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.

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.

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.

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.

Chemotherapy of low-grade gliomas.

Histologic subtypes of low-grade gliomas include pilocytic astrocytomas (World Health Organization [WHO] grade I), diffuse infiltrating astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas (WHO grade II). Although extended survival is typical with these tumors, most patients eventually succumb to recurrent or progressive disease despite receiving either adjuvant radiation therapy or radiation at the time of recurrence. Not surprisingly, chemotherapy for low-grade gliomas has primarily been evaluated in the salvage setting of postradiotherapy progression in both adults and children. Unfortunately, the published body of literature describing chemotherapy for these tumors is small and subject to a number of confounding methodologic limitations. Nonetheless, some guidelines for the use of chemotherapy in these patients can be inferred from the published experience. The data reviewed clearly identifies a potential benefit for PCV chemotherapy (procarbazine, CCNU, and vincristine) in at least a subset of patients with low-grade oligodendroglial tumors. Nitrosoureas and platinum agents appear to have modest efficacy in recurrent oligodendroglial tumors and in some patients with newly diagnosed or progressive low-grade astrocytomas; however, surgery and radiation remain the primary treatment modalities for this group of malignancies. Until new data becomes available, chemotherapy still should be used only as a salvage option in previously irradiated patients with recurrent or progressive low-grade gliomas.

Utility of decompressive surgery in the prophylaxis and treatment of cisplatin neuropathy in adult rats.

Cisplatin produces a dose-dependent and dose-limiting peripheral neuropathy in patients. This study tested the hypothesis that this clinical neuropathy results from the chronic compression of peripheral nerves rendered susceptible to injury because of cisplatin-induced microtubular dysfunction. A quantitative model of cisplatin neurotoxicity was developed by administering cisplatin to rats and measuring the neuropathy by hindlimb walking track assay. The study aims were: (1) to characterize neuropathy induced by cisplatin in the adult rat; (2) to evaluate the role of decompressive surgery in the prevention of cisplatin neuropathy; and (3) to determine whether decompressive surgery was an effective treatment for established neuropathy. The assay demonstrated an increased print length in animals after 8 weeks of cisplatin (p < 0.01). This neuropathy progressed for 6 weeks after cisplatin was stopped, and reversed slowly over 3 months. These abnormalities were prevented by early tarsal tunnel decompression. Decompressive surgery was also beneficial, if performed early in the course of the neuropathy; abnormalities reversed in 5 weeks and remained normal for the remainder of the study. Control animals had progressive abnormalities which slowly resolved over a period of 18 weeks after discontinuing cisplatin. However, decompressive surgery performed after the neuropathy was established did not alter the neuropathic walking-track pattern. These studies provide insight into the etiology and possible therapeutic approaches to cisplatin neuropathy. Although further studies are required, they suggest that, in selected patients, decompressive surgery may have a role in the prevention or early treatment of cisplatin-induced neuropathy. Patients with underlying clinical or subclinical compressive neuropathies could be at high risk for the development of cisplatin neuropathy, and quantitative monitoring of neuropathies may be useful.

Chemotherapy of cerebral metastases from solid tumors.

With proper staging, patients with parenchymal brain metastases from solid tumors are usually found to have widespread extracranial disease. Systemic chemotherapy offers the potential advantage of simultaneous therapy of both intracranial and extracranial tumor. Limited data is available on the efficacy of drug therapy alone in this patient population for selected patients with chemosensitive malignancies and brain metastases, systemic chemotherapy administration represents a useful treatment modality when given at presentation or following recurrence after surgery or radiation therapy.

In vitro and in vivo studies of subcutaneous hydromorphone implants designed for the treatment of cancer pain.

Unrelieved cancer pain remains a significant problem worldwide. Patients receive inadequate analgesia for a variety of complex and multifactorial reasons. Limited availability of opioids secondary to concerns about potential diversion of these medications for illicit use and poor compliance with oral regimens are significant factors in many countries. This study was designed to develop and test an implantable opioid delivery device capable of releasing a potent opioid subcutaneously at a continuous rate for 4 weeks. A low temperature solvent casting technique was used to formulate ethylene vinyl acetate (EVA) copolymer disks containing 50% hydromorphone by weight. The release characteristics of disks of different height and diameter, coated and uncoated, and with and without a central uncoated channel were studied. The effect of temperature and pH were also evaluated. In vitro assessments were conducted in phosphate buffer using UV spectrophotometry. In vivo studies employed New Zealand White Rabbits and a radioimmunoassay. Plasma levels following hydromorphone delivery by polymer, osmotic pump, and intravenous administration were compared. In vitro, uncoated EVA polymer disks measuring 1.05 cm in diameter and 0.27 cm in height released an initial large burst of hydromorphone. Coating the disks with 100-200 microM of poly(methyl-methacrylate) prevented drug egress from the polymer. A central uncoated channel measuring 1.25 mm in diameter in an otherwise coated polymer virtually eliminated the initial burst of drug release and provided near zero-order hydromorphone release at an average rate of 164 micrograms per hour for 4 weeks. Doubling the height of the polymer approximately doubled the release rate while doubling the diameter of the polymer extended the duration of drug release to over 8 weeks. In rabbits, stable plasma hydromorphone concentrations (23-37 ng/ml) were sustained for 4 weeks following implantation of 2 polymers with an uncoated central channel. No initial burst of hydromorphone release was noted. Increasing the number of polymers produced sustained and predictable increases in plasma hydromorphone concentrations. Plasma levels were similar with subcutaneous hydromorphone delivered by polymer and osmotic pump and much less variable than with intravenous bolus hydromorphone. A uniquely configured implantable drug delivery device has been developed using materials which are approved for human use. It safely and reproducibly releases hydromorphone for weeks in vitro and in vivo without an initial burst of drug release. Varying the thickness, diameter, and number of implants provides flexibility in the release rate and duration of release. This implantable opioid delivery device could provide a sustained subcutaneous infusion of hydromorphone to patient with cancer pain in developed and developing nations without pumps, catheters, or extensive outpatient support services. In addition, it should improve compliance and reduce concern regarding illicit diversion of opioids.

Tissue and tumor distribution of C-penclomedine in rats.

Penclomedine, a lipophilic alpha-picoline derivative, is undergoing clinical development presently because of its pronounced antitumor activity against intracerebral (i.c.) tumor xenografts. Penclomedine may be metabolized in vivo to a more potent compound. Although it may be useful in the treatment of brain tumors, the drug has caused significant neurotoxicity in early clinical trials. The possibility that antitumor activity and neurotoxicity may be mediated by different mechanisms prompted a study assessing the differential distribution of penclomedine and penclomedine metabolites to brain and i.c.-implanted tumors in rats. In the present study, quantitative autoradiographic analysis demonstrated a homogenous distribution of 14C-penclomedine in all organs within 1 h of administration. Levels of 14C-penclomedine in both i.c. and s.c. tumors were three times higher than in normal brain tissue. High-performance liquid chromatography combined with gas chromatography and mass spectrophotometry demonstrated that two metabolites, O-demethyl penclomedine and penclomic acid, were responsible for most of the plasma radioactivity. Penclomic acid was also the most common urinary metabolite of penclomedine. In liver samples, although a large number of metabolite peaks were detected, no parent compound could be identified. However, in tumors and all other tissues, penclomedine was the main compound detected. The finding of penclomedine in normal brain tissue indicates not only that this drug may be useful in tumors with normal blood-brain barrier function, but also that it may be directly neurotoxic.

The distribution of systemically administered [3H]-paclitaxel in rats: a quantitative autoradiographic study.

Paclitaxel is an important agent in the treatment of many common malignancies. Although the symptomatic peripheral neuropathy caused by this drug is its principal nonhematologic toxicity, little is known about the distribution of paclitaxel within the peripheral or central nervous system following systemic administration. In order to study paclitaxel's distribution in neural and extraneural tissues, adult Sprague-Dawley rats were sacrificed 2 h after a tail vein injection of [3H]-paclitaxel (0.03 mg/kg, 250 microC/rat). Samples of lung, heart, liver, spleen, kidney, skeletal muscle, brain, spinal cord, dorsal root ganglion, and peripheral nerve were then removed and snap-frozen. These tissues were sectioned at 10 microns in a cryostat and exposed to autoradiography film for 2 weeks. The distribution and concentrations of [3H]-paclitaxel in plasma, urine and cerebrospinal fluid were also determined using liquid scintillation spectrometry. [3H]-paclitaxel concentrations (and organ/plasma concentration ratios) in plasma, urine and cerebrospinal fluid were 2.6 nM (1), 38 nM (15) and 0.7 nM (0.3), respectively. A relatively homogeneous distribution of [3H]-paclitaxel was observed in liver [412 nM (151)], spleen [351 nM (133)], heart [319 nM (117)], lung [268 nM (93)] and muscle [69 nM (26)]. Higher concentrations of [3H]-paclitaxel were noted in the portal triads [869 nM (361)], glomeruli [797 nM (304)], and renal medulla [961 nM (363)], which may reflect biliary excretion and glomerular filtration. A high concentration of [3H]-paclitaxel was also noted in the choroid plexus [432 nM (167)], but [3H]-paclitaxel was not detected in the brain parenchyma, spinal cord, dorsal root ganglion, peripheral nerve, or the testicles. The pathogenesis of paclitaxel-induced neurotoxicity remains obscure given its limited distribution in the nervous system. In addition, these results suggest that systemically administered paclitaxel is not likely to be effective for the treatment of malignancies in the testes or the nervous system.

The chemotherapy of adult primary brain tumors.

Adult patients with primary malignant brain tumors are a heterogeneous group. Most patients will have high-grade astrocytomas and can be expected to obtain minimal benefit from current standard chemotherapy regimens. Intra-arterial chemotherapy, high-dose chemotherapy with autologous bone marrow rescue, and new chemotherapeutic agents designed to penetrate the blood-brain barrier have not resulted in significant advances to date. However, there are exciting new directions in the chemotherapy of high-grade astrocytomas which are entering clinical trials. Two potentially promising approaches include interstitial chemotherapy using surgically implanted polymers and the continuous infusion of combinations of active chemotherapeutic agents. Other therapeutic modalities such as radioactive seed implants, stereotactic radiosurgery, and gene therapy are also being evaluated. Hopefully, this intense activity by subspecialists with a wide range of interests and expertise will produce novel and effective treatments for the large number of patients with malignant astrocytomas. In contrast, patients with many of the less common neoplasms of the central nervous system may benefit from the addition of chemotherapy to their treatment. Primary germ cell tumors or lymphomas of the central nervous system are very sensitive to chemotherapy. The germ cell tumors respond to the cisplatin-containing regimens developed for testicular malignancies. The optimal chemotherapy for CNS lymphoma is not clear but exciting results have been reported with a combination of radiation, systemic and intrathecal methotrexate, and systemic cytosine arabinoside. Although limited, the available literature suggests that patients with anaplastic oligodendrogliomas may also benefit from chemotherapy at diagnosis or at relapse. Studies in children suggest a benefit for adjuvant chemotherapy and radiation therapy in poor risk patients with medulloblastomas although these findings have not been confirmed in adults. Finally, anecdotal reports suggest that chemotherapy may be useful in the very rare patient who presents with a pineal tumor or an ependymoma.

Hydrophobicity of amino acid subgroups in proteins.

Protein folding studies often utilize areas and volumes to assess the hydrophobic contribution to conformational free energy (Richards, F.M. Annu. Rev. Biophys. Bioeng. 6:151-176, 1977). We have calculated the mean area buried upon folding for every chemical group in each residue within a set of X-ray elucidated proteins. These measurements, together with a standard state cavity size for each group, are documented in a table. It is observed that, on average, each type of group buries a constant fraction of its standard state area. The mean area buried by most, though not all, groups can be closely approximated by summing contributions from three characteristic parameters corresponding to three atom types: (1) carbon or sulfur, which turn out to be 86% buried, on average; (2) neutral oxygen or nitrogen, which are 40% buried, on average; and (3) charged oxygen or nitrogen, which are 32% buried, on average.

Hydrophobicity of amino acid residues in globular proteins.

During biosynthesis, a globular protein folds into a tight particle with an interior core that is shielded from the surrounding solvent. The hydrophobic effect is thought to play a key role in mediating this process: nonpolar residues expelled from water engender a molecular interior where they can be buried. Paradoxically, results of earlier quantitative analyses have suggested that the tendency for nonpolar residues to be buried within proteins is weak. However, such analyses merely classify residues as either "exposed" or "buried." In the experiment reported in this article proteins of known structure were used to measure the average area that each residue buries upon folding. This characteristic quantity, the average area buried, is correlated with residue hydrophobicity.