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Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. - British journal of haematology
Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T-cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH. The average age was 53Â years (range 18-77Â years) and 43 were male (63%). Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%). Patients were treated with disease-specific therapy and immunomodulatory agents. After a median follow-up of 32Â·2Â months, 46 patients had died (69%). The median overall survival was 4Â months (95% CI: 0Â·0-10Â·2Â months). Patients with malignancy had a worse prognosis compared to those without (median survival 2Â·8Â months versus 10Â·7Â months, PÂ =Â 0Â·007). HLH is a devastating disorder with a high mortality. Further research is needed to improve treatment and outcomes.Â© 2015 John Wiley & Sons Ltd.
Stereotactic radiosurgery for large brain metastases. - Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
We evaluated patient outcomes following stereotactic radiosurgery (SRS)-treatment of large brain metastasis (â©¾3 cm) at our institution. SRS is an established treatment for limited brain metastases. However, large tumors pose a challenge for this approach. For this study, 343 patients with 754 total brain metastases were treated with SRS, of which 93 had large tumors. The tumor size was 3-3.5, 3.5-4, and â©¾4 cm in 29%, 32%, and 39% of these patients. Surgical resection was performed prior to SRS in 68% of patients, and 53% achieved a gross total resection. The local control of large metastases was inferior compared to smaller tumors, with 1 year local control of 68 versus 86%, respectively (p<0.001). Among the patients with large metastases, no correlation between local control and surgical resection (p=0.747), or extent of surgery (gross total versus subtotal resection; p=0.120), was identified. Histology (p=0.939), tumor size (3-4 versus >4 cm; p=0.551), and SRS dose (â©½16 versus >16 Gy; p=0.539) also showed no correlation with local failure. The overall survival at 1, 2, and 5 years was 46%, 29% and 5%, respectively. Prolonged survival was seen in patients with age <65 years (p=0.009), primary treatment compared with salvage (p=0.077), and controlled primary tumors (p=0.022). Radiation necrosis developed in 10 patients (11.8%). For patients with large brain metastases, SRS is well tolerated and can achieve local central nervous system disease control in the majority of patients, and extended survival in some, though the local control rate is suboptimal. Further strategies to improve the outcomes in this subgroup of patients are needed.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases. - Frontiers in oncology
To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach.Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1-4 brain metastases, Karnofsky performance status â‰¥70, and life expectancy â‰¥3â€‰months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with â‰¥1-year WBRT-free survival (Nâ€‰=â€‰104), and those who died or required salvage WBRT within 3â€‰months of SRS (Nâ€‰=â€‰56). Differences between these groups were assessed by univariate and multivariate analyses.Median survival for all patients was 11â€‰months. Among patients with â‰¥1-year WBRT-free survival, median survival was 33â€‰months (12-107â€‰months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (pâ€‰<â€‰0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (â‰¤5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival.A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone.
Novel treatment approaches for locally advanced pancreatic cancer. - JOP : Journal of the pancreas
Despite decades of research, pancreatic cancer remains essentially incurable for patients with unresectable tumors. In the United States, most patients with locally advanced pancreatic cancer are treated with chemotherapy alone or combined with conventionally fractionated radiotherapy. Regardless of the treatment strategy, average survival for these patients is less than 1 year, indicating that the current approaches are indisputably inadequate. For locally advanced pancreatic cancer patients, effective local-regional control is not only crucial for any hope at long-term survival, but also for symptom management. The aim of this paper is to highlight abstracts from the 2014 ASCO Gastrointestinal Cancers Symposium that demonstrate the use of novel local-regional therapies in locally advanced pancreatic cancer. Abstracts #317, #328, and #361 describe their results with an advanced method of delivering radiation called stereotactic body radiation therapy (SBRT). In these studies, patients treated with combined chemotherapy and SBRT had exceptional local control rates and acceptable toxicity. An innovative alternative to radiation for local-regional treatment is presented in Abstract #270. This study shows encouraging results from a phase I investigation of a regionally delivered siRNA that targets the K-ras(G12D) mutation. Investigation of novel approaches such as those presented here holds the greatest promise for improving treatment of this deadly disease.
Histone 3 lysine 9 trimethylation is differentially associated with isocitrate dehydrogenase mutations in oligodendrogliomas and high-grade astrocytomas. - Journal of neuropathology and experimental neurology
Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.
Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. - Oncotarget
The molecular foundations of lower-grade gliomas (LGGs)-astrocytoma, oligodendroglioma, and oligoastrocytoma-remain less well characterized than those of their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events. However, while IDH mutations appear to dramatically alter cellular epigenomic landscapes, definitive downstream transformative mechanisms have not been characterized. It remains likely, therefore, that additional genomic abnormalities collaborate with IDH mutation to drive oncogenesis in LGG. We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, and found a high incidence of mutations in the ATRX gene (Î± thalassemia/mental retardation syndrome X-linked). ATRX forms a core component of a chromatin remodeling complex active in telomere biology. Mutations in ATRX have been identified in multiple tumor types and appear to cause alternative lengthening of telomeres (ALT), a presumed precursor to genomic instability. In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma. Moreover, ATRX mutation was highly enriched in tumors of so-called early progenitor-like transcriptional subclass (~85%), which our prior work has linked to specific cells of origin in the forebrain subventricular zone. Finally, ATRX mutation correlated with ALT, providing a mechanistic link to genomic instability. In summary, our findings both identify ATRX mutation as a defining molecular determinant for a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs.
IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. - Clinical cancer research : an official journal of the American Association for Cancer Research
Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma [World Health Organization (WHO) IV], its most malignant subtype, lower grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notable clinical heterogeneity. Accordingly, we sought to identify and characterize clinically relevant molecular subclasses of lower grade diffuse astrocytic gliomas.We conducted multidimensional molecular profiling, including global transcriptional analysis, on 101 lower grade diffuse astrocytic gliomas collected at our own institution and validated our findings using publically available gene expression and copy number data from large independent patient cohorts.We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, platelet-derived growth factor receptor (PDGFR)A overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone. This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors.We have elucidated molecularly distinct subclasses of lower grade diffuse astrocytic glioma that dictate clinical behavior and show fundamental associations with both IDH mutational status and neuroglial developmental stage.Â©2012 AACR.
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