Factors influencing survival among patients with HER2-positive metastatic breast cancer treated with trastuzumab.

PURPOSE: We have limited capability to predict survival among patients treated for metastatic HER2-positive breast cancer. Further research is warranted to identify significant prognostic and predictive factors. METHODS: We identified all HER2-positive metastatic breast cancer patients receiving trastuzumab at the Sunnybrook Odette Cancer Centre (SOCC) from 1999 to 2013 through the Cancer Care Ontario (CCO) Registry (n = 256) and selected patients with available pathology reports (n = 154). A retrospective review was completed documenting clinical, pathologic, and laboratory characteristics at the time of first trastuzumab therapy and survival outcomes. Cox proportional hazards regression models were used to identify prognostic factors for overall survival (OS) (primary endpoint) and failure-free survival (FFS), adjusted for the known prognostic factors of the presence of CNS metastases and the presence of ≥ 2 distant metastatic sites. RESULTS: A multivariable model identified older age [hazard ratio (HR) 1.18/decade, 95% confidence interval (CI) 1.02-1.37)], increased platelet-to-lymphocyte ratio (PLR) (HR 1.75/log-unit, 95% CI 1.25-2.46), increased serum alkaline phosphatase (ALP) (HR 1.87/log-unit, 95% CI 1.41-2.49), and ER positivity (HR 0.63, 95% CI 0.42-0.96) as significant prognostic factors for OS after adjusting for the presence of CNS metastasis (HR 3.19, 95% CI 1.59-6.38) and the presence of ≥ 2 distant metastatic sites (HR 2.10, 95% CI 1.19-3.70). PLR (HR 1.54/log-unit, 95% CI 1.12-2.12) was the only prognostic factor associated with FFS after adjusting for CNS and ≥ 2 distant metastatic sites. CONCLUSION: Older age, increased PLR, and ALP were identified as poor prognostic factors and ER positivity as a favorable prognostic factor for OS after adjusting for the presence of CNS metastasis and the presence of number of ≥ 2 distant metastatic sites. Increased PLR was a poor prognostic factor for both OS and FFS, and warrants further investigation into its prognostic ability amongst patients with HER2-positive metastatic breast cancer.

Case report of very late gastric cancer recurrence.

Very late recurrence of gastric cancer is rare. Here, we report a dramatic recurrence of gastric cancer, with isolated skeletal metastasis and bone marrow carcinomatosis, 22 years after the patient's initial presentation. Gastric cancer recurrence involving bone or bone marrow is also uncommon and associated with poor prognosis. Pathology from a bone marrow biopsy showed signet ring cell morphology. The patient in this case demonstrated a surprising response-lasting 11 months-to palliative chemotherapy with cisplatin and capecitabine. This case report and literature review describes the characteristics of late gastric cancer recurrence and an approach to the diagnosis and management of patients with bone metastasis or bone marrow carcinomatosis.

Topotecan and cyclophosphamide in adults with relapsed sarcoma.

UNLABELLED: Background. The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing's sarcoma (EWS). We sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Patients and Methods. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75 mg/m(2)/day (days 1-5) and C = cyclophosphamide at 250 mg/m(2)/day (days 1-5) every 21 days. Results. Fifteen patients, median age 31 years (range 17.5-56) had nonpleomorphic rhabdomyosarcoma (RMS, n = 6), EWS, n = 5, synovial sarcoma (SS, n = 2) leiomyosarcoma (LMS, n = 1), and desmoplastic small round cell tumour (DSRCT, n = 1). Median time to progression was 2.5 months (range 1.6-13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. CONCLUSION: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients.

Association of fibrinogen with Parkinson disease in elderly Japanese-American men: a prospective study.

BACKGROUND: The purpose of this prospective study was to examine whether fibrinogen level is associated with Parkinson disease (PD) for both prevalent and incident cases. METHODS: The Honolulu Asia-Aging Study is a longitudinal study of Japanese-American men based on the Honolulu Heart Study birth cohort. The original cohort consisted of 8,006 participants with selective service records who were living on the island of Oahu, Hawaii, in 1965. For this analysis, baseline was defined as the 1991-1993 examination (n = 3,845) when men were aged 71-93 years old. Multivariate logistic regression and Cox proportional hazards models were used, adjusting for potential confounders. RESULTS: We identified 61 prevalent cases and 61 incident cases of PD during the follow-up. High fibrinogen level (presence in the top quintile) was associated with higher frequency of PD for both prevalent (OR = 2.07, 95% CI = 1.10-3.88, p = 0.024) and incident cases (HR = 3.05, 95% CI = 1.34-6.97, p = 0.008) among men aged 76-93 years, after adjusting for age, smoking, and low-density lipoprotein cholesterol. CONCLUSIONS: These results suggest high fibrinogen level is associated with increased risk of PD among men over 75 years.

PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53.

Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide. Our results showed that E1B-55K/PML binding is not required for p53, Mre11 and Daxx interaction. We also observed that E1B-55K lacking subnuclear PML localization because of either PML-IV or PML-V-binding deficiency was no longer capable of mediating E1B-55K-dependent SUMOylation of p53, inhibition of p53-mediated transactivation or efficiently transforming primary rodent cells. These results together with the observation that E1B-55K-dependent SUMOylation of p53 is required for efficient cell transformation, provides evidence for the idea that the SUMO ligase activity of the E1B-55K viral oncoprotein is intimately linked to its growth-promoting oncogenic activities.

Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130.

The murine Unp gene encodes a widely expressed ubiquitin-specific protease. The predicted sequence of the UNP protein features motifs common to viral oncoproteins through which these proteins interact with the retinoblastoma gene product pRb, as well as the related 'pocket proteins' p107 and p130. We have explored the possibility that UNP interacts with pocket proteins, and report here that such associations can be detected in vitro and in cells. Associations of UNP and pocket proteins are sensitive to site-directed mutations in a manner directly analogous to those documented in viral oncoproteins. We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130.

Invasive treatment for coronary artery disease in the elderly.

The widespread availability of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty presents important treatment options for the older patient. The findings from a number of surgical series of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty are summarized. Certain trends are evident. Perioperative mortality, cardiovascular morbidity, and other complications, while declining, remain somewhat higher in elderly patients. However, the impact of age alone is slight. In both coronary artery bypass grafting and percutaneous transluminal coronary angioplasty, complications are more closely correlated with the presence of serious concomitant disease. Long-term survival and pain relief after coronary artery bypass grafting are excellent in older patients, and percutaneous transluminal coronary angioplasty may be the treatment of choice in some elderly patients with coronary artery disease. As in younger patients, prolongation of survival should not be the exclusive goal. Rather, a focus on quality of life and freedom from dependency should be seriously considered.

The detection of dementia in the primary care setting.

BACKGROUND: Recognition and medical record documentation of dementia in the primary care setting are thought to be poor. To our knowledge, previous studies have not examined these issues in private practice office settings within the United States. OBJECTIVE: To determine the rate of unrecognized and undocumented dementia in a primary care internal medicine private practice. METHODS: This was a cross-sectional study of 297 ambulatory persons aged 65 years and older attending an internal medicine private group practice within an Asian American community of Honolulu, Hawaii. Of the subjects, 95% had been with their current primary care physician for at least 1 year. Each subject's primary care physician noted the presence or absence of dementia by questionnaire at the time of an office visit. An investigating physician (V.G.V.) subsequently assessed cognitive function using the Cognitive Abilities Screening Instrument, and confirmed the presence of dementia and its severity, if present, using Benson and Cummings' criteria and the Clinical Dementia Rating Scale, respectively. A trained research assistant completed telephone interviews to proxy informants for collateral information concerning cognition, behavior, and occupational or social function. Subjects' outpatient medical records were reviewed for documentation of problems with cognition. RESULTS: Twenty-six cases of dementia were identified. Of these 26, 17 (65%) (95% confidence interval, 44.3-82.8) were not documented in outpatient medical records; of 18 patients, 12 (67%) (95% confidence interval, 40.9-86.7) were not thought to have dementia by their physicians at the time of the office visit. Recognition and documentation rates increased with advancing stage of disease. CONCLUSION: Dementia is often unrecognized and undocumented in private practice settings. Arch Intern Med. 2000;160:2964-2968

Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging Study.

BACKGROUND: The Honolulu Heart Program (HHP) is a prospective study of heart disease and stroke that has accumulated risk factor data on a cohort of 8,006 Japanese American men since the study began in 1965. A recent examination of the cohort identified all patients with vascular dementia (VaD) using the criteria of the California Alzheimer's Disease Diagnostic and Treatment Center. OBJECTIVE: To characterize patients with VaD by stroke subtype and to investigate risk factors for VaD in a cohort of Japanese American men, aged 71 to 93, living in Hawaii and participating in the HHP. METHODS: Sixty-eight men with VaD were compared with 3,335 men without dementia or stroke (NSND). Men with VaD were also compared with 106 men with stroke who were not demented (SND). Candidate risk factors were measured prospectively. RESULTS: Of the 68 men with VaD there were 34 (50%) whose VaD was attributed to small vessel infarcts, 16 (23%) whose VaD was related to large vessel infarcts, and 11 (16%) with both large and small vessel infarcts. The remainder could not be classified. In a multivariate logistic regression model for VaD compared with NSND containing variables found to be associated with VaD in a univariate analysis, age (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.13 to 1.27), coronary heart disease (OR 2.50, 95% CI 1.35 to 4.62), and 1-hour postprandial glucose (OR 1.41, 95% CI 1.06 to 1.88) remained significantly predictive of VaD, whereas preference for a Western diet (OR 0.54, 95% CI 0.30 to 0.98) as opposed to an Oriental or mixed diet and use of supplementary vitamin E (OR 0.32, 95% CI 0.12 to 0.82) were protective. A similar model for the comparison of men with VaD and SND revealed age (OR 1.24, 95% CI 1.14 to 1.35) was predictive of VaD, whereas preference for a Western diet (OR 0.43, 95% CI 0.22 to 0.86) was protective. CONCLUSIONS: The most common stroke subtype associated with VaD was lacunar stroke. Age and traditional vascular risk factors are important contributors to the development of VaD in late life. The antioxidant vitamin E and presently unknown factors related to a Western diet as opposed to an Oriental diet may be protective against developing VaD.

Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance.

OBJECTIVE: To assess the relationship between impaired glucose tolerance and both vascular dementia and AD. BACKGROUND: Diabetes and abnormalities of glucose metabolism have been associated with stroke and poor cognitive function. In addition, glycoproteins and glycosylation have been postulated to be associated with the development of neuritic plaques characteristic of AD. METHODS: A historical prospective cohort study of Japanese-American men (n = 3,774), who were examined at ages 45 to 68 (1965 through 1968) and again at ages 71 to 93 (1991 through 1993). Measurements were obtained by clinical and home examinations: assessment of glucose intolerance (nonfasting 1 hour after glucose load) from 1965 through 1968 and history of diabetes diagnosed by a physician at examinations given from 1965 through 1968 and from 1976 through 1978. At the 1991 through 1993 examinations, the Cognitive Assessment Screening Instrument (CASI)-an instrument designed for use in cross-cultural settings combining features of the Folstein Mini-Mental State Examination, the Modified Mini-Mental State Examination, and the Hasegawa Dementia Screening Scale-was used. Diagnosis and classification of AD and vascular dementia were made by a consensus panel using neuropsychologic assessment data, a neurologist's evaluation, and information from a family informant. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised criteria were used to establish dementia, and subclassification by cause was based on other published criteria. RESULTS: No association between AD and diabetes, present either 25 or 15 years previously, was found after adjustment for age and education in a multiple regression model. A significant association was found between impaired glucose tolerance at baseline and vascular dementia (p < 0.01). CONCLUSIONS: These findings confirm expected relationships between impaired glucose tolerance and stroke-related dementia but do not support an association of disordered glucose metabolism with AD.

Frequency of bowel movements and the future risk of Parkinson's disease.

BACKGROUND: Constipation is frequent in PD, although its onset in relation to clinical PD has not been well described. Demonstration that constipation can precede clinical PD could provide important clues to understanding disease progression and etiology. The purpose of this report is to examine the association between the frequency of bowel movements and the future risk of PD. METHODS: Information on the frequency of bowel movements was collected from 1971 to 1974 in 6790 men aged 51 to 75 years without PD in the Honolulu Heart Program. Follow-up for incident PD occurred over a 24-year period. RESULTS: Ninety-six men developed PD an average of 12 years into follow-up. Age-adjusted incidence declined consistently from 18.9/10,000 person-years in men with <1 bowel movement/day to 3.8/10,000 person-years in those with >2/day (p = 0.005). After adjustment for age, pack-years of cigarette smoking, coffee consumption, laxative use, jogging, and the intake of fruits, vegetables, and grains, men with <1 bowel movement/day had a 2.7-fold excess risk of PD versus men with 1/day (95% CI: 1.3, 5.5; p = 0.007). The risk of PD in men with <1 bowel movement/day increased to a 4.1-fold excess when compared with men with 2/day (95% CI: 1.7, 9.6; p = 0.001) and to a 4.5-fold excess versus men with >2/day (95% CI: 1.2, 16.9; p = 0.025). CONCLUSIONS: Findings indicate that infrequent bowel movements are associated with an elevated risk of future PD. Further study is needed to determine whether constipation is part of early PD processes or is a marker of susceptibility or environmental factors that may cause PD.

Midlife adiposity and the future risk of Parkinson's disease.

BACKGROUND: Evidence suggests that nigrostriatal system disorders are associated with PD and adiposity. Whether patterns of adiposity coexist or predate clinical PD is unknown. This report examines the relation between midlife adiposity and the risk of PD. METHODS: Measurement of adiposity occurred from 1965 to 1968 in 7,990 men in the Honolulu Heart Program (aged 45 to 68 years and without PD). Adiposity measures included body mass index (BMI), subscapular skinfold thickness (SSF), and triceps skinfold thickness (TSF). Follow-up for incident PD occurred over a 30-year period. RESULTS: During the course of follow-up, PD was observed in 137 men. Among the measures of adiposity, age-adjusted incidence of PD increased threefold from 3.7/10,000 person-years in the bottom quartile of TSF (1 to 5 mm) to 11.1/10,000 person-years in the top quartile (11 to 32 mm, p < 0.001). Effects of TSF on PD were independent of cigarette smoking, coffee consumption, physical activity, daily caloric and fat intake, and the other measures of adiposity (p < 0.001). Whereas rates of PD were lowest in the bottom quartile of BMI and SSF vs higher quartiles, associations with PD were weaker than they were for TSF. The effect of TSF on clinical onset before age 65 years was similar to the effect that was observed in later life. CONCLUSIONS: Increased triceps skinfold thickness measured in midlife is associated with an elevated risk of future PD. Whether patterns of adiposity reflect a unique metabolic pathology in individuals at a high risk of PD warrants further study.

Accuracy of clinical criteria for AD in the Honolulu-Asia Aging Study, a population-based study.

OBJECTIVE: To determine diagnostic accuracy for AD in a population-based study of Japanese-American men. AD is neuropathologically confirmed for more than 80% of cases at major referral centers (primarily Caucasians); however, information on diagnostic accuracy in population-based studies and studies of different ethnic groups is limited. METHODS: There were 3,734 men who participated in the Honolulu-Asia Aging Study 1991 through 1993 dementia examination and 2,603 in the 1994 through 1996 examination. Diagnoses were based on published criteria. Neuropathologists blinded to clinical data quantified neurofibrillary tangles (NFT) and neuritic plaques (NP). RESULTS: Of 220 autopsied subjects, clinical evaluation revealed 68 with normal cognition, 73 intermediate, and 79 with dementia: 20 AD, 27 vascular dementia, 19 AD + other, and 13 other dementia. Among 20 cases with pure AD, the median value for maximum neocortical NFT density was 6.9/mm(2) and for neocortical NP density was 8.0/mm2. Corresponding densities for other groups were <3.0/mm2. Using established neuropathologic criteria, 25% (5/20) of clinical AD cases had enough NP to meet definite AD criteria, whereas 65% (13/20) had sufficient NP to meet neuropathologic definite or probable AD criteria. Among nine AD cases with moderately severe dementia, only two (22%) had NP densities great enough to meet definite neuropathologic criteria, whereas seven (78%) met neuropathologic criteria for probable AD. CONCLUSIONS: Neuropathologic confirmation and NP density among decedents with clinical AD in this population-based study were lower than reported by referral centers and similar to reports from two other community studies. Ethnic differences in propensity for amyloid deposition as well as differences in clinical severity and representativeness of cases might contribute to these findings.

Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material.

Severe acute and chronic hepatic damage occurred in a white man who had taken phenelzine sulfate (Nardil) 45 mg daily for 70 days. Liver biopsy showed a mixed hepatitic and cholestatic pattern with extracellular deposition of a unique homogeneous collagenous substance. Portal cirrhosis developed and has persisted. The patient was found to have a "rapid acetylator phenotype" and high rate of metabolism of antipyrine. These innate factors may have predisposed to hepatic injury due to phenelzine.

Influence of myocardial infarction, coronary artery bypass surgery, and stroke on cognitive impairment in late life.

Relations between cognitive test scores in later life and prior myocardial infarction (MI), coronary artery bypass graft surgery (CABG), and stroke were examined for this study. Subjects were 3,734 Japanese-American men (80% of surviving Honolulu Heart Program cohort) aged 71 to 93 years at the time of cognitive testing. Impairment was defined as scoring below the 16th percentile on a validated cognitive assessment scale. Prior MI, stroke, and CABG were established using hospital surveillance, history, and record review. After adjustment for age, years of education, and years of childhood spent in Japan, men with prior stroke were significantly more likely than others to have poor cognitive performance (odds ratio 4.4, 95% confidence limits 3.0 to 6.7). History of > 1 stroke was associated with an odds ratio of 50 (95% confidence limits 10.5 to 238.3). There was no significant association between cognitive performance and > or = 1 prior MI or history of CABG. Time between events and cognitive function testing did not affect results. Analyses support a significant association between clinical stroke and persistent cognitive impairment, but fail to implicate CABG or MI.

Levodopa-induced dyskinesia: facts and fancy. What does the MPTP monkey model tell us?

Levodopa-induced dyskinesia, one of the most frequent long-term side effects of antiparkinsonian therapy, is often attributed to denervation supersensitivity of dopamine receptors and perhaps more specifically the D-1 receptor. The available evidence based not only on clinico-pathological studies in patients but also on results of experiments performed on methyl-phenyl-tetrahydropyridine (MPTP)-treated monkeys suggests that the mechanisms may be more complex than heretofore believed. Thus it appears that no single receptor is the sole culprit, that some form of denervation supersensitivity is probably involved but not in the form of increased density of dopamine receptors. Moreover, other neurotransmitter systems must be considered such as GABA, excitatory aminoacids and peptides. The MPTP monkey model remains very useful for predicting the potential of new drugs for inducing dyskinesia. Such trials however must be performed in drug-naive animals.

Pathophysiology of hypertension.

Environmental factors such as excessive sodium ingestion and increasing adiposity are suspected to play a major role in the development of hypertension in elderly persons. Both aging and hypertension are associated with similar vascular structural changes including atherosclerosis. Despite the observed age-related changes in vascular structure, other factors must be important in contributing to the elevated pressure in isolated systolic hypertension. Alterations in sympathetic nervous system function may play a major role in the age-related increases in blood pressure and hypertension, especially isolated systolic hypertension.

Blood pressure dysregulation syndrome. The case for control throughout the circadian cycle.

Blood pressure dysregulation syndrome is characterized by abnormal swings in blood pressure following postural changes, meals, exercise, and during sleep. Although the syndrome may occur in normotensive individuals, a growing body of evidence suggests an association between blood pressure dysregulation and hypertension. Diagnosis can be aided using 24-hour ambulatory blood pressure monitoring. Improved understanding of the syndrome and heightened awareness of its existence in older persons can help clinicians provide more effective management of hypertension. Adequate control of blood pressure throughout the circadian cycle should be a treatment objective.

Age-based rationing of health care.

The U.S. has focused attention on the rising costs of health care coincident with the increasing age of the population. Arguments have been made to overtly ration care to older persons; however, general acceptance of the need to ration scarce resources, whether or not such a policy is actually formalized, can lead to covert rationing. Some overt rationing has already occurred, some of the data put forth to justify that rationing needs to be challenged, and ethical principles need to be applied to provide appropriate and perhaps less costly care.