Phase III randomized comparison of
postoperative adjuvant chemotherapy with 2-year oral
uracil/tegafur versus 6-cycle
cyclophosphamide/methotrexate/5-fluorouracil in high-risk
node-negative breast cancer patients.Cochrane Abstract of review: The
efficacy of aldose reductase inhibitors inFoot Care in Patients With Diabetes
Mellitus Associations of ankle-brachial index
with clinical coronary heart disease, stroke and preclinical
carotid and popliteal atherosclerosis: : the Atherosclerosis Risk
in Communities (ARIC) Study Phase III randomized comparison of
postoperative adjuvant chemotherapy with 2-year oral
uracil/tegafur versus 6-cycle
cyclophosphamide/methotrexate/5-fluorouracil in high-risk
node-negative breast cancer patients.
Source: Cancer Chemother Pharmacol 1998;42 Suppl:S68-70
The value of
cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type regimens
in surgical adjuvant therapy in certain subsets of patients with
axillary lymph node-negative breast cancer has been evaluated in
Europe and the USA. However, Japan has a distinctive standpoint
regarding the indications for surgical adjuvant chemotherapy for
breast cancer patients. In addition, oral fluoropyrimidines are
widely used to treat breast cancer patients in both adjuvant and
metastatic settings due to their low toxicity and convenience for
long-term administration. Although the antitumor activity and the
ability to prolong disease-free survival times of oral
fluoropyrimidines have been evaluated in patients with breast
cancer, available data are not sufficient to justify replacing
CMF-type regimens with oral fluoropyrimidines in postoperative
chemotherapy for breast cancer patients. To evaluate the utility
of oral fluoropyrimidines in surgical adjuvant chemotherapy, the
National Surgical Adjuvant Study Group (N-SAS) was founded in
1995 as a government-funded research group, and nationwide
multiinstitutional trials were designed for breast cancer as well
as colon and gastric cancers. For high-risk, node-negative breast
cancer patients, a prospective randomized trial of surgical
adjuvant chemotherapy comparing 6 cycles of CMF with 2 years of
daily uracil/tegafur (UFT) started in October 1996. The endpoints
of this study include disease-free and overall survival, adverse
reactions, quality of life, and cost.
Cochrane Abstract of review: The
efficacy of aldose reductase inhibitors in
the treatment of diabetic peripheral neuropathy
Source:
http://som.flinders.edu.au/fusa/cochrane/cochrane/revabstr/ab000003.htm
Objectives: To assess the
efficacy of aldose reductase inhibitors in the prevention,
reversal or delay in the progression of
diabetic peripheral neuropathy.
Search strategy: The Cochrane Diabetes Group's database was
searched and the citation lists of identified trials and
previousreviews checked. Investigators identified as active in
the field were approached for overlooked studies.
Selection criteria: Randomised controlled trials of aldose
reductase inhibitors versus placebo, no treatment or other
treatment in diabetic patients with or without clinical
neuropathy.
Data collection and analysis: Nerve conduction velocity was the
only end point measured in all trials. Treatment effect was
evaluated in terms of nerve conduction velocity mean difference
in median and peroneal motor and median and sural sensory nerves.
Main results: 19 trials, testing 4 different aldose reductase
inhibitors for between 4 to 208 weeks duration (median 24 weeks),
met the inclusion criteria for the meta-analysis. A small but
statistically significant reduction in decline of median and
peroneal motor nerve conduction velocities was present in the
treated group when compared to the control group (weighted mean
0.66 m/s 95% CI 0.18-1.14 m/s and 0.53 m/s 95% CI 0.02-1.04m/s
respectively). No clear benefit of aldose reductase inhibitor
treatment was observed in either of the sensory nerves.
Conclusions: Although aldose reductase inhibitor treatment has
been demonstrated to diminish the reduction in motor nerve
conduction velocity, the clinical relevance of such a change in
this outcome measure is uncertain. There was no effect in terms
of this outcome measure in the smaller sensory fibres,
degeneration of which is primarily responsible for the most
common
neuropathic syndrome associated with diabetes, that of severe
pain and loss of sensation in the extremity leading in some cases
to ulceration and eventual amputation.
Foot Care in Patients With Diabetes
Mellitus
Source: Diabetes Care
1998;21(S1):S54
Foot ulcers and
other foot problems are a major cause of morbidity, mortality,
and disability in people with diabetes. In the presence of
neuropathy and/or ischemia, the sequence of minor trauma leading
to cutaneous ulceration and wound-healing failure is a frequent
cause of lower-extremity amputations in diabetic patients. Once
the amputation of one limb has occurred, the prognosis for the
contralateral limb is poor .
Techniques to prevent amputation range from the simple, but often
neglected, foot inspection to complicated vascular surgery.
Appropriate management can prevent and heal diabetic foot ulcers,
thereby greatly reducing the amputation rate. The guidelines
herein outline the essentials of foot care for people with
diabetes.
Patients are at high risk of developing foot ulcers if they have
either loss of protective sensation (neuropathy severe enough
that they cannot feel injury) or vascular disease. In such
"at-risk" patients, additional risk factors are
structural deformities, and skin or nail abnormalities. Patients
who have experienced previous ulcers or amputation have, by
definition, the necessary risk factors for future ulceration. All
patients should be seen at regular frequent intervals by a
qualified health care professional with experience in the care of
diabetic foot problems.
Patients have a low risk of developing foot lesions if they have
none of the above abnormalities. They should receive instruction
on basic preventive foot care and have routine foot inspections.
Patients at low risk should be reassured, so that they do not
worry unnecessarily about the possibility of ulceration or
amputation.
GENERAL GUIDELINES FOR FOOT EVALUATION A comprehensive screening
including vascular, neurological, musculoskeletal, and skin and
soft tissue evaluations should be done at least annually. The
emphasis of this examination must be on identifying high-risk
feet, specifically feet with loss of protective sensation or with
significant vascular disease. The skills needed to identify these
high-risk characteristics should be in the repertoire of the
diabetes primary care provider or could be deferred to another
qualified health care professional. Once high-risk abnormalities
are discovered, a foot exam should be performed at each routine
diabetes visit several times a year, and ongoing care by a
qualified health care professional with
experience in the care of diabetic foot problems should be
initiated.
The vascular evaluation should include palpation of the pulses in
the lower extremities and inspection of the feet and legs for any
gross ischemic changes. If the patient has disabling claudication
or a nonhealing ulcer in an obviously ischemic limb, a vascular
consultation should be requested. A patient without claudication
or ulcer but with evidence of significant peripheral vascular
disease should be considered a high-risk patient and should have
a foot exam at each visit.
The neurological exam should include a sensorimotor examination
of the lower extremities. The goal of this examination is to
ascertain whether protective sensation has been lost. A 10-g
(5.07) Semmes-Weinstein monofilament should be used. If a patient
cannot consistently feel the touch of this monofilament,
protective sensation has been lost. If loss of protective
sensation is discovered, a comprehensive ongoing program of
patient education, appropriate daily self-care, professional nail
and callus care, and appropriate footwear should be initiated.
All patients with loss of protective sensation should wear at
least an athletic shoe or a shoe of similar design. Currently,
Medicare will provide reimbursement for one pair of extra-depth
shoes and three pairs of inserts or one pair of custom-molded
shoes plus two additional pairs of inserts each year for
patients with high-risk feet.
For a patient at high risk, the evaluation should include
assessment of soft tissues and a lower-extremity musculoskeletal
exam, including assessment of gait and determination of range of
motion at the ankle and hallux. The most important aspect of the
soft tissue exam is, of course, checking for ulcers or other skin
breakdown. Many ulcers begin at the site of a callus. Pre-ulcers
(blisters, macerated skin, hemorrhage into callus) are indicative
of extremely high-risk feet and mandate immediate intervention.
Effective treatment for fungal infection is now available.
PATIENT EDUCATION Patients with diabetes must be educated and
understand proper foot care. Low-risk patients should be
instructed about 1) foot hygiene, 2) proper footwear, 3)
avoidance of foot trauma, 4) the need to stop smoking, and 5)
actions to take if problems develop, which include seeing a
health care professional when needed. It is always important to
instill confidence in the low-risk patient to prevent unfounded
fear. Good basic foot hygiene in a low-risk patient should
guarantee that major problems will not develop. In addition,
high-risk patients and their family members should be taught to
perform daily foot care and should understand the role that loss
of protective sensation plays in foot injury. Education
should continue until the patient can verbalize and demonstrate
proper foot care practices. Neuropathic and vascular
complications and their relationships to foot problems should be
explained.
DIABETIC FOOT ULCERS Prompt and proper care of diabetic foot
ulcers is essential. The health care professional should 1)
establish the ulcer's etiology; 2) measure its size; 3) establish
its depth and determine the involvement of deep structures; 4)
examine it for purulent exudate, necrosis, sinus tracts, and
odor; 5) assess the surrounding tissue for signs of edema,
cellulitis, abscess, and fluctuation; 6) exclude systemic
infection; and 7) perform a vascular evaluation. The ability to
gently probe through the ulcer to bone has been shown to be
highly predictive of osteomyelitis.
Radiological examination
A radiological examination is frequently useful to exclude
subcutaneous gas, presence of a foreign body, osteomyelitis, and
Charcot's foot. Plain radiographs may demonstrate periosteal
resorption and osteolysis, which are consistent with but not
diagnostic of osteomyelitis. To differentiate osteomyelitis from
Charcot's foot, additional imaging studies (e.g., triple-phase
bone scan, 111In white blood cell imaging, magnetic resonance
imaging) or a bone biopsy may be necessary.
Bacterial cultures and antibiotics
Bacterial infections of foot lesions are commonly polymicrobial.
Thus, if infection is suspected, broad-spectrum antibiotic
coverage should be initiated immediately and modified as
necessary based on culture results and the patient's response to
therapy. Deep specimens obtained by curettage of the base of the
wound may provide the most reliable culture results.
Debridement
All abscessed infections should be incised and drained.
Debridement must extend to viable noninfected tissue.
Wound care
The use of topical agents in the treatment of diabetic foot
ulcers is controversial. Although several topical agents (e.g.,
antiseptic solutions, growth factors, tissue supplements) have
been proposed to speed the healing of diabetic foot ulcers, there
are no adequately controlled studies that demonstrate their
efficacy. Prolonged immersion of the foot in water is not
recommended.
Mechanical stress
It is essential to minimize weight bearing on the ulcer.
Modifications of weight bearing include the use of bed rest and
crutches, total-contact casts, shoe inserts, and special shoes.
All patients for whom bed rest is prescribed should have heel and
ankle protection and daily inspection of both legs. When
neuropathic ulcers continue to be subjected to even limited
weight bearing, they will not heal. The most common cause of
nonhealing of a neuropathic ulcer is ongoing mechanical trauma.
Circulation
Patients with slow or inadequate healing who have decreased
pulses and/or pressures by Doppler examination may be candidates
for vascular reconstruction. Vasodilator drugs have not been
demonstrated to aid in the healing of diabetic foot ulcers.
Vasoconstrictor drugs should be avoided.
Metabolic control
Infection and/or inflammation may result in widely fluctuating
blood glucose levels. Surgical and antibiotic treatment of
abscesses or deep infection may help bring blood glucose levels
under better control. Conversely, patients with severe
hyperglycemia may have decreased ability to fight infection;
therefore, good control of blood glucose should be a primary goal
of the patient's total care. Poor nutritional status may hinder
the healing process and should be promptly addressed.
Posthealing treatment
Patients with healed foot ulcers are at risk for future
ulceration. The education program for these patients should
stress daily examination of the feet and prompt notification of a
health care provider if problems arise (see PATIENT EDUCATION).
Patients whose work requires them to be on their feet for
extended periods may require job modification. Prescribed
footwear will benefit patients with a history of foot ulcers.
Footwear options include walking or athletic shoes, soft insoles,
extra-depth shoes with custom-molded inlays, and custom-molded
therapeutic shoes. If unfamiliar with therapeutic footwear, the
health care provider should seek assistance from a qualified
footwear specialist.
CHARCOT'S FOOT The physician must be aware that an acutely
swollen foot with no significant radiographic changes in a
patient with diabetes may represent the early stage of Charcot's
foot. When present, this condition requires careful observation
and appropriate rest, elevation, and immobilization.
Distinguishing Charcot's foot from infection or monarticular
arthritis may be difficult, and careful follow-up is required.
The most important task is recognition. It is mandatory that
every patient with recognized or possible Charcot's foot be
referred to a specialist experienced in treating this condition.
Associations of ankle-brachial index with
clinical coronary heart disease, stroke and preclinical carotid
and popliteal atherosclerosis: : the Atherosclerosis Risk in
Communities (ARIC) Study
Source: Atherosclerosis, 1997, 131:1:115
- 125
The resting ankle-brachial index (ABI) is a non-invasive method
to assess the patency of the lower extremity arterial system and
to screen for the presence of peripheral occlusive arterial
disease. To determine how the ABI is associated with clinical
coronary heart disease (CHD), stroke, preclinical carotid plaque
and far wall intimal-medial thickness (IMT) of the carotid and
popliteal arteries, we conducted analyses in 15 106 middle-aged
adults from the baseline examination (1987–1989) of the
Atherosclerosis Risk in Communities (ARIC) Study. The prevalence
of clinical CHD, stroke/transient ischemic attack (TIA) and
preclinical carotid plaque increased with decreasing ABI levels,
particularly at those of <0.90. Individuals with ABI<0.90
were twice as likely to have prevalent CHD as those with
ABI>0.90 (age-adjusted odds ratio (OR) ranging from 2.2 (95%
CI: 1.0–5.1) in African-American men to 3.3 (95% CI:
2.1–5.0) in white men). Men with ABI<0.90 were more than
four times as likely to have stroke/TIA as those with ABI>0.90
(age-adjusted OR: 4.2 (95% CI: 1.8–9.5) in African-American
men and 4.9 (95% CI: 2.6–9.0) in white men). In women the
association was weaker and not statistically significant. Among
those free of clinical cardiovascular disease, individuals with
ABI0.90 had statistically significantly
higher prevalence of preclinical carotid plaque compared to those
with ABI>0.90 (age-adjusted ORs ranging from 1.5 (95% CI:
1.0–1.9) in white women to 2.6 (95% CI: 1.06.6) in
african-american men). The ABI was also inversely associated with
far wall IMT of the carotid arteries (in both men and women) and
the popliteal arteries (in men only). The associations of ABI
with clinical CHD, stroke, preclinical carotid plaque and IMT of
the carotid and popliteal arteries were attenuated and often not
statistically significant after further adjustment for LDL
cholesterol, cigarette smoking, hypertension and diabetes. These
data demonstrate that low ABI levels, particularly those of
<0.90, are indicative of generalized atherosclerosis.
In this bi-ethnic population sample of middle-aged adults the
prevalence of clinical CHD, stroke/TIA and preclinical carotid
plaque increased with decreasing ABI levels particularly at those
of 0.90. The results confirm the findings reported from the
Cardiovascular Heath Study (CHS) [13] where Newman et al.
observed a graded relationship between clinical and preclinical
cardiovascular disease and ABI, categorized as <0.8,
0.8–0.9, 0.9–1.0 and >1.0. The ARIC population is
relatively young (45–64 years at baseline versus >65
years in the CHS), had higher mean ABI (1.17 versus 1.07 in the
CHS) and few participants (0.7%) had an ABI of <0.8, thus this
study is unable to further categorize the ABI cut-off point of
0.8 in the analysis.
In clinical practice it has generally been assumed that a resting
ABI>1.0 signifies the absence of significant arterial
narrowing. This study, along with others, indicates that ABI has
a wide range of values with a mean value well above 1.0. The
variability of these values may only be partly related to lower
extremity arterial stenosis. Other sources of variation may
include the method of measurement, method of ABI calculation and
non-pathological inter-individual differences in arterial
architecture. In any case the assumption that there are important
non-pathological determinants of ABI variability means that no
single cut-off point will be unambiguously indicative of
peripheral arterial disease (PAD) . An ABI cut-off point of 0.9
or less has been used in clinical practice and epidemiologic
studies as the indicator of PAD. Our data suggest that ABI at
this level is statistically significantly associated with higher
prevalence of clinical CHD, stroke, and preclinical
atherosclerosis and may be indicative of generalised
atherosclerosis in middle aged men.
The association of ABI with B-mode ultrasound measured carotid
atherosclerosis, assessed by either preclinical plaque or far
wall IMT, was particularly strong and consistent in all race and
gender groups and of a graded nature. Newman et al. reported a
graded relationship between ABI levels and carotid plaques and
B-mode ultrasound determined carotid stenosis in the CHS. In
patients with systolic hypertension, Sutton et al. observed a
high prevalence of carotid stenosis among those with an
ABI<0.90. ?Gren et al. also reported an increased prevalence
of carotid stenosis in patients with ABI0.90. The correlation
between ABI and B-mode ultrasound measured carotid
atherosclerosis suggests a similar risk factor profile and
pathogenesis of atherosclerosis in carotid and lower extremity
arteries.
This is one of the only two population based studies to examine
the association between ABI and carotid IMT. Similarly to the
results from the Dutch study , we found that mean carotid
intimal-medial thickness increased with decreasing ABI levels.
Furthermore, our study shows that the inverse association of ABI
with carotid IMT may be best described as a quadratic curve
rather than a straight-line relation. The polynomial associations
of ABI with carotid IMT, along with the graded association of ABI
with prevalent CVD, suggest that the ABI is more meaningful in
the low end of its distribution.
The association of ABI with popliteal artery wall thickness,
assessed by ultrasonography, has not been investigated
previously. In this population there was weak association of ABI
with popliteal artery wall thickness in men but not at all in
women. In the ARIC Study approximately 30% of participants had
missing popliteal artery measurements due to poor quality of
ultrasound image, equipment failure, difficulty to scan in obese
participants and other reasons. Compared to those with the
popliteal artery measurement participants with missing data had
lower mean levels of ABI and HDL cholesterol, higher mean levels
of plasma LDL cholesterol, fibrinogen and body mass index and a
higher prevalence of CHD, stroke/TIA, hypertension, diabetes and
obesity. The impact of this unbalanced missing data would likely
bias our results toward an apparent lack of a significant
association between ABI and popliteal IMT. Since the ABI
measurement reflects overall functional and hemodynamic
impairment due to occlusive processes in the main proximal
arteries , while popliteal IMT is only indicative of one site
anatomical change, it is not surprising that their correlation is
weak. One should be aware that the popliteal may not be an area
of predilection for atherosclerosis but certainly is an easier
one to scan, thus IMT measurement at popliteal level may not be a
good marker for atherosclerosis in the lower extremities. The
discrepancy in the association between ABI and popliteal IMT by
gender in our data (contrasted to the similarity by gender for
carotid IMT) is intriguing.
One of the possible explanations for the gender difference in the
association of ABI with popliteal IMT is that the natural history
of lower extremity arterial disease is much delayed in women
compared to men, at least as measured by IMT at the popliteal
arteries. It is possible that lower extremity arterial disease is
more rapidly progressive in men than women, thus it might extend
into the popliteal artery sooner in men than in women.
This study found that the magnitude of the association of ABI
with prevalent CVD was similar in African-Americans and whites,
but generally weaker in white women. This is consistent with
weaker associations of ABI-defined peripheral arterial disease to
CVD risk factors in white women in this and other populations.
One possible explanation is that ABI measurement may be less
sensitive and specific in detecting true LEAD in women; however
no validation studies based on substantial numbers of women exist
in the literature. Further studies are required to examine the
gender difference in ABI and its associations with CVD risk
factors and manifestations .
There are several potential limitations to this study. Clinical
CHD and stroke/TIA were based mainly on information ascertained
from interviewer administered questionnaires which are prone to
misclassification of some participants as either having disease
or being disease free. The impact of this misclassification on
the estimate of the association between ABI and clinical CVD
would likely bias our results toward an apparent lack of
significant association. In addition, individuals with severe
forms of CHD, stroke and peripheral arterial disease, are less
likely to have survived or been able to participate in a
population-based study such as this. Ankle blood pressures were
recorded in the prone position while brachial blood pressures
were recorded in supine position after ankle blood pressures.
This may have introduced a systematic error, thus overestimating
the ABI value. Furthermore, ankle blood pressure was measured
only in one leg which is likely to underestimate PAD prevalence
since the disease is often unilateral. Thus, the associations of
ABI with prevalent atherosclerotic disease may have been
underestimated. The African-American population in this study was
predominantly inducted at one study site, i.e. Jackson, MS. Thus
the results may not be generalizable to all segments of the US
african-american population.
In conclusion, the present study demonstrates inverse
associations of ABI with clinical and preclinical atherosclerotic
disease in a variety of arterial beds, suggesting that a low ABI
reflects systemic atherosclerosis. It suggests the usefulness of
ABI in assessing atherosclerosis in prospective observational
studies and clinical trials and its potential clinical
applicability to assess the risk of future cardiovascular events.
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