Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.

Examining prognostic factors and patterns of failure in nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy: impact on future clinical trials.

PURPOSE: Concomitant chemotherapy and radiotherapy (CCRT), followed by adjuvant chemotherapy, has improved the outcome of nasopharyngeal carcinoma (NPC). However, the prognosis and patterns of failure after this combined-modality treatment are not yet clear. In this report, the prognostic factors and failure patterns we observed with CCRT may shed new light in the design of future trials. METHODS AND PATIENTS: One hundred forty-nine (149) patients with newly diagnosed and histologically proven NPC were prospectively treated with CCRT followed by adjuvant chemotherapy between April 1990 and December 1997. One hundred and thirty-three (89.3%) patients had MRI of head and neck for primary evaluation before treatment. Radiotherapy was delivered either at 2 Gy per fraction per day up to 70 Gy or 1.2 Gy per fraction, 2 fractions per day, up to 74.4 Gy. Chemotherapy consisted of cisplatin and 5-fluorouracil. According to the AJCC 1997 staging system, 32 patients were in Stage II, 53 in Stage III, and 64 in Stage IV (M0). RESULTS: Univariate analysis revealed that WHO (World Health Organization) Type II histology, T4 classification, and parapharyngeal extension were poor prognostic factors for locoregional control. Multivariate analysis revealed that T4 disease was the most important adverse factor that affects locoregional control, the risk ratio being 5.965 (p = 0.02). Univariate analysis for distant metastasis revealed that T4 and N3 classifications, serum LDH level > 410 U/L (normal range, 180-460), parapharyngeal extension, and infiltration of the clivus were significantly associated with poor prognosis. Multivariate analysis, however, revealed that T4 classification and N3 category were the only two factors that predicted distant metastasis; the risk ratios were 3.994 (p = 0.02) and 3.390 (p = 0.01), respectively. Therefore, based on the risk factor analysis, we were able to identify low-, intermediate-, and high-risk patients. Low-risk patients were those without the risk factors mentioned above. They consisted of Stage II patients with T2aN0, T1N1, and T2aN1 categories and of Stage III patients with T1N2 and T2aN2 categories. Their risk of recurrence is low (4%). Intermediate-risk patients were those with at least one univariate risk factor. They are Stage II patients with T2bN0 and T2bN1 categories and Stage III patients with T2bN2 and T3N0-2 categories. The risk of recurrence is modest (18%). High-risk patients have risk factors by multivariate analysis. They are stage T4 or N3 patients. Their risk of recurrence is high (36%). CONCLUSION: Low-risk patients have an excellent outcome. Future trials should focus on reducing treatment-associated toxicities and complications and reevaluate the benefit of sequential adjuvant chemotherapy. The recurrence in treatment of intermediate-risk patients is modest; CCRT and adjuvant chemotherapy may be the best standard for them. Patients with T4 and N3 disease have poorer prognosis. Hyperfractionated radiotherapy may be considered for the T4 patients. Future study in these high-risk patients should also address the problem of distant spread of the disease.

Long-term survival of nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy.

PURPOSE: The purpose of this study is to demonstrate long-term survival of nasopharyngeal carcinoma treated with concomitant chemotherapy and radiotherapy (CCRT) followed by adjuvant chemotherapy. METHODS AND PATIENTS: One hundred and seven patients with Stage III and IV (American Joint Committee on Cancer, AJCC, 1988) nasopharyngeal carcinoma (NPC) were treated with concomitant chemotherapy and radiotherapy (CCRT) followed by adjuvant chemotherapy between April 1990 and December 1997 in Koo Foundation Sun Yat-Sen Cancer Center, Taipei. The dose of radiation was 70 Gray (Gy) given in 35 fractions, 5 fractions per week. Two courses of chemotherapy, consisting of cisplatin and 5-fluorouracil, were delivered simultaneously with radiotherapy in Weeks 1 and 6 and two additional monthly courses were given after radiotherapy. According to the AJCC 1997 staging system, 32 patients had Stage II disease, 44 had Stage III, and 31 had Stage IV disease. RESULTS: With median follow-up of 44 months, the 5-year overall survival rate in all 107 patients was 84.1%, disease-free survival rate was 74.4%, and locoregional control rate was 89.8%. The 3-year overall survival for Stage II was 100%, for Stage III it was 92.8%, and for Stage IV, 69. 4% (p = 0.0002). The 3-year disease-free survival for Stage II was 96.9%, for Stage III it was 87.7%, and for Stage IV it was 51.9% (p = 0.0001). CONCLUSION: CCRT and adjuvant chemotherapy is effective in Taiwanese patients with advanced NPC. The prognosis of AJCC 1997 Stage II and III disease is excellent, but, for Stage IV (M0), it is relatively poor. Future strategies of therapy should focus on high-risk AJCC 1997 Stage IV (M0) cohort.

Differential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist.

To investigate synaptic mechanisms underlying information processing in auditory cortex, we examined cholinergic modulation of synaptic transmission in a novel slice preparation containing thalamocortical and intracortical inputs to mouse auditory cortex. Extracellular and intracellular recordings were made in cortical layer IV while alternately stimulating thalamocortical afferents (via medial geniculate or downstream subcortical stimulation) and intracortical afferents. Either subcortical or intracortical stimulation elicited a fast, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive, monosynaptic EPSP followed by long-duration, polysynaptic activity. The cholinergic agonist carbachol suppressed each of the synaptic potentials to different degrees. At low concentrations (5 microM) carbachol strongly reduced (>60%) the polysynaptic slow potentials for both pathways but did not affect the monosynaptic fast potentials. At higher doses (10-50 microM), carbachol also reduced the fast potentials, but reduced the intracortically-elicited fast potential significantly more than the thalamocortically-elicited fast potential, which at times was actually enhanced. Atropine (0.5 microM) blocked the effects of carbachol, indicating muscarinic receptor involvement. We conclude that muscarinic modulation can strongly suppress intracortical synaptic activity while exerting less suppression, or actually enhancing, thalamocortical inputs. Such differential actions imply that auditory information processing may favor sensory information relayed through the thalamus over ongoing cortical activity during periods of increased acetylcholine (ACh) release.

Do cerebral potentials to magnetic stimulation of paraspinal muscles reflect changes in palpable muscle spasm, low back pain, and activity scores?

OBJECTIVE: Previous studies have shown that cortical-evoked potentials on magnetic stimulation of muscles are influenced by muscle contraction, vibration, and muscle spasm. This study was carried out to determine whether these potentials correlate with palpatory muscle spasm, patient symptoms, and disability in patients with low back pain. METHODS: A prospective observational study was performed on 13 subjects with a history of low back pain visiting an orthopedic hospital-based clinic. Patients were screened for serious pathologic conditions by an orthopedic surgeon. The patients were then evaluated for the presence of muscle spasm by one of the investigators who was blinded to the results of the evoked potential studies. Patients were asked to complete a low back pain visual analogue scale (VAS) and a Roland-Morris Activity Scale (RMAS). Cortical-evoked potentials were recorded with a magnetic stimulator placed over the lumbar paraspinal muscles with the patient in the prone position. The palpatory examination, VAS, RMAS, and the cortical potentials were repeated after 2 weeks of therapy commonly used to reduce muscle spasm. RESULTS: The patients demonstrated a significant decrease in low back pain VAS and RMAS scores after treatment compared with before treatment. There was a reduction in the amount of palpatory muscle spasm in 11 of 13 cases. The cortical potentials before treatment were attenuated compared with previously reported controls and showed a significant increase before and after treatment in the amplitude of these potentials with multivariate analysis of variance. There was significant correlation between the changes in cortical potentials after treatment and the changes noted in paraspinal muscle spasm and VAS and RMAS scores. CONCLUSIONS: This study confirms the previous report that the amplitude of cerebral-evoked potentials on magnetic stimulation of paraspinal muscles is depressed in the presence of palpable muscle spasm. The close correlation among these potentials, paraspinal muscle spasm, and clinical symptoms suggests that the measurement of muscle activity may be more important in the assessment of low back pain than is commonly accepted.

Lumbosacral transitional segments: classification, prevalence, and effect on disk height.

OBJECTIVE: To determine the rate of lumbosacral transitional segments among chiropractic practice settings and to determine if this anomaly would affect the height of the lumbosacral disk. STUDY DESIGN: Retrospective review of radiographs. SETTING: Los Angeles College of Chiropractic outpatient clinic and a private chiropractic office. SAMPLES: A total of 20 lumbar series with lumbosacral transitional segments from a private chiropractic office, 47 lumbar series with lumbosacral transitional segments, and 60 age- and sex-matched control series from a college clinic. RESULTS: A total of 2.3% of 882 lumbar series at the private chiropractic office and 6.5% of 786 lumbar series at the Whittier Health Center showed lumbosacral transitional segments of types II, III, or IV. The L5-S1 intervertebral disk height was significantly smaller in patients with lumbosacral transitional segments compared with those without (ie, 11% vs 19% of total lumbar disk height, respectively). When bilateral bony fusion of L5 to the sacrum was present, the L5-S1 disk height was significantly smaller than that without bony fusion (ie, 8% vs. 12% to 14% of total lumbar disk height, respectively). CONCLUSIONS: We conclude that the rate of occurrence of lumbosacral transitional segments is low in chiropractic practice. In the presence of lumbosacral transitional segments, especially when there was bony fusion, the lumbosacral intervertebral disk was significantly narrower than the upper lumbar disks, which should not be considered as disk degeneration or displacement. The type of lumbosacral transitional segment present also showed a significant effect on the height of the lumbosacral disk.

Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis.

Curcumin has been widely used as a spice and coloring agent in foods. Recently, curcumin was found to possess chemopreventive effects against skin cancer, forestomach cancer, colon cancer and oral cancer in mice. Clinical trials of curcumin for prevention of human cancers are currently ongoing. In this study, we examine the chemopreventive effect of curcumin on murine hepatocarcinogenesis. C3H/HeN mice were injected i.p. with N-diethylnitrosamine (DEN) at the age of 5 weeks. The curcumin group started eating 0.2% curcumin-containing diet 4 days before DEN injection until death. The mice were then serially killed at the scheduled times to examine the development of hepatocellular carcinoma (HCC) and changes in intermediate biological markers. At the age of 42 weeks, the curcumin group, as compared with the control group (DEN alone), had an 81% reduction in multiplicity (0.5 versus 2.57) and a 62% reduction in incidence (38 versus 100%) of development of HCC. A series of intermediate biological markers were examined by western blot. While hepatic tissues obtained from the DEN-treated mice showed a remarkable increase in the levels of p21(ras), PCNA and CDC2 proteins, eating a curcumin-containing diet reversed the levels to normal values. These results indicate that curcumin effectively inhibits DEN-induced hepatocarcinogenesis in the mouse. The underlying mechanisms of the phenomenon and the feasibility of using curcumin in the chemoprevention of human HCC should be further explored.

A prospective randomized three-week trial of spinal manipulation, transcutaneous muscle stimulation, massage and corset in the treatment of subacute low back pain.

STUDY DESIGN: A randomized prospective trial of manipulation, massage, corset and transcutaneous muscle stimulation (TMS) was conducted in patients with subacute low back pain. OBJECTIVES: The authors determined the relative efficacy of chiropractic treatment to massage, corset, and TMS. SUMMARY OF BACKGROUND DATA: Although all of these treatments are used for subacute low back pain treatment, there have been few comparative trials using objective outcome criteria. Patients were enrolled for a period of 3 weeks. They were evaluated once a week by questionnaires, visual analog scale, range of motion, maximum voluntary extension effort, straight leg raising and Biering-Sorensen fatigue test. The dropout rate was highest in the muscle stimulation and corset groups and lowest in the manipulation group. Rates of full compliance did not differ significantly across treatments. A measure of patient confidence was greatest in the manipulation group. RESULTS: After 3 weeks, the manipulation group scored the greatest improvements in flexion and pain while the massage group had the best extension effort and fatigue time, and the muscle stimulation group the best extension. CONCLUSION: None of the changes in physical outcome measures (range of motion, fatigue, strength or pain) were significantly different between any of the groups.

Range of motion of the lumbar spine required for four activities of daily living.

OBJECTIVE: To assess the range of motion of the lumbar spine required for four activities of daily living. DESIGN: Descriptive study. SETTING: Chiropractic college research laboratory. SUBJECTS: Forty-eight young and healthy subjects. INSTRUMENTATION: OSI CA-6000 computerized spinal motion analyzer. RESULTS: The intraclass correlation coefficient ranged from .99-.95 for peak flexion measurements. Stand-to-sit and sit-to-stand activities required approximately 56-66% of lumbar flexion. Putting on socks required about 90% of lumbar flexion. Picking an object off the floor required almost full lumbar flexion (95%). Analysis of variance showed significant differences among all four activities (p < .001). Scheffe tests revealed that the differences were found between sit/stand activities and picking up an object from the floor, and also between sit/stand activities and putting on socks. CONCLUSION: We showed that four activities of daily living could be reliably measured by an OSI CA-6000 motion analyzer. Putting on socks and picking up an object off the floor were found to require more lumbar flexion motion than sit/stand activities. Also, different strategies were observed in performing these activities. Future research shall address these activities and their changes in low back pain patients.

Functional outcomes of low back pain: comparison of four treatment groups in a randomized controlled trial.

The revised Oswestry Low Back Pain Questionnaire (ROLBPQ) and Roland-Morris Activity Scale (RMAS) were compared in a randomized controlled trial of chiropractic manipulation, stroking massage, corset and transcutaneous muscular stimulation (TMS). This trial employed specific inclusion and exclusion criteria, including nonspecific low back pain for a duration of 3 wk to 6 months and ages between 18 and 55. We had the opportunity to ask 85 patients to answer the questionnaires. Sixty-three patients, who completed the initial and final evaluations, were used for data analysis. Both ROLBPQ and RMAS showed good internal consistency with alpha coefficients ranging from .77 to .93. Both instruments showed a significant difference between the chiropractic manipulation and massage groups (p less than .05). RMAS was able to further show significant differences between the chiropractic manipulation and TMS groups, and between the corset and massage groups, but the ROLBPQ failed to do so. RMAS also showed that chiropractic manipulation had a better but nonsignificant result than corset, possibly due to insufficient sample size and/or duration of treatment. We conclude that both instruments are reliable for measuring low back pain disability, and chiropractic manipulation has a superior short-term benefit when compared to stroking massage and TMS in subacute low back pain patients. In addition, it appears that RMAS is preferable in a clinical trial situation for subacute low back pain because it is more sensitive than ROLBPQ to detect changes.

Forefoot pain associated with muscle strain in the lower extremity.

A case of forefoot pain at the first metatarsophalangeal joint is discussed. Local treatment with ultrasound failed to bring significant relief. However, dramatic and lasting relief occurred when treatment was applied to the muscle belly of the extensor hallucis longus. The patient also suffered from hallux valgus with mild foot pronation. Two years after therapy, the patient stated she had not experienced any foot pain since the last treatment, and she continued to wear the prescribed flexible foot orthotics on a daily basis.

Reliability of manual muscle testing with a computerized dynamometer.

The purpose of this study was to investigate the reliability of manual dynamometry. Three testers participated and performed the doctor- and patient-initiated testing methods as described in the applied kinesiology literature. Three muscles from each subject were tested. Fifteen normal volunteer adults had their muscles tested by the doctor-initiated method and another 15 had their muscles tested by the patient-initiated method. Each tester took two observations per muscle. The testing procedures were repeated 7 days later. The results showed that the intratester reliability coefficients were 0.55, 0.75 and 0.76 for testers 1, 2 and 3, respectively, when the doctor-initiated method was used; 0.96, 0.99 and 0.97 when the patient-initiated method was used. The intertester reliability coefficients were 0.77 and 0.59 on day 1 and day 2, respectively, for the doctor-initiated method; 0.95 and 0.96 for the patient-initiated method. It is concluded that manual dynamometry is an acceptable procedure for the patient-initiated method and is not acceptable for the doctor-initiated method.