abnormal cerebrospinal fluid with malignant cytologic study results. We report a case of relapsed leptomeningeal lymphomatosis in which ventricular cerebrospinal fluid was entirely normal while lumbar spinal fluid was diagnostically abnormal. To our knowledge, this is the first such reported case, and it highlights the importance of sampling cerebrospinal fluid close to the site of clinical involvement.

Transgene expression in malignant glioma using a replication-defective adenoviral vector containing the Egr-1 promoter: activation by ionizing radiation or uptake of radioactive iododeoxyuridine.

One approach to improving the specificity of gene therapy involves using radiosensitive promoters to activate gene expression selectively in the radiation field. In this study, we evaluated the ability of irradiation to regulate the transcription of a recombinant replication-defective adenovirus vector, Ad.Egr-1/lacZ, containing the radiation-inducible Egr-1 promoter driving the beta-galactosidase reporter gene in glioma cells. Transcripts of the Egr-1 gene in human and rat glioma cells were induced following irradiation with as little as 2 Gy. This dose was 10-fold less than previously reported, and comparable to doses of irradiation used clinically in standard fractionated radiotherapy for brain tumors. When 9L rat gliosarcoma cells were infected with Ad.Egr-1/lacZ in vitro and exposed to 2 Gy of external beam irradiation, there was a threefold increase in beta-galactosidase expression. Irradiation of intracerebral 9L tumors infected with the Ad.Egr-1/lacZ virus, using either external beam radiotherapy (2 Gy) or the thymidine analog 5-iodo-2'-deoxyuridine radiolabeled with the Auger electron emitter iodine-125 ([125I]IdUrd), also resulted in increased beta-galactosidase activity of the tumor cells. These results indicate that the use of viral vectors containing radiation-inducible promoters represents a novel therapeutic approach that enables gene therapy to be spatially and temporally regulated by ionizing radiation. These findings also support a potential role for radiation-inducible promoters in the treatment of malignant brain tumors.

Systemic metastasis in glioblastoma may represent the emergence of neoplastic subclones.

Glioblastomas only rarely metastasize to sites outside the central nervous system, for reasons that are poorly understood. We report the clinicopathological and molecular genetic findings in 6 patients with metastatic glioblastoma. Four patients were under the age of 32 and all but 1 patient died within 2 yr of diagnosis. The number of metastases ranged from 1 to 3. At the time of death, 3 patients had apparent tumor control at their primary site. We evaluated DNA from both primary and metastatic glioblastomas for genetic alterations commonly found in glioblastomas: TP53 mutations, CDKN2A/p16 deletions, EGFR amplification, and allelic loss of chromosomes 1p, 10q and 19q. Four of 6 cases had TP53 mutations and only single cases had EGFR amplification, CDKN2A/p16 deletions, or allelic loss of 1p, 10q and 19q; 2 cases had no detectable genetic alterations. In 2 cases, the primary and metastatic tumors had identical genotypes. Remarkably, however, 2 cases had different TP53 alterations in the primary and metastatic lesions, or among the metastatic tumors, which suggests that some metastatic deposits may represent emergence of subclones that were not necessarily dominant in the primary tumor. The present observations and a review of the recent literature demonstrate that metastatic glioblastomas tend to occur in younger adults who do not follow long clinical courses, and may be characterized by TP53 mutations and differential clonal selection.