Sandra K. Johnston

Stress exposure, psychological distress, and physiological stress activation in midlife women with insomnia

Objective The objective of this study was to describe perceived and polysomnograhic (PSG) sleep patterns and determine whether stress exposure, psychological distress, and physiological stress activation differed among midlife women with psychophysiologic-type (PP-type) or subjective only-type (SO-type) insomnia or no insomnia. Methods Women had their sleep monitored, collected urine samples, and completed questionnaires in a week-long field study, and 53 women met criteria for insomnia types or no insomnia based on reported sleep quality and PSG sleep efficiency. Results As expected, women with PP-type insomnia were found to have the lowest sleep efficiency, took longer to fall asleep, had more wakefulness after sleep onset, and had more fragmented sleep. Perceptions of stress exposure, either for major or minor events, did not differ among groups. Despite there being no differences in perceived stress exposure, women with both types of insomnia scored higher on psychological distress (SCL-90R), especially on the somatization subscale, than women with no insomnia. Of the physiological stress activation indicators tested, a morning-to-evening difference in urinary cortisol statistically differed across the groups (p < .005). Women in the PP-type insomnia group had the highest levels of urinary cortisol in an early morning urine sample. Conclusions These data provide support for the hypothesis that, in midlife women, cognitive or emotional arousal with chronic stress neuroendocrine activation underlies chronic insomnia, particularly the PP-type.

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

BACKGROUNDnTemozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT(hi)). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.nnnMETHODSnWe enrolled 7 newly diagnosed glioblastoma patients with MGMT(hi) tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.nnnRESULTSnGene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5-57+) months and OS of 20 (range 13-57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG.nnnCONCLUSIONnThese data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.nnnTRIAL REGISTRATIONnClinicaltrials.gov NCT00669669.nnnFUNDINGnR01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

Neoplastic Meningitis–Related Prognostic Significance of the Karnofsky Performance Status

BACKGROUNDnThe prognostic significance of Karnofsky performance status in neoplastic meningitis (NM) has not been demonstrated in patient groups similarly matched for known prognostic variables.nnnOBJECTIVEnTo determine the effect of performance status on survival in NM.nnnDESIGNnRetrospective comparison.nnnSETTINGnA university tertiary medical center.nnnPATIENTSnTwo well-matched cohorts with cytologically positive NM with (n = 30; group A) and without (n = 30; group B) independence in activities of daily living as defined by a Karnofsky performance status score of 70 or greater or less than 70, respectively.nnnMAIN OUTCOME MEASURESnGroups were matched on age, primary tumor, site of NM disease (cranial nerves or spinal cord), treatment (radiotherapy and chemotherapy; systemic and intraventricular), and absence of cerebrospinal fluid compartmentalization, NM-related encephalopathy, and neuroradiographic bulky central nervous system disease. Primary tumor histologic diagnoses included breast cancer (20 patients), non-Hodgkin lymphoma (10 patients), lung cancer (10 patients), melanoma (8 patients), and others (12 patients). At presentation, NM revealed cranial neuropathy (30 patients) or spinal cord dysfunction (39 patients). Radiotherapy was administered to 49 patients (whole brain only in 12 patients; restricted spine only in 35; whole brain and restricted spine in 2). All the patients received intraventricular chemotherapy, and 49 received concurrent tumor-specific systemic chemotherapy.nnnRESULTSnMedian survival was 6 weeks (range, 3-10 weeks) in group B compared with 15.5 weeks (range, 8-58 weeks) in group A (P < .001). No treatment-related deaths were observed. All the patients demonstrated progressive disease and died of either NM or systemic cancer.nnnCONCLUSIONSnA low Karnofsky performance status score predicts poor survival in patients with NM. Patients with a low Karnofsky performance status score may be best served by offering supportive care.

Invasion and proliferation kinetics in enhancing gliomas predict IDH1 mutation status

BACKGROUNDnGlioblastomas with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene have a better prognosis than gliomas with wild-type IDH1.nnnMETHODSnHere we compare the IDH1 mutational status in 172 contrast-enhancing glioma patients with the invasion profile generated by a patient-specific mathematical model we developed based on MR imaging.nnnRESULTSnWe show that IDH1-mutated contrast-enhancing gliomas were relatively more invasive than wild-type IDH1 for all 172 contrast-enhancing gliomas as well as the subset of 158 histologically confirmed glioblastomas. The appearance of this relatively increased, model-predicted invasive profile appears to be determined more by a lower model-predicted net proliferation rate rather than an increased model-predicted dispersal rate of the glioma cells. Receiver operator curve analysis of the model-predicted MRI-based invasion profile revealed an area under the curve of 0.91, indicative of a predictive relationship. The robustness of this relationship was tested by cross-validation analysis of the invasion profile as a predictive metric for IDH1 status.nnnCONCLUSIONSnThe strong correlation between IDH1 mutation status and the MRI-based invasion profile suggests that use of our tumor growth model may lead to noninvasive clinical detection of IDH1 mutation status and thus lead to better treatment planning, particularly prior to surgical resection, for contrast-enhancing gliomas.

Neoplastic meningitis: survival as a function of cerebrospinal fluid cytology.

BACKGROUNDn: This retrospective comparison evaluated survival in 2 well-matched cohorts of patients with neoplastic meningitis (NM) presenting with or without positive cerebrospinal fluid (CSF) cytology.nnnMETHODSn: Two patient cohorts were studied: 42 individuals with (Group A) and 42 without (Group B) positive CSF cytology. Groups were matched with respect to age; primary tumor; Karnofsky performance status; site of NM disease (cranial nerves or spinal cord); treatment (radiotherapy and chemotherapy; systemic and intraventricular); and absence of CSF compartmentalization, NM-related encephalopathy, and neuroradiographic bulky central nervous system disease. Primary tumor histology included breast (28 patients), non-Hodgkin lymphoma (14 patients), nonsmall cell lung cancer (14 patients), melanoma (12 patients), and others (16 patients). NM at presentation revealed cranial neuropathy (40 patients) or spinal cord dysfunction (58 patients). Radiotherapy was administered to 69 patients (whole brain only in 14 patients [7 each in Groups A and B], restricted spine only in 51 patients [25 in Group A and 26 in Group B], and both whole brain and restricted spine in 4 patients [2 each in Groups A and B]). All patients received intraventricular chemotherapy and 60 (30 each in Groups A and B) received concurrent tumor-specific systemic chemotherapy.nnnRESULTSn: The median, 3-month, 6-month, and 12-month survival rates for patients with NM were not significantly different between those patients with positive CSF cytology (18 weeks, 83%, 33%, and 9.5%, respectively) and those without positive CSF cytology (20 weeks, 90.5%, 40.5%, and 9.5%, respectively). All patients demonstrated progressive disease and died of either NM or systemic cancer.nnnCONCLUSIONSn: In patients with NM who were matched for known prognostic variables, the presence or absence of CSF cytology did not appear to influence survival. Cancer 2009. (c) 2009 American Cancer Society.This retrospective comparison evaluated survival in 2 well‐matched cohorts of patients with neoplastic meningitis (NM) presenting with or without positive cerebrospinal fluid (CSF) cytology.

Recurrent spinal cord glioblastoma: salvage therapy with bevacizumab.

Primary spinal cord tumors constitute 2–4% of all primary central nervous system malignancies in adults of which less than 5% are glioblastoma. A retrospective evaluation to determine toxicity and response to bevacizumab in patients with recurrent spinal cord glioblastoma. Six patients (4 males; 2 females: median age 34 years) with recurrent spinal cord glioblastoma were treated with bevacizumab (10xa0mg/kg given once every 2 weeks wherein 2 treatments constituted a cycle of therapy). All patients had failed surgery and temozolomide-based chemoradiotherapy and post-radiotherapy temozolomide. Blood counts, chemistry panel, urine protein to creatinine ratio and neurologic examination were obtained bi-weekly. Contrast-enhanced spine MRI was performed after one cycle of therapy and thereafter following every two cycles of bevacizumab. Treatment-related complications included fatigue in six patients, constipation in 4, hypertension in 2, venous thrombosis in 2, and infection without neutropenia in 2. There were three grade 3 toxicities (1 each fatigue, leukopenia and venous thrombosis). There were no treatment-related deaths. After one cycle of bevacizumab, one patient (17%) demonstrated progressive disease, 2 (34%) partial responses and three (51%) stable disease. Overall median response or stable disease duration (disease free progression) was 7xa0months (range 3–11xa0months). Overall median survival was 9xa0months (range of 5–13xa0months). Bevacizumab is well tolerated, has tolerable toxicity and apparent activity in this small cohort of adults with recurrent spinal cord glioblastoma.

Patient-Specific Metrics of Invasiveness Reveal Significant Prognostic Benefit of Resection in a Predictable Subset of Gliomas

Object Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would improve survival in patients with relatively less invasive gliomas. Methods In 243 patients presenting with contrast-enhancing gliomas, estimates of the relative invasiveness of each patients tumor, in terms of the ratio of net proliferation rate of the glioma cells to their net dispersal rate, were derived by applying a patient-specific mathematical model to routine pretreatment MR imaging. The effect of varying degrees of extent of resection on overall survival was assessed for cohorts of patients grouped by tumor invasiveness. Results We demonstrate that patients with more diffuse tumors showed no survival benefit (Pu200a=u200a0.532) from gross total resection over subtotal/biopsy, while those with nodular (less diffuse) tumors showed a significant benefit (Pu200a=u200a0.00142) with a striking median survival benefit of over eight months compared to sub-totally resected tumors in the same cohort (an 80% improvement in survival time for GTR only seen for nodular tumors). Conclusions These results suggest that our patient-specific, model-based estimates of tumor invasiveness have clinical utility in surgical decision making. Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection.

Natural Killer Cell Cytotoxicity: A Methods Analysis of Versus Flow Cytometry Chromium Release:

The purpose of this study is to describe design considerations for the use of flow cytometry (FC) com-pared to 51 chromium ( 51 Cr)-release assays utilizing cryopreserved peripheral blood mononuclear cells (PBMCs) to detect natural killer (NK) cell cytotoxicity. Subjects were 10 healthy women aged 18 to 39 years. Intra-assay variability between methods differed only at the lowest effector-target ratios evaluated. Interassay variability was wide but did not differ between methods. The relationship of lytic unit-10 between methods was strongly positive. Cytotoxicity detected by 51 Cr release was higher than that detected by FC for all 10 subjects. Cost was comparable. How-ever, had more assays been performed, technician time would have been greater with flow cytometry. More whole blood was needed to perform the flow cytometry cytotoxicity assay than 51 Cr-release cytotoxicity assay. The authors found no compelling reason to adopt NK cell cytotoxicity by flow cytometry over 51 Cr release.

Designing and testing a web-based interface for self-monitoring of exercise and symptoms for older adults with chronic obstructive pulmonary disease.

The use of information and communication technologies to support collaborative management of chronic obstructive pulmonary disease and associated symptoms is particularly appealing since most people with chronic obstructive pulmonary disease continue to experience dyspnea despite optimal medical therapy and therefore must engage in the long-term tasks of self-management. Exercise is an effective therapy to reduce dyspnea in patients with chronic obstructive pulmonary disease. The purpose of this article was to describe our process of developing a set of integrated tools to support collaborative symptom and exercise monitoring for patients with chronic obstructive pulmonary disease. This process could be followed by other researchers and clinicians interested in developing collaborative management tools for other chronic conditions. User-centered design principles guided the 4-phase development process of a set of integrated tools for self-symptom management. The usability challenges uncovered during the field testing were mostly minor and were easily corrected. Patients had a strong preference for a calendar-like display of completed exercise coupled with simultaneous goal viewing. Field usability testing showed that the integrated set of tools was relatively easy to learn, efficient to use, and with minimal errors and has a high level of user satisfaction. An iterative, multimodal process is essential to successful development of acceptable Web-based tools for self-management in chronic obstructive pulmonary disease.

Distinct Phenotypic Clusters of Glioblastoma Growth and Response Kinetics Predict Survival

PURPOSEnDespite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype-growth before treatment and during each treatment to recurrence -has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK.nnnPATIENTS AND METHODSnFrom our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment.nnnRESULTSnThere was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%).nnnCONCLUSIONnDichotomizing the heterogeneity of GBMs into two populations-one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival-suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.