Erin M. Dunbar

The relationship between circulating natural killer cells after reduced intensity conditioning hematopoietic stem cell transplantation and relapse-free survival and graft-versus-host disease

The findings of this study indicate that high natural killer cell reconstitution is associated with decreased relapse and death following reduced intensity conditioning allogeneic stem cell transplantation. Background Natural killer cells are known to have anti-tumor activity in haploidentical hematopoietic stem cell transplantation. We hypothesized that reconstituted circulating natural killer cells may be associated with improved relapse-free survival after HLA-matched hematopoietic stem cell transplantation. Design and Methods Serial peripheral blood absolute natural killer cell counts were prospectively measured by flow cytometry of lymphocytes expressing CD56 and CD16 in 167 patients. Cluster analysis was used at engraftment and 60 days post-transplant to distinguish patients with high and low absolute natural killer cell counts. At engraftment 80 patients had high counts (> 22.2/mm3) and 43 had low counts. At 60 days post-transplant 84 patients had high counts (> 18.2/mm3) and 38 had low counts. The primary study end-points were death, relapse and acute graft-versus-host disease. The median follow-up was 373 days (range, 67–1767). Results Among patients given reduced intensity conditioning, a low absolute natural killer cell count at 60 days post-transplant was independently associated with relapse [adjusted hazard ratio (AHR) = 28.4, 95% confidence interval (CI) 4.3–186.4] and death (AHR = 17.5, 95% CI 4.3–71.3). Furthermore, patients given reduced intensity conditioning who had a high absolute natural killer cell count at 60 days had a significantly better 1-year survival than those with a low count by Kaplan-Meier analysis (83% vs. 11%, p<0.001). Multivariate analysis confirmed that low 60-day absolute natural killer count in patients given reduced intensity conditioning was independently associated with an increase in relapse or death (AHR = 20.22, 95% CI 4.76–85.40). In contrast, there was no significant association between 60-day absolute natural killer cell counts and clinical outcomes in patients receiving myeloablative conditioning. There was no significant association between absolute natural killer cell count and graft-versus-host disease. Conclusions High natural killer cell reconstitution is associated with reduced relapse and death without an increased incidence of graft-versus-host-disease after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Measuring reconstituted natural killer cells expressing CD56+/CD16+ post-transplant may have novel prognostic and therapeutic implications.

Modern multidisciplinary management of brain metastases.

Ideal management of brain metastases (BMs) requires simultaneous control of the existing brain metastasis (local brain control), prevention of future BMs (distant brain control), and control of the systemic cancer (systemic control). Available tools include whole brain radiation therapy (WBRT), surgery, stereotactic radiosurgery (SRS), and systemic therapies, such as chemotherapies, biologic agents, and radiosensitizing agents. Selecting the combination of these tools is highly individualized and is impacted by numerous factors involving the tumor, patient, provider, and evolving evidence. Historically, patients received WBRT, either alone or with local treatments (surgery or SRS). However, concern about the effects of WBRT, coupled with improvements in local control and survival in select patients, with the combination treatment, has led to a reconsideration of the role of WBRT. Additionally, there have been advancements in the efficacy and tolerance of systemic therapies and clarification regarding the relative risks and symptoms of tumor recurrence versus treatment complications. Thankfully, individualizing modern multidisciplinary management for patients with BMs is being aided by numerous recently completed, ongoing, and planned prospective series.

Ethynyldeoxyuridine (EdU) suppresses in vitro population expansion and in vivo tumor progression of human glioblastoma cells

Thymidine analogs (TAs) are synthetic nucleosides that incorporate into newly synthesized DNA. Halogenated pyrimidines (HPs), such as bromodeoxyuridine (BrdU), are a class of TAs that can be detected with antibodies and are commonly used for birthdating individual cells and for assessing the proliferative index of cell populations. It is well established that HPs can act as radiosensitizers when incorporated into DNA chains, but they are generally believed not to impair normal cell function in the absence of secondary stressors. However, we and others have shown that HP incorporation leads to a sustained suppression of cell cycle progression in mammalian cells, resulting in cellular senescence in somatic cells. In addition, we have shown that HP incorporation results in delayed tumor progression in a syngeneic rat model of glioma. Here we examine ethynyldeoxyuridine (EdU), a newly developed and alkylated TA, for its anti-cancer activity, both in vitro and in vivo. We show that EdU, like HPs, leads to a severe reduction in the proliferation rate of normal and transformed cells in vitro. Unlike HPs, however, EdU incorporation also causes DNA damage resulting in the death of a substantial subset of treated cells. When administered over an extended time as a monotherapy to mice bearing subcutaneous xenografts of human glioblastoma multiforme tumors, EdU significantly reduces tumor volume and increases survival without apparent significant toxicity. These results, combined with the fact that EdU readily crosses the blood–brain barrier, support the continued investigation of EdU as a potential therapy for malignant brain tumors.

Understanding gustatory sweating

Abstract. Gustatory sweating results from a disruption of the auriculotemporal nerve pathways. Damage to the nerve may cause a misdirected re-growth that results in parasympathetic innervation of sympathetic receptors and, therefore, facial sweating and flushing with gustatory stimulation. Over the past 300 years, the history of gustatory sweating has included observations of typhus-induced parotiditis, war injuries, and occupational accidents. Despite religious and personal persecution, Lucja Frey (1889–1943) systematically investigated gustatory sweating. Following the discovery of a German World War II document regarding Lucja Frey, an international committee was organized to research the history of gustatory sweating and of Dr. Freys contributions to the understanding of the syndrome. Twenty original scientific publications from 1700 to 1950 on gustatory sweating were reviewed. Frey was the first to describe gustatory sweating as a disorder of both sympathetic and parasympathetic innervation. She proposed novel pathologic and pharmacologic mechanisms to explain the syndrome. Subsequent discoveries, including the work of André-Thomas in 1927, have provided a more complete understanding of gustatory sweating and the pathologic mechanism of aberrant neuronal regeneration.

The future of glioma treatment: stem cells, nanotechnology and personalized medicine

The development of novel therapies, imaging techniques and insights into the processes that drive growth of CNS tumors have allowed growing enthusiasm for the treatment of CNS malignancies. Despite this energized effort to investigate and treat brain cancer, clinical outcomes for most patients continue to be dismal. Recognition of diverse tumor subtypes, behaviors and outcomes has led to an interest in personalized medicine for the treatment of brain tumors. This new paradigm requires evaluation of the tumor phenotype at the time of diagnosis so that therapy can be specifically tailored to each individual patient. Investigating novel therapies involving stem cells, nanotechnology and molecular medicine will allow diversity of therapeutic options for patients with brain cancer. These exciting new therapeutic strategies for brain tumors are reviewed in this article.

Training mid-level providers on palliative care: bringing advanced directives and symptom assessment and management to community oncology practices.

Palliative care services are not available in most outpatient oncology practices. A program training 11 mid-level providers from oncology practices on advanced directive discussions and supportive symptom assessment and management performed by palliative care specialists was completed. A follow-up session 9 months later identified barriers to implementation. Of the 11 mid-level providers, 8 participated in the follow-up session, and 9 of the 11 providers implemented advanced directive’s discussions and symptom assessment and management for patients with metastatic cancer. Main barriers included uncertainties about reimbursement, patients’ lack of knowledge about palliative care, and lack of access to supportive services. This program successfully promoted advanced directive discussions and supportive/palliative care symptom assessment and management to community oncology practices, which will hopefully translate into improved quality of life for patients with metastatic cancer.

Training Mid-level Providers on Palliative Care

Palliative care services are not available in most outpatient oncology practices. A program training 11 mid-level providers from oncology practices on advanced directive discussions and supportive symptom assessment and management performed by palliative care specialists was completed. A follow-up session 9 months later identified barriers to implementation. Of the 11 mid-level providers, 8 participated in the follow-up session, and 9 of the 11 providers implemented advanced directive’s discussions and symptom assessment and management for patients with metastatic cancer. Main barriers included uncertainties about reimbursement, patients’ lack of knowledge about palliative care, and lack of access to supportive services. This program successfully promoted advanced directive discussions and supportive/palliative care symptom assessment and management to community oncology practices, which will hopefully translate into improved quality of life for patients with metastatic cancer.

A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma

Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.

Quality improvement in neurology: Neuro-oncology quality measurement set

Over 78,000 new CNS tumors are diagnosed each year in the United States, nearly one-third of which are primary malignant brain tumors,1 and the US prevalence of primary brain tumors is approximately 688,000.2 While primary CNS neoplasms represent only 1.4% of new cancer diagnoses, approximately 2.7% of cancer deaths are related to CNS neoplasms,3 and it is estimated that 16,947 deaths will result from primary CNS tumors in 2017.1 Population-based studies have shown that socioeconomic disparities are present within the neuro-oncology community,4–7 highlighting the need for a unified system of quality metrics in this growing field. Toward this end, several authors have published work on quality-based practice and on the inclusion of patient-reported outcomes in brain tumor care.8–12

Chordoid glioma of the third ventricle: report of a rapidly progressive case

Chordoid gliomas are slowly growing third ventricular tumors that can be challenging to manage clinically. Rapid progression causing death has not been previously reported for this tumor type. We present and discuss a case of chordoid glioma that arose in a 46-year-old female who presented with progressive fatigue, headache, and altered mental status, attributable to severe hydrocephalus caused by a third ventricular mass. She underwent urgent subtotal resection and ventriculo-peritoneal shunt placements. Post-operative MRI noted residual tumor in the anterior resection cavity. An MRI performed 9 weeks later showed substantial progression, with marked tumor enlargement and compression of adjacent hypothalamic structures and the optic chiasm. Despite a course of radiation therapy, the tumor continued to enlarge, and the patient died from tumor progression 7 months after initial presentation. Post-mortem exam demonstrated a mass that expanded the third ventricle and compressed adjacent hypothalamic, thalamic and suprasellar structures. Histologic and immunohistochemical studies confirmed a chordoid glioma and revealed multifocal coagulative necrosis and intravascular thrombosis, which are unusual in this tumor type. Cytogenomic microarray testing revealed numerous DNA copy number abnormalities, many of which had not previously been reported in this tumor. The pathologic and cytogenetic changes may correlate with the aggressive behavior of this chordoid glioma and can be pursued by future investigation of additional cases.