Changes in Physical Activity, Functional Capacity, and Cardiac Function during Breast Cancer Therapy.

PURPOSE: Functional capacity and cardiac function can decline during breast cancer (BC) therapy. In non-cancer populations, higher physical activity (PA) is associated with better physical function and cardiac health. This study compared baseline PA, functional capacity, and cardiac function between women with and without BC and tested if greater PA participation was related to higher functional capacity and/or better heart function after three months of BC therapy. METHODS: Data was collected in 104 women without BC (82% Caucasian, baseline only) and 110 women with stage I-III BC (82% Caucasian) before therapy and after three months of treatment. Participants self-reported PA and underwent six-minute walk distance (6MWD) testing to measure functional capacity and cardiovascular magnetic resonance to assess left ventricular ejection fraction (LVEF). Analyses were adjusted for age, race, body mass index (BMI), and medication use. RESULTS: The BC group was older (56.2 ± 10.7 vs 52.1 ± 14.7 yrs, P=0.02) with a higher average BMI than the non-cancer group (30.3 ± 6.8 vs 27.7 ± 6.2 kg/m2, P<0.01). Pre-treatment, BC participants reported lower PA scores (27.9 ± 2.8 vs 34.9 ± 2.8, P=0.04) with similar 6MWD and LVEF relative to those without cancer (485 ± 11 vs 496 ± 11 m, P=0.4 and 59.7 ± 0.7 vs 58.9 ± 0.8%, P=0.37, respectively). After three months of BC therapy, declines were observed for PA scores (27.9 ± 2.8 vs 18.3 ± 2.5, P=0.02), 6MWD (485 ± 11 vs 428 ± 10 m, P<0.001), and LVEF (59.7 ± 0.7 vs 56.1 ± 0.7%, P<0.001). Compared to BC participants who reported no PA at three months (n=24, 22%), BC women who reported any PA (n=78, 86%) had higher 6MWD (442 ± 11 vs 389 ± 17 m, P=0.006) but similar LVEF (56.5 ± 0.9 vs 55.3 ± 1.5%, p=0.5). Women who reported any PA were less likely to exhibit an LVEF below normal (<50%) or decline in LVEF of 'â•10 points compared to inactive women (BMI-adjusted, OR [95% CI]: 0.27 [0.09, 0.85]). CONCLUSIONS: These preliminary results indicate that self-reported PA, LVEF and 6MWD decline in the first three months of BC treatment, but PA participation during BC treatment may mitigate declines in functional capacity and cardiac function. Further research is needed to identify barriers and facilitators of PA participation during BC therapy. FUNDING: Data collection was funded by the Wake Forest NCORP Research Base grant 2UG1CA189824 with support of the NCI Community Oncology Research Program (NCORP). Additional funding for this study was provided by grants from the National Institutes of Health, National Cancer Institute (1R01CA199167 and 5T32CA093423). CLINICAL TRIAL ID: NCT02791581 for WF97415 UPBEAT.

Postoperative Complications of Ab Interno Gelatin Microstent.

PURPOSE: To report 4 previously undescribed postoperative complications in 4 cases of ab interno XEN45 Gel Stent (XEN) implantation following uncomplicated surgeries. PATIENTS AND METHODS: A total of 51 consecutive XEN implantations performed between July 1, 2017 and April 30, 2018 were reviewed. All cases were performed by 7 experienced glaucoma surgeons affiliated with the William Beaumont Hospital, Department of Ophthalmology. Cases with postoperative complications were identified, and a literature review was performed on PubMed.gov between April 5, 2018 and June 2, 2018 to identify previously unreported XEN complications. RESULTS: Case 1 consisted of an 86-year-old woman who suffered a suprachoroidal hemorrhage and associated rhegmatogenous retinal detachment following XEN implantation. One month after sclerotomy drainage and pars plana vitrectomy repair, an amputated XEN was found to have eroded through the conjunctiva. Case 2 consisted of a 68-year-old man with persistent elevated intraocular pressure due to recurrent Tenon's capsule fibrosis who developed complete XEN retraction into the subconjunctival space. Cases 3 and 4 consisted of a 68-year-old man and a 78-year-old woman who developed occlusion of the microstent's internal ostium by a partially detached Descemet's membrane. Case 3 maintained normal intraocular pressure on timolol, whereas case 4 resulted in bleb failure, despite Nd:YAG laser lysis of the occluded XEN internal ostium. CONCLUSIONS: Although the XEN is a promising new surgical option for the management of primary open-angle glaucoma, it can present unique postoperative challenges that are still being elucidated. Timely intervention or prevention of these complications can be improved by early surgeon recognition and effective communication with comanaging ophthalmologists.

MMP19 expression in the human optic nerve.

PURPOSE: The defining feature of glaucoma is excavation of the optic nerve head; however, the mechanism of this loss of tissue is not well understood. We recently discovered a copy number variation upstream of matrix metalloproteinase 19 (MMP19) in a large, autosomal dominant pedigree with a congenital malformation of the optic disc called cavitary optic disc anomaly (CODA). Patients with CODA have abnormal optic discs that exhibit an excavated shape similar to cupping seen in glaucoma. The goal of this study is to characterize the localization of MMP19 within the human optic nerve. METHODS: The MMP19 protein in the optic nerve was evaluated with western blot analysis and with immunohistochemistry in sagittal and en face/cross sections of optic nerves obtained from healthy human donor eyes. RESULTS: The MMP19 protein was detected in the human optic nerve, retina, and RPE/choroid with western blot analysis, with highest expression in the retina and the optic nerve. Using immunohistochemistry, MMP19 was localized within the optic nerve to the extracellular space within the septa that separate bundles of optic nerve axons into fascicles. The presence of MMP19 within the optic nerve septa was further confirmed by the colocalization of MMP19 to this structure with type IV collagen. Strong labeling of MMP19 was also detected in the arachnoid layer of the optic nerve sheath. Finally, immunohistochemistry of the optic nerve cross sections demonstrated that MMP19 shows a peripheral to central gradient, with more abundant labeling along the edges of the optic nerve and in the arachnoid layer than in the center of the nerve. CONCLUSIONS: Abundant MMP19 was detected in the optic nerve head, the primary site of pathology in patients with CODA. The localization of MMP19 to the optic nerve septa is consistent with its predicted secretion and accumulation within the extracellular spaces of this tissue. Moreover, the lateral localization of MMP19 observed in the optic nerve cross sections suggests that it might have a role in regulating adhesion to the optic nerve to the scleral canal and remodeling the extracellular matrix that provides the structural integrity of the optic disc. Dysregulation of MMP19 production might, therefore, undermine the connections between the optic nerve and the scleral canal and cause a collapse of the optic disc and the development of CODA. Similar processes might also be at work in the formation of optic disc cupping in glaucoma.

Making the most of the imaging we have: using head MRI to estimate body composition.

AIM: To investigate the use of clinical head magnetic resonance imaging (MRI) in determining body composition and to evaluate how well it correlates with established measures based on abdominal computed tomography (CT). MATERIALS AND METHODS: Ninety-nine consecutive patients were identified who had undergone both brain MRI and abdominal CT within a 2-week span. Volumes of fat and muscle in the extracranial head were measured utilising several techniques by both abdominal CT and head MRI. RESULTS: MRI-based total fat volumes in the head correlated with CT-based measurements of fat in the abdomen using both single-section (r=0.64, p<0.01) and multisection (r=0.60, p<0.01) techniques. No significant correlation was found between muscle volumes in the abdomen and head. CONCLUSION: Based on the present results, head MRI-based measures may provide a useful surrogate for CT measurements of abdominal fat, particularly in patients with neurological cancers, as head MRI (and not abdominal CT) is routinely and repeatedly obtained for the purpose of clinical care for these patients.

A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy.

PURPOSE: Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors. METHODS: Women who received adjuvant chemotherapy 1-5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks. RESULTS: Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory-the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p = 0.033) and HVLT-R Discrimination (p = 0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life. CONCLUSION: Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal. IMPLICATIONS FOR CANCER SURVIVORS: Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results.

Impact of temozolomide on gonadal function in patients with primary malignant brain tumors.

BACKGROUND: Cumulative exposure to alkylating agents may produce impaired reproductive function. Temozolomide is an alkylating agent approved for treating malignant gliomas. OBJECTIVE: A pilot study was undertaken to investigate the effects of temozolomide on semen integrity in men with newly diagnosed or recurrent malignant gliomas. METHODS: Eligible patients had no known fertility problems or impotence. Comprehensive semen analysis and serum sex hormones were obtained at baseline and following 3 and at least 6 months of temozolomide. RESULTS: Thirteen men were recruited. Mean age was 42 years (28-58). Three had recurrent and 10 newly diagnosed malignant glioma. Four were unable to ejaculate or were azoospermic at baseline. Four provided samples at baseline and after at least 6 months of temozolomide. Five were unable to complete the study. Two of four patients with paired baseline and 6-month samples received 6 months of standard monthly temozolomide. Two patients received standard radiation and concurrent temozolomide followed by adjuvant temozolomide. At 6 months, three of these four patients demonstrated low sperm motility (two low at baseline); three had abnormally low percent normal forms (one abnormal at baseline); two developed abnormally low sperm density. Sex hormone values were normal in all four patients at all time points. CONCLUSION: Changes in semen analysis parameters following 6 months of temozolomide were observed. The small sample size precludes any firm conclusions regarding the importance and duration of these findings and their relation to temozolomide exposure. With validation in a larger study, these results may have important implications for counseling prior to initiation of temozolomide therapy in these patients.

Does MR perfusion imaging impact management decisions for patients with brain tumors? A prospective study.

BACKGROUND AND PURPOSE: MR perfusion imaging can be used to help predict glial tumor grade and disease progression. Our purpose was to evaluate whether perfusion imaging has a diagnostic or therapeutic impact on clinical management planning in patients with glioma. MATERIALS AND METHODS: Standard MR imaging protocols were interpreted by a group of 3 NRs in consensus, with each case being interpreted twice: first, including routine sequences; and second, with the addition of perfusion imaging. A multidisciplinary team of treating physicians assessed tumor status and created hypothetical management plans, on the basis of clinical presentation and routine MR imaging and then routine MR imaging plus perfusion MR imaging. Physicians' confidence in the tumor status assessment and management plan was measured by using Likert-type items. RESULTS: Fifty-nine consecutive subjects with glial tumors were evaluated; 50 had known pathologic diagnoses. NRs and the treatment team agreed on tumor status in 45/50 cases (κ = 0.81). With the addition of perfusion, confidence in status assessment increased in 20 (40%) for NRs and in 28 (56%) for the treatment team. Of the 59 patient-care episodes, the addition of perfusion was associated with a change in management plan in 5 (8.5%) and an increase in the treatment team's confidence in their management plan in 34 (57.6%). NRs and the treatment team found perfusion useful in most episodes of care and wanted perfusion included in future MR images for >80% of these subjects. CONCLUSIONS: Perfusion imaging appears to have a significant impact on clinical decision-making and subspecialist physicians' confidence in management plans for patients with brain tumor.

Cholesterol and LDL relate to neuritic plaques and to APOE4 presence but not to neurofibrillary tangles.

UNLABELLED: Elevated serum total cholesterol (TC) has been considered a risk factor for Alzheimer's disease (AD), but conflicting results have confused understanding of the relationships of serum lipids to the presence of AD in the elderly. METHODS: To clarify these issues, we evaluated correlations of admission TC, low-density (LDL) and high-density (HDL)cholesterol directly with the densities of Alzheimer hallmarks--neuritic plaques (NP) and neurofibrillary tangles (NFT)--in nursing home residents (n=281). RESULTS: Significant positive associations of TC and LDL with NP densities were found in both the neocortex (TC: r=0.151, p=0.013 and LDL: r=0.190, p=0.005) and the hippocampal/entorhinal (allocortical)region (TC: r=0.182, p=0.002 and LDL: r=0.203, p=0.003). Associations of HDL with NP were less strong but also significant.In contrast, after adjustment for confounders, no correlations of NFT with any lipid were significant.When subjects with any non-AD neuropathology (largely vascular) were excluded, the TC-plaque and LDL-plaque associations for the remaining "Pure AD" subgroup were consistently stronger than for the full sample. The TC- and LDL-plaque correlations were also stronger for the subgroup of 87 subjects with an APOE ε4 allele. CONCLUSIONS: The findings indicate that serum TC and LDL levels clearly relate to densities of NP, but not to densities of NFT. The stronger associations found in the subgroup that excluded all subjects with non-AD neuropathology suggest that cerebrovascular involvement does not explain these lipid-plaque relationships. Since the associations of TC/LDL with NP were particularly stronger in ε4 carriers, varying prevalence of this allele may explain some discrepancies among prior studies.

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons.

OBJECTIVE: To test the hypothesis that use of antihypertensive medication is associated with lower Alzheimer disease (AD) neuropathology. METHODS: This was a postmortem study of 291 brains limited to those with normal neuropathology or with uncomplicated AD neuropathology (i.e., without other dementia-associated neuropathology) in persons with or without hypertension (HTN) who were and were not treated with antihypertensive medications. Neuritic plaque (NP) and neurofibrillary tangle (NFT) densities, quantified in selected brain regions according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathologic criteria, with additional cortical NP counts, yielded 24 neuropathologic regional measures or summaries. Medicated hypertension (HTN-med; n = 77), nonmedicated HTN (HTN-nomed; n = 42), and non-HTN (no-HTN; n = 172) groups were compared by analyses of variance. RESULTS: The HTN-med group had significantly less neuropathology than the no-HTN group. The no-HTN group averaged over 50% higher mean NP and NFT ratings, and double the mean NP count, of the HTN-med group. The HTN-nomed group had significantly more neuropathology than the HTN-med group, but not significantly less than the no-HTN group. CONCLUSIONS: There was substantially less Alzheimer disease (AD) neuropathology in the medicated hypertension group than the nonhypertensive group, which may reflect a salutary effect of antihypertensive medication against AD-associated neuropathology.

Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology.

OBJECTIVE: To examine the association between treatment for diabetes and Alzheimer disease (AD) neuropathology. METHODS: This postmortem study matched 124 subjects with diabetes to 124 without diabetes from the Mount Sinai School of Medicine Brain Bank, on age (mean = 81.2 + 9.3), sex (57.3% F), and severity of dementia (Clinical Dementia Rating [CDR] 2.4 + 1.7). Densities of neuritic plaques (NPs) and of neurofibrillary tangles (NFTs) were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Diabetic subjects were classified according to their recorded lifetime antidiabetic medications: none (n = 29), insulin only (n = 49), diabetes medications other than insulin only (n = 28), or concomitant use of both insulin and any oral antidiabetic medications (n = 18). For each dependent variable, analysis of covariance controlling for age at death, sex, and CDR distinguished among the nondiabetic patients and four diabetic subgroups. RESULTS: There were differences among the five groups for NP ratings in the entorhinal cortex (p = 0.003), amygdala (p = 0.009), and overall NP (p = 0.014) as well as counts of NPs in all regions examined (p values ranging from 0.009 to 0.04). NP ratings in the hippocampus (p = 0.057) and the combined neocortical measure (p = 0.052) approached significance. In each analysis, the concomitant medication group had significantly fewer NPs (approximately 20%) than any of the other groups, which were relatively similar. No significant NFT differences were found. CONCLUSION: The results of this study suggest that the combination of insulin with other diabetes medication is associated with substantially lower neuritic plaque density consistent with the effects of both on the neurobiology of insulin.

Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers.

OBJECTIVE: To examine the associations between postmortem Alzheimer disease (AD) neuropathology and autopsy-verified cardiovascular disease. METHODS: The authors examined 99 subjects (mean age at death = 87.6; SD = 8.7) from the Mount Sinai School of Medicine Department of Psychiatry Brain Bank who were devoid of cerebrovascular disease-associated lesions or of non-AD-related neuropathology. Density of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) as well as coronary artery and aortic atherosclerosis, left ventricular wall thickness, and heart weight were measured. Partial correlations were used to assess the associations of the four cardiovascular variables with NPs and NFTs in the hippocampus, entorhinal cortex, and multiple regions of the cerebral cortex after controlling for age at death, sex, dementia severity, body mass index, and ApoE genotype. These analyses were also repeated separately for ApoE4 carriers and noncarriers. RESULTS: The extent of coronary artery disease and to a lesser extent atherosclerosis were significantly associated with the density of cardinal neuropathologic lesions of AD in this autopsy sample (significant correlations between 0.22 and 0.29). These associations were more pronounced for the ApoE4 allele carriers (n = 42; significant correlations between 0.34 and 0.47). CONCLUSIONS: The degree of coronary artery disease is independently associated with the cardinal neuropathological lesions of Alzheimer disease. These associations are primarily attributable to individuals with the ApoE4 allele.

Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease.

BACKGROUND: Little is known about Alzheimer disease at advanced ages, although its incidence continues to increase at least through the ninth decade of life. OBJECTIVE: To examine the effects of age on the relationship between clinical dementia severity and neuropathologic hallmarks in a large sample spanning the full age range. METHODS: The authors assessed 81 subjects during life for dementia severity, and examined their brains. They analyzed plaque and tangle burden, as well as the activities of the cholinergic marker enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), in relation to age at death and the clinical severity of dementia. RESULTS: Dementia severity was strongly related to plaque and tangle burden in relatively young patients (aged < 75 years), but this correlation diminished with age and disappeared in the ninth decade of life. Among the oldest patients studied, there was no difference in plaque and tangle load between the mild and severe dementia cases. This interaction (p < 0.0001 for plaque density) was not observed for the cholinergic markers ChAT and AChE. CONCLUSION: The nature or expression of Alzheimer disease may be different in severely demented older patients, who have equal cholinergic deficits but significantly lower plaque and tangle burden. If confirmed in a prospective study, these findings have diagnostic and therapeutic implications.

Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study.

PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue. PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed. RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients. CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.

Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of twice-weekly gemcitabine and concurrent thoracic radiation in patients with Stage IIIa/IIIb non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Seventeen patients with histologically confirmed Stage IIIa and IIIb NSCLC were studied. Gemcitabine was administered via a 30-min i.v. infusion twice weekly for 6 weeks concurrent with 60 Gy of thoracic radiation. Gemcitabine, starting at a twice-weekly dose of 10 mg/m2 (20 mg/m2/week), was escalated in 10-15 mg/m2 increments in successive cohorts of 3 to 6 patients until dose-limiting toxicity was observed. RESULTS: Of the 17 patients entered, 16 were evaluable for toxicity. The dose-limiting toxicity at 50 mg/m2 given twice weekly (100 mg/m2/week) was Grade 3 pneumonitis observed in 1 patient, Grade 3 pulmonary fibrosis in a second patient, and Grade 4 esophagitis observed in two additional patients. Twice-weekly gemcitabine at a dose of 35 mg/m2 was determined to be the MTD. The overall response rate for the 16 evaluable patients was 88%. The median survival for the entire group is 16.0 months. CONCLUSIONS: The MTD of twice-weekly gemcitabine is 35 mg/m2 (70 mg/m2/week) given with thoracic radiation. A Phase II study within the Cancer and Leukemia Group B to ascertain the potential efficacy of this treatment regimen is in development.

Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas.

PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas. PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas. RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who "progressed" after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations. CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome.