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Jay S Loeffler

Publications and source records attributed to Jay S Loeffler.

At least 19 recordsLinked to original sources
PubMed2007

AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Brain Edema↗
PubMed2006

Personal hair dye use and risks of glioma, meningioma, and acoustic neuroma among adults.

Previous studies have suggested an association of personal hair dye use with bladder and hematopoietic cancers. Risks for brain tumors are not well understood. The authors investigated associations between use of synthetic hair dyes and risk of brain tumors in a hospital-based case-control study. The study included adults newly diagnosed with glioma (n = 489), meningioma (n = 197), or acoustic neuroma (n = 96) between 1994 and 1998 at three urban US hospitals and 799 controls. Odds ratios were estimated and 95% confidence intervals were calculated using unconditional logistic regression. Detailed exposure histories were obtained by interview. There was no consistent pattern of elevated odds ratios for glioma, meningioma, or acoustic neuroma with use or prolonged use of permanent, semipermanent, temporary, or gradual hair dyes. Although use of permanent brown hair dye for 20 or more years was associated with glioma among women, the estimate was imprecise (odds ratio = 3.8, 95% confidence interval: 1.2, 12.5) and was based on just 13 exposed cases; thus, this could be a chance finding. Overall, there was little consistent evidence for an association of synthetic hair dye use with glioma, meningioma, or acoustic neuroma. However, prolonged use of dark-colored permanent dyes warrants further investigation given the high prevalence of hair dyeing.

Adolescent↗
PubMed2006

Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms.

PURPOSE: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells. EXPERIMENTAL DESIGN: Using a panel of four primary human glioblastoma cell lines with heterogeneous O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide. RESULTS: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O(6)-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O(6)-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings. CONCLUSIONS: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O(6)-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.

Animals↗
PubMed2006

Primary CNS lymphoma.

Primary CNS lymphoma (PCNSL), an uncommon form of extranodal non-Hodgkin's lymphoma (NHL), has increased in incidence during the last three decades and occurs in both immunocompromised and immunocompetent hosts. PCNSL in immunocompetent patients is associated with unique diagnostic, prognostic, and therapeutic issues, and the management of this malignancy is different from that of other forms of extranodal NHL. Characteristic imaging features should be suggestive of the diagnosis, avoidance of corticosteroids, if possible, and early neurosurgical consultation for stereotactic biopsy. Because PCNSL may involve the brain, CSF, and eyes, diagnostic evaluation should include assessment of all of these regions as well as screening for possible occult systemic disease. Resection provides no therapeutic benefit and should be reserved for the rare patient with neurologic deterioration due to brain herniation. Whole-brain radiation therapy (WBRT) alone is insufficient for durable tumor control and is associated with a high risk of neurotoxicity in patients older than age 60. Neurotoxicity typically is associated with significant cognitive, motor, and autonomic dysfunction, and has a negative impact on quality of life. Chemotherapy and WBRT together improve tumor response rates and survival compared with WBRT alone. Methotrexate-based multiagent chemotherapy without WBRT is associated with similar tumor response rates and survival compared with regimens that include WBRT, although controlled trials have not been performed. The risk of neurotoxicity is lower in patients treated with chemotherapy alone.

Central Nervous System Neoplasms↗
PubMed2006

Proton beam radiation therapy for skull base adenoid cystic carcinoma.

OBJECTIVE: To determine the treatment outcome and prognostic factors in patients with adenoid cystic carcinoma of the skull base treated with proton beam radiation therapy. DESIGN: Retrospective analysis. SETTING: Massachusetts General Hospital, Massachusetts Eye and Ear Infirmary, and Harvard Medical School, Boston. PATIENTS: From 1991 to 2002, 23 patients with newly diagnosed adenoid cystic carcinoma with skull base extension were treated with combined proton and photon radiotherapy. There was tumor involvement of the sphenoid sinus in 61% of patients (14), nasopharynx in 61% (14), clivus in 48% (11), and cavernous sinus in 74% (17). The extent of surgery was biopsy alone in 48% (11), partial resection in 39% (9), and gross total resection with positive margins in 13% (3). The median total dose to the primary site was 75.9 cobalt-gray equivalent. The median follow-up of all surviving patients was 64 months. MAIN OUTCOME MEASURES: Locoregional control and disease-free survival and overall survival rates. RESULTS: Tumors recurred locally in 2 patients at 33 and 68 months, respectively. No patients developed neck recurrence. Eight patients had distant metastasis as the first site of recurrence. The local control rate at 5 years was 93%. The rate of freedom from distant metastasis at 5 years was 62%. The disease-free and overall survival rates at 5 years were 56% and 77%, respectively. In multivariate analysis, significant adverse factors predictive for overall survival were change in vision at presentation (P = .02) and involvement of sphenoid sinus and clivus (P = .01). CONCLUSIONS: High-dose conformal proton beam radiation therapy results in a very encouraging local control rate in patients with adenoid cystic carcinoma of the skull base. Changes in vision at presentation and tumor involvement of the sphenoid sinus and clivus are important prognostic factors.

Adult↗
PubMed2006

Lessons from phase III clinical trials on anti-VEGF therapy for cancer.

In randomized phase III trials two anti-vascular endothelial growth factor (VEGF) approaches have yielded survival benefit in patients with metastatic cancer. In one approach, the addition of bevacizumab, a VEGF-specific antibody, to standard chemotherapy improved overall survival in colorectal and lung cancer patients and progression-free survival in breast cancer patients. In the second approach, multitargeted tyrosine kinase inhibitors that block VEGF receptor and other kinases in both endothelial and cancer cells, demonstrated survival benefit in gastrointestinal stromal tumor and renal-cell-carcinoma patients. By contrast, adding bevacizumab to chemotherapy failed to increase survival in patients with previously treated and refractory metastatic breast cancer. Furthermore, addition of vatalanib, a kinase inhibitor developed as a VEGF receptor-selective agent, to chemotherapy did not show a similar benefit in metastatic colorectal cancer patients. These contrasting responses raise critical questions about how these agents work and how to combine them optimally. We summarize three of the many potential mechanisms of action of anti-VEGF agents, and also discuss progress relating to the identification of potential biomarkers for anti-VEGF-agent efficacy in humans.

Angiogenesis Inhibitors↗
PubMed2006

Metastatic epidural spinal cord compression: update on management.

Until recently, patients with metastatic epidural spinal cord compression (MESCC) were routinely treated with corticosteroids and radiotherapy (RT). However, major advances in imaging, recognition of new prognostic factors, and new techniques in RT and surgery have led to a number of management choices that need to be considered when treating a patient with MESCC. In our view, the management should be individualized taking into account many variables. We present here some of the advances we believe are among the most important. A historical background to the modern management of this condition is first presented.

Epidural Neoplasms↗
PubMed2005

Genetic analyses for predictors of radiation response in glioblastoma.

PURPOSE: Radiotherapy (RT) for patients with glioblastoma improves survival and is recommended for nearly all patients with this diagnosis. However, the response to RT is variable in this patient population. Prior studies have suggested that underlying genetic alterations in the tumor may account for some of this treatment-related heterogeneity. It has been previously reported that epidermal growth factor receptor (EGFR) gene amplification and TP53 mutation correlate with the response to RT in patients with glioblastoma. METHODS AND MATERIALS: We sought to identify molecular markers that could predict the response to RT, progression-free survival after RT, and overall survival among 75 glioblastoma patients treated with RT at a single institution. Genetic analyses assessed EGFR amplification, TP53 mutations, CDKN2A/p16 deletion, and losses of chromosomes 1p, 10q, and 19q. RESULTS: Unlike previous reports, no association of EGFR amplification with response to RT, progression-free survival, or overall survival was found. Moreover, no association was found between these endpoints and the other genetic alterations assayed (TP53 mutation, CDKN2A/p16 deletion, loss of heterozygosity 1p, loss of heterozygosity 10q, and loss of heterozygosity 19q). However, in accordance with recent observations that the prognostic effects of genetic alterations in glioblastoma may depend on patient age, we observed age-dependent prognostic effects of TP53 and CDKN2A/p16 alterations in our patient population. For patients > or = 57 years old, those harboring TP53 mutations had a decreased overall survival compared with patients without TP53 mutations. Similarly, deletion of CDKN2A/p16 in patients > or = 57 years was associated with decreased progression-free survival after RT and a trend toward a shorter time to progression after RT compared with similar patients without the deletion. CONCLUSION: These data contrast with previous studies regarding the significant prognostic effect of EGFR with respect to RT response. Although our observations regarding the age-dependent prognostic effects of TP53 and CDKN2A/p16 are consistent with a prior report regarding these alterations, the present results should be considered preliminary, given the small sample size.

Adolescent↗
PubMed2005

Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma.

PURPOSE: This study evaluates the efficacy and toxicity of whole-brain radiation therapy (WBRT) as salvage therapy for immunocompetent patients who failed initial high-dose methotrexate for primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: The study cohort included 27 consecutive patients who failed initial high-dose methotrexate and then received salvage WBRT (median dose, 36 Gy). Actuarial survival was measured from the initiation of radiotherapy. RESULTS: Ten patients (37%) achieved a complete radiographic response (CR), and 10 patients (37%) a partial response to WBRT, for a 74% overall radiographic response rate. At the time of maximal response, Karnofsky performance status improved in 12 (44%) of 27 patients and at least stabilized in 67%. Median estimated survival from initiation of WBRT was 10.9 months (range, 0.3 to 63.7 months). The univariate predictor of longer survival was age less than 60 years at the time of WBRT (P = .028). Among patients who survived 4 months, achievement of a CR to WBRT by 4 months (P = .002) predicted longer survival. Late treatment-associated neurotoxicity was diagnosed in four patients (15%) and was significantly associated with total radiation doses greater than 36 Gy (P = .04). No patient treated with daily fractions less than 1.8 Gy developed late neurotoxicity. CONCLUSION: For patients with PCNSL who experience treatment failure with methotrexate, WBRT provides high response rates (74%) and a median survival of 10.9 months. Age less than 60 years and response to WBRT predict post-WBRT survival. Modest rates of late neurotoxicity (15%) were seen and were associated with a total dose greater than 36 Gy.

Antimetabolites, Antineoplastic↗
PubMed2005

Facial numbness in a man with inguinal and retroperitoneal masses.

BACKGROUND: A 37-year-old Brazilian man was admitted to Massachusetts General Hospital for evaluation of left-sided facial numbness, left-sided ataxia, dizziness, and vertigo. Seven weeks prior to admission, he reported numbness of the left oral cavity and tongue after a dental procedure. Three weeks prior to presentation, he developed left-sided incoordination with dizziness and vertigo. One week later, he noticed difficulty using a box cutter at work and presented to the emergency department for evaluation. A CT scan without contrast revealed no abnormalities and he was discharged home. Three days prior to admission, the patient developed diplopia. Cranial MRI revealed a 1.6 cm irregular enhancing mass in the left middle cerebellar peduncle. Neurologic examination was significant for diminished sensation over the left face to pinprick, left-sided dysmetria, and mild lateral instability of the trunk while walking. INVESTIGATIONS: MRI, lumbar puncture, CT scans of the abdomen and pelvis, needle biopsy of the lymph node, and paraneoplastic antibodies. DIAGNOSIS: Possible paraneoplastic demyelination. MANAGEMENT: Orchiectomy, adjuvant radiation, and corticosteroids.

Adult↗
PubMed2005

Stereotactic radiotherapy for vestibular schwannomas: favorable outcome with minimal toxicity.

OBJECTIVE: To determine the outcome and toxicity in patients with vestibular schwannomas treated with conventionally fractionated stereotactic radiotherapy (SRT) and to identify prognostic factors that are predictive of outcome. METHODS: Between 1992 and 2001, 70 patients with vestibular schwannomas were treated with linear accelerator-based SRT in our institutions. Eleven patients had neurofibromatosis Type II (NF2). The median age was 53 years (range, 17-82 yrs). The median tumor volume was 2.4 cm3 (range, 0.05-21.1 cm3). The indications for SRT were distributed as follows: 47% newly diagnosed, 31% progressive tumors after watchful waiting, 3% adjuvant postoperative radiation, and 19% recurrent tumors after surgical resection. The median dose was 54 Gy in 1.8 Gy per fraction, prescribed to 95% of the isodose line. Relocatable stereotactic frames were used for daily treatments. The median follow-up was 45.3 months. RESULTS: Tumor recurrence was defined as progressive enlargement of tumor on follow-up magnetic resonance imaging studies. One patient had a tumor recurrence at 38 months after SRT. The actuarial tumor control rates were 100 and 98% at 3 and 5 years, respectively. Three patients with a median tumor volume of 16.2 cm3 required surgical resection for persistent or increasing symptoms at a median of 37 months. The actuarial freedom from resection rates were 98 and 92% at 3 and 5 years, respectively. In multivariate analysis, tumor volume at time of treatment was predictive for neurosurgical intervention (surgical resection or shunt placement) after SRT (P = 0.001). The 3- and 5-year actuarial rates of freedom from any neurosurgical intervention were 100 and 97% for patients with tumor volume less than 8 cm3 and 74 and 47% respectively for patients with tumor of at least 8 cm3 (P < 0.0001). The 3-year actuarial rates of facial and trigeminal nerve preservation were 99 and 96%, respectively. Surgery before SRT was predictive of posttreatment trigeminal neuropathy. The 3-year actuarial rates of freedom from trigeminal neuropathy were 86 and 98% for patients with and without previous resection, respectively (P = 0.04). There was no difference in tumor control and cranial nerve function preservation rates seen in NF2 patients compared with non-NF2 patients. No second primary cancer or malignant transformation was observed. CONCLUSION: SRT in the conventionally fractionated approach results in a very favorable outcome with minimal toxicity, with results comparable to those of the best of the radiosurgery series. Patients with large tumors are more likely to undergo neurosurgical interventions after SRT. Patients who have undergone previous surgery are at increased risk of developing trigeminal neuropathy.

Adolescent↗
PubMed2005

Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium.

OBJECT: Pituitary adenomas are very common neoplasms, constituting between 10 and 20% of all primary brain tumors. Historically, the treatment armamentarium for pituitary adenomas has included medical management, microsurgery, and fractionated radiotherapy. More recently, radiosurgery has emerged as a viable treatment option. The goal of this research was to define more fully the efficacy, safety, and role of radiosurgery in the treatment of pituitary adenomas. METHODS: Medical literature databases were searched for articles pertaining to pituitary adenomas and stereotactic radiosurgery. Each study was examined to determine the number of patients, radiosurgical parameters (for example, maximal dose and tumor margin dose), duration of follow-up review, tumor growth control rate, complications, and rate of hormone normalization in the case of functioning adenomas. A total of 35 peer-reviewed studies involving 1621 patients were examined. Radiosurgery resulted in the control of tumor size in approximately 90% of treated patients. The reported rates of hormone normalization for functioning adenomas varied substantially. This was due in part to widespread differences in endocrinological criteria used for the postradiosurgical assessment. The risks of hypopituitarism, radiation-induced neoplasia, and cerebral vasculopathy associated with radiosurgery appeared lower than those for fractionated radiation therapy. Nevertheless, further observation will be required to understand the true probabilities. The incidence of other serious complications following radiosurgery was quite low. CONCLUSIONS: Although microsurgery remains the primary treatment modality in most cases, stereotactic radiosurgery offers both safe and effective treatment for recurrent or residual pituitary adenomas. In rare instances, radiosurgery may be the best initial treatment for patients with pituitary adenomas. Further refinements in the radiosurgical technique will likely lead to improved outcomes.

Adenoma↗
PubMed2005

Brain metastases in patients with breast cancer: new horizons.

Brain metastases occur in as many as one third of patients with disseminated breast cancer. In this article, we discuss various presentations of brain metastases from breast cancer and review evidence that supports different treatment options. Because no prospective, randomized, controlled studies, to our knowledge, have focused solely on patients with brain metastases from breast cancer, we will first review retrospective studies of patients with brain metastases from breast cancer. Randomized studies of patients with brain metastases caused by multiple primary cancers will also be examined, and the conclusions from these studies will be extrapolated to patients with breast cancer. Because brain metastases from breast cancer occur in a variety of different clinical settings, ranging from a single metastasis without extensive extracranial disease to multiple brain metastases with widespread extracranial disease, treatment approaches must be tailored to the specific circumstances of each patient. For different clinical scenarios, neurosurgical resection, radiosurgery, and/or whole-brain radiation therapy may be appropriate treatment options. For patients with brain metastases from breast cancer that overexpresses HER2/neu, trastuzumab could alter the natural history of the non-central nervous system (CNS) disease. Therefore, HER2 status could also influence the treatment of brain metastases from breast cancer. Given the prevalence of brain metastases in patients with metastatic breast cancer in contemporary series, the rationale for clinical trials of CNS screening and prophylactic cranial irradiation will be discussed.

Brain Neoplasms↗