Qian Ma

All Publications

• Durable responses to trastuzumab deruxtecan in patients with leptomeningeal metastases from breast cancer with variable HER2 expression. Journal of neuro-oncology Rogawski, D., Cao, T., Ma, Q., Roy-O'Reilly, M., Yao, L., Xu, N., Nagpal, S. 2024

  Abstract

  PURPOSE: Emerging data suggest that trastuzumab deruxtecan (T-DXd) is an active treatment for brain metastases from HER2+breast cancer. We aimed to characterize the activity of T-DXd in the treatment of leptomeningeal metastases (LM) from a range of HER2-altered cancers.METHODS: We reviewed neuro-oncology clinic records between July 2020 and December 2023 to identify patients who received T-DXd to treat LM.RESULTS: Of 18 patients identified, 6 had HER2+breast cancer, 8 had HER2-low/negative breast cancer, 2 had HER2+gastroesophageal cancer, and 2 had HER2-mutant non-small cell lung cancer (NSCLC). 10/18 (56%) patients had cytologically confirmed LM by CSF cytology or circulating tumor cell (CTC) capture. A partial response (PR) on MRI using the EORTC/RANO-LM Revised-Scorecard occurred in 4/6 (67%) patients with HER2+breast LM, 2/8 (25%) patients with HER2-low/negative breast cancer, and 0/4 (0%) patients with HER2+gastroesophageal cancer or HER2-mutant NSCLC. Median overall survival after initiating T-DXd was 5.8 months. Survival after initiating T-DXd was numerically longer for HER2+breast cancer patients compared with HER2-low/negative breast and HER2-altered non-breast cancer patients (13.9 months vs. 5.2 months and 4.6 months, respectively). Landmark analysis showed that patients with radiologic LM response to T-DXd by 2.5 months had longer survival than non-responders (14.2 months vs. 2.6 months, HR 0.18, 95% CI 0.05-0.63, p<0.05), and landmark analyses at 3.5 and 4.5 months after starting T-DXd showed a similar but nonsignificant trend.CONCLUSION: T-DXd induces LM responses in a subset of patients, and such responses may be associated with prolongation of survival. Prospective trials are needed to clarify the role of T-DXd in treating LM and which patients are most likely to benefit.

  View details for DOI 10.1007/s11060-024-04788-y

  View details for PubMedID 39073687

• A rare non-gadolinium enhancing sarcoma brain metastasis with microenvironment dominated by tumor-associated macrophages. Acta neuropathologica communications Rogawski, D., Wheeler, J., Nie, E., Zhu, W., Villanueva, E., Coffey, G., Ma, Q., Ganjoo, K., Fischbein, N., Iv, M., Vogel, H., Nagpal, S. 2024; 12 (1): 15

  Abstract

  Brain metastases occur in 1% of sarcoma cases and are associated with a median overall survival of 6 months. We report a rare case of a brain metastasis with unique radiologic and histopathologic features in a patient with low grade fibromyxoid sarcoma (LGFMS) previously treated with immune checkpoint inhibitor (ICI) therapy. The lone metastasis progressed in the midbrain tegmentum over 15 months as a non-enhancing, T2-hyperintense lesion with peripheral diffusion restriction, mimicking a demyelinating lesion. Histopathology of the lesion at autopsy revealed a rich infiltrate of tumor-associated macrophages (TAMs) with highest density at the leading edge of the metastasis, whereas there was a paucity of lymphocytes, suggestive of an immunologically cold environment. Given the important immunosuppressive and tumor-promoting functions of TAMs in gliomas and carcinoma/melanoma brain metastases, this unusual case provides an interesting example of a dense TAM infiltrate in a much rarer sarcoma brain metastasis.

  View details for DOI 10.1186/s40478-023-01713-8

  View details for PubMedID 38254244

  View details for PubMedCentralID 5021195

• What I Learned From Cancer. Academic medicine : journal of the Association of American Medical Colleges Ma, Q. 2022

  View details for DOI 10.1097/ACM.0000000000005005

  View details for PubMedID 36206578

• SorCS2 is required for social memory and trafficking of the NMDA receptor. Molecular psychiatry Yang, J., Ma, Q., Dincheva, I., Giza, J., Jing, D., Marinic, T., Milner, T. A., Rajadhyaksha, A., Lee, F. S., Hempstead, B. L. 2021; 26 (3): 927-940

  Abstract

  Social memory processing requires functional CA2 neurons, however the specific mechanisms that regulate their activity are poorly understood. Here, we document that SorCS2, a member of the family of the Vps10 family of sorting receptors, is highly expressed in pyramidal neurons of CA2, as well as ventral CA1, a circuit implicated in social memory. SorCS2 specifically localizes to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. We have discovered that SorCS2 is a selective regulator of NMDA receptor surface trafficking in hippocampal neurons, without altering AMPA receptor trafficking. In addition, SorCS2 regulates dendritic spine density in CA2 neurons where SorCS2 expression is enriched, but not in dorsal CA1 neurons, which normally express very low levels of this protein. To specifically test the role of SorCS2 in behavior, we generated a novel SorCS2-deficient mouse, and identify a significant social memory deficit, with no change in sociability, olfaction, anxiety, or several hippocampal-dependent behaviors. Mutations in sorCS2 have been associated with bipolar disease, schizophrenia, and attention deficient-hyperactivity disorder, and abnormalities in social memory are core components of these neuropsychiatric conditions. Thus, our findings provide a new mechanism for social memory formation, through regulating synaptic receptor trafficking in pyramidal neurons by SorCS2.

  View details for DOI 10.1038/s41380-020-0650-7

  View details for PubMedID 31988435

  View details for PubMedCentralID 4000264

• Neurology trial registrations on ClinicalTrials.gov between 2007 and 2018: A cross-sectional analysis of characteristics, early discontinuation, and results reporting. Journal of the neurological sciences Turner, B. E., Magnani, C. J., Frolov, A., Weeks, B. T., Steinberg, J. R., Huda, N., Shah, L. M., Zuroff, L., Gu, B. J., Rasmussen, H., Edwards, J. G., Save, A. V., Shen, M., Ren, M., Bryant, B. R., Ma, Q., Feng, A. Y., Liang, A. C., Santini, V. E. 2021; 428: 117579

  Abstract

  Increasing neurological disease burden and advancing treatment options require clinical trials to expand the evidence base of clinical care. We aimed to characterize neurology clinical trials registered between October 2007 and April 2018 and identify features associated with early discontinuation and results reporting.We compared 16,994 neurology (9.4%) and 163,714 non-neurology comparison trials registered to ClinicalTrials.gov. Trials therapeutic focus within neurology was assigned via combination programmatic and manual review. We performed descriptive analyses of trial characteristics, cox regression of early discontinuation, and multivariable logistic regression for results reporting within 3 years of completion.Most neurology trials were academic-funded (58.5%) followed by industry (31.9%) and US-government (9.6%). Neurology trials focused more on treatment than prevention compared to non-neurology studies. Of neurology trials, 11.3% discontinued early, and 32.2% of completed trials reported results by April 30, 2018. In multivariable analysis accounting for time-to-event, neurology trials were at lower risk of discontinuation than non-neurology trials (adjusted hazard 0.83, p < 0.0001). Both academic and government-funded trials had greater risk of discontinuation than industry (adjusted hazard 0.57 and 0.46, respectively). Among completed trials, government-funded studies (adjusted odds ratio 2.12, p < 0.0001) had highest odds of results reporting while academic trials reported less (adjusted odds ratio 0.51, p < 0.0001).Funding source is associated with trial characteristics and outcomes in neurology. Improvements in trial completion and timely dissemination of results remain urgent goals for the field.

  View details for DOI 10.1016/j.jns.2021.117579

  View details for PubMedID 34332371

• SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington's disease. JCI insight Ma, Q., Yang, J., Milner, T. A., Vonsattel, J. G., Palko, M. E., Tessarollo, L., Hempstead, B. L. 2017; 2 (9)

  Abstract

  Motor dysfunction is a prominent and disabling feature of Huntington's disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-D-aspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein-domain (VPS10P-domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs. In the zQ175 striatum, SorCS2 is markedly decreased in an age- and allele-dependent manner. Notably, SorCS2 selectively interacts with mutant huntingtin (mtHTT), but not WT huntingtin (wtHTT), and is mislocalized to perinuclear clusters in striatal neurons of human HD patients and zQ175 mice. Genetic deficiency of SorCS2 accelerates the onset and exacerbates the motor coordination deficit of zQ175 mice. Together, our results identify SorCS2 as an interacting protein of mtHTT and demonstrate that impaired SorCS2-mediated NR2A subunit trafficking to dendritic surface of MSNs is, to our knowledge, a novel mechanism contributing to motor coordination deficits of HD.

  View details for DOI 10.1172/jci.insight.88995

  View details for PubMedID 28469074

  View details for PubMedCentralID PMC5414556

• Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease. Neurobiology of disease Ma, Q., Yang, J., Li, T., Milner, T. A., Hempstead, B. L. 2015; 82: 466-477

  Abstract

  Huntington's disease (HD) is a neurodegenerative disorder characterized by massive loss of medium spiny neurons in the striatum. However, the mechanisms by which mutant huntingtin leads to this selective neuronal death remain incompletely understood. Brain-derived neurotrophic factor (BDNF) has been shown to be neuroprotective on HD striatal neurons both in vitro and in vivo. ProBDNF, the precursor of mature BDNF (mBDNF), also can be secreted but promotes apoptosis of neurons expressing p75(NTR) and sortilin receptors. Although a reduction of total striatal BDNF protein has been reported in HD patients and mouse models, it remains unclear whether conversion of proBDNF to mBDNF is altered in HD, and whether the proBDNF receptors, p75(NTR) and sortilin are dysregulated, leading to impaired striatal neuron survival. To test these hypotheses, we generated bdnf-HA knock-in (KI) mice on the zQ175 HD background to accurately quantitate the levels of both proBDNF and mBDNF in the HD striatum. In aged zQ175 HD mice, we observed a significant loss of mBDNF and decreased TrkB activation, but no increase of proBDNF or p75(NTR) levels either in the sensorimotor cortex or the striatum. However, immunoreactivities of p75(NTR) and sortilin receptor are both increased in immature striatal oligodendrocytes, which associate with significant myelin defects in the HD striatum. Taken together, the present study indicates that diminished mature BDNF trophic signaling through the TrkB receptor, rather than an induction in proBDNF, is a main contributing factor to the vulnerability of striatal neurons in the zQ175 HD mouse model.

  View details for DOI 10.1016/j.nbd.2015.08.008

  View details for PubMedID 26282324

  View details for PubMedCentralID PMC4819334

• proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell reports Yang, J., Harte-Hargrove, L. C., Siao, C. J., Marinic, T., Clarke, R., Ma, Q., Jing, D., Lafrancois, J. J., Bath, K. G., Mark, W., Ballon, D., Lee, F. S., Scharfman, H. E., Hempstead, B. L. 2014; 7 (3): 796-806

  Abstract

  Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF.

  View details for DOI 10.1016/j.celrep.2014.03.040

  View details for PubMedID 24746813

  View details for PubMedCentralID PMC4118923