Revision adenoidectomy in children: a meta-analysis.

BACKGROUND: To estimate the rate of revision surgery after previous adenoidectomy in children and to compare the rate of revision adenoidectomy in children with different conditions and by using different surgical techniques. METHODOLOGY: The study protocol was registered on PROSPERO (CRD42018107877). Two authors independently searched databases, specifically PubMed, MEDLINE, EMBASE, and the Cochrane Review database. The keywords used were "adenoids","adenoidectomy","reoperation","revision"and "regrowth". The revision rate was pooled using a random-effect model. Subgroup analyses were conducted for children based on different settings, countries, risks of bias, and surgical techniques. RESULTS: A total 16 studies with 95 727 children were analyzed (mean age: 4.69 (1.62) years; 60% boys; sample size: 5983 patients). Five studies had a low risk of bias, 10 studies had a moderate risk of bias, and one study had a high risk of bias. The rate of revision adenoidectomy was 1.9%. Ages at initial surgery and follow-up were not significantly associated with revision surgeries. The revision rate was not significantly different in children receiving surgeries in different settings (single center vs multicenter vs population-based, country (non-United States vs United States, and risk of bias. Moreover, surgical techniques, such as curettage, suction cautery, microdebridement, and coblation did not significantly affect revision rates in children who received adenoidectomy. CONCLUSIONS: Revision surgery was undertaken with a frequency of 1.9% in children who underwent adenoidectomy. A lack of strong evidence exists to correlate surgical techniques with revision rate in pediatric adenoidectomy.

Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study.

Background: Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods: This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results: In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion: Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information: NCT00201396.

Prognostic factors for the outcome of extracorporeal shockwave therapy for calcific tendinitis of the shoulder.

AIMS: We conducted a study to identify factors that are prognostic of the outcome of extracorporeal shockwave therapy (ESWT) for calcific tendinitis of the shoulder. PATIENTS AND METHODS: Since 1998, patients with symptomatic calcific tendinitis of the rotator cuff have been treated with ESWT using an electrohydraulic mode shockwave device. One year after ESWT, patients were grouped according to the level of resorption of calcification. RESULTS: Of 241 symptomatic shoulders, complete resorption (CR) of calcification occurred in 134 (CR group). The remaining 107 shoulders had incomplete resorption (ICR) (ICR group). Gartner type I calcification was most common (64.5%) in the ICR group. The mean duration of symptoms before ESWT was significantly longer in the ICR group. Overall, 81% of the CR group and 23.4% of the ICR group were symptom free. There was a strong relationship between subsidence of symptoms and remission of calcification. Poor prognosis was significantly related to Gartner type I calcification, calcification extent > 15 mm and duration of symptoms > 11 months. CONCLUSION: Patients with calcific tendinitis of the shoulder who have the factors identified for a poor outcome after ESWT should undergo a different procedure. Cite this article: Bone Joint J 2017;99-B:1643-50.

Neuropeptide Y mediates glucocorticoid-induced osteoporosis and marrow adiposity in mice.

UNLABELLED: Increased neuropeptide Y (NPY) expression occurred in the glucocorticoid-induced osteoporotic skeleton. NPY knockout mice exhibited a minor response to the glucocorticoid-mediated exacerbation of bone accretion and fatty marrow pathogenesis. NPY deletion restored SITR1 signaling and enhanced PPARγ ubiquitination of bone tissue, an alternative strategy for ameliorating glucocorticoid-induced skeletal deterioration. INTRODUCTION: Glucocorticoid excess is observed to worsen the pathogenesis of osteoporosis and fatty marrow. This study was undertaken to investigate the contribution of neuropeptide Y (NPY) to glucocorticoid-induced bone loss and marrow adiposity. METHODS: NPY knockout and wild-type mice were administered methylprednisolone for four consecutive weeks. Bone mineral density, microarchitecture, and calcein-labeled mineral acquisition were quantified by µCT, dual energy X-ray absorptiometry, and histomorphometry. Expression of osteogenic and adipogenic markers and acetylation states of PPARγ were detected by RT-quantitative PCR, immunoprecipitation, and immunoblotting. RESULTS: High NPY levels were associated with glucocorticoid-induced trabecular bone deterioration and marrow fat accumulation. Mice lacking NPY had high bone mass concomitant with spacious trabecular and cortical bone microstructure. NPY deletion shielded skeletal tissues from the glucocorticoid-induced impediment of bone mass, trabecular morphometric characteristics, mineral accretion activity, and fatty marrow development. Ex vivo, NPY deficiency sustained osteogenic differentiation capacity and curtailed the glucocorticoid-mediated escalation of adipocyte formation reactions of primary bone-marrow mesenchymal cells. NPY deletion appeared to modulate Y1 and Y2 receptors, sirtuin 1, ERK, and p38 signaling pathways, an effect that facilitated hypoacetylation and ubiquitination of adipogenic transcription factor PPARγ in the skeletal tissues exposed to glucocorticoid stress. CONCLUSIONS: NPY mediates the glucocorticoid-induced disturbance of mineral accretion and marrow adipogenesis through post-translational modification of PPARγ. This study brings a new molecular insight into the disintegration of adipogenic and osteogenic activities within glucocorticoid-mediated osteoporotic skeletons. Control of NPY is an alternative strategy to ameliorate glucocorticoid-induced bone destruction and fatty marrow.

Trismus, xerostomia and nutrition status in nasopharyngeal carcinoma survivors treated with radiation.

The aims of the study were to: (1) examine levels of trismus, xerostomia and nutritional status; (2) compare levels of trismus, xerostomia and nutritional status in patients with nasopharyngeal carcinoma (NPC) receiving different types of radiation modalities; and (3) identify factors related to NPC survivors' risk status for malnutrition and existing malnutrition. A cross-sectional study with consecutive sampling was conducted. NPC survivors were recruited from otolaryngology/oncology outpatient clinics in a medical centre in Northern Taiwan. Study measures included (1) Mandibular Function Impairment Questionnaire, (2) Xerostomia Questionnaire, (3) Mini Nutrition Assessment, (4) Hospital Anxiety and Depression Scale - Depression subscale, and (5) Symptom Severity Scale. A total of 110 subjects were recruited. Those receiving intensity-modulated radiation therapy had less trismus and xerostomia than patients receiving two-dimensional radiation therapy. Patients with female gender, advanced stage, completion of treatments within 1 year, higher levels of depression, more severe trismus and higher symptom severity tended to have malnutrition or were at risk of malnutrition. Trismus and xerostomia are long-term problems in some NPC survivors and may contribute to malnutrition. To better manage a patient's trismus and xerostomia and to enhance nutritional status, clinicians should develop a patient-specific care programme based on careful assessment and targeted measures to improve oral function and insure adequate nutritional intake.

Tag single nucleotide polymorphisms of alcohol-metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis.

Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol-metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital-based case-control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age- and gender-matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14-5.80] and 2.59 [1.79-3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21-113.29] and 70.08 [33.65-145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08-2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24-2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other environmental factors, like carcinogen consumption, in the screening analysis.

Intensity-modulated radiation therapy for T4 nasopharyngeal carcinoma. Treatment results and locoregional recurrence.

PURPOSE: The purpose of this work was to examine outcomes in patients with T4 nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Between 2007 and 2010, 154 patients with nonmetastatic T4 NPC were treated with IMRT to a total dose of 70 Gy in 33-35 fractions. In addition, 97% of patients received concurrent platinum-based chemotherapy. The median follow-up time was 52.8 months. RESULTS: The rates of 5-year actuarial locoregional control, distant metastasis-free survival, progression free-survival, and overall survival (OS) were 81.2, 72.2, 61.9, and 78.1%, respectively. A total of 27 patients had locoregional recurrence: 85.2% in-field failures, 11.1% marginal failures, and 3.7% out-of-field failures. Fourteen patients with locoregional recurrence received aggressive treatments, including nasopharyngectomy, neck dissection, or re-irradiation, and the 5-year OS rate tended to be better (61.9%) compared to those receiving conservative treatment (32.0%, p=0.051). In patients treated with 1 course of radiotherapy, grade ≥3 toxicities of ototoxicity, neck fibrosis, xerostomia, epistaxis, and radiographic temporal lobe necrosis occurred in 18.2, 9.8, 6.3, 2.1, and 5.6% of patients, respectively. Increased ototoxicity, osteonecrosis, severe nasal bleeding, and temporal necrosis were observed in patients treated by re-irradiation. CONCLUSION: IMRT offers good locoregional control in patients with T4 NPC. For patients with locoregional recurrence after definitive radiotherapy, aggressive local treatment may be considered for a better outcome.

Salivary cortisol, 17ß-estradiol, progesterone, dehydroepiandrosterone, and α-amylase in patients with burning mouth syndrome.

OBJECTIVE: The aim of this study was to investigate salivary markers related with burning mouth syndrome (BMS). MATERIALS AND METHODS: Thirty female patients with BMS and twenty female control subjects were included. Unstimulated (UWS) and stimulated whole saliva samples (SWS) were collected, and their flow rates were determined. Salivary levels of cortisol, 17ß-estradiol, progesterone, dehydroepiandrosterone (DHEA), and enzymatic activity of α-amylase were determined. Salivary transferrin level was measured to determine the level of blood contamination in saliva samples. RESULTS: The levels of all analytes in UWS were significantly correlated with those of SWS. The levels of 17ß-estradiol, progesterone, and DHEA in UWS were significantly correlated with age. Age-matched comparisons revealed that the patient group had significantly higher levels of cortisol in UWS and of 17ß-estradiol in SWS. When the patients were divided into older (≥60years) and younger (<60years) groups, the older group showed a significantly lower level of progesterone in UWS. There were no significant relationships between treatment efficacy and levels of salivary analytes. CONCLUSIONS: In conclusion, patients with BMS showed significantly higher levels of cortisol in UWS and of 17ß-estradiol in SWS compared with controls.

Clinical characteristics and risk of melanoma development from giant congenital melanocytic naevi in Korea: a nationwide retrospective study.

BACKGROUND: Giant congenital melanocytic naevi (GCMN) are known risk factors for the development of melanoma. However, melanoma risk among Asians is rarely evaluated. OBJECTIVES: To evaluate the clinical characteristics and risk of melanoma development from GCMN in Koreans, we performed a nationwide retrospective cohort study in Korea. GCMN were defined as those comprising ≥5% body surface area in children or measuring ≥20cm in adults. METHODS: In total, 131 patients with GCMN were enrolled, with a mean age of 10·3years (range: birth-70years). RESULTS: The posterior trunk was the most common site (67, 51·1%), followed by lateral trunk, anterior trunk, legs, both anterior and posterior trunk, buttocks, and arms. Satellite naevi were present in 69 cases (52·7%), and axial areas were more commonly involved in patients with satellite naevi than in those without satellite lesions. Atypical features such as rete ridge elongation and bridges were seen, and, among these, pagetoid spread and ballooning cell changes were more common in patients <4years old. Proliferative nodules were found in three cases. Melanomas had developed in three of 131 patients (2·3%; a 6-year-old girl, a 14-year-old girl and a 70-year-old man), and the incidence rate was 990 per 100000 person-years. Melanomas in these three patients consisted of two cutaneous melanomas and one extracutaneous meningeal melanoma. CONCLUSIONS: We should be aware of melanoma development from GCMN, and lifelong follow-up is required due to the risk of melanoma arising in GCMN.

Salivary flow rate and clinical characteristics of patients with xerostomia according to its aetiology.

The purpose of the present study was to investigate the differences in salivary flow rates and dry mouth-related subjective symptoms and behaviours in patients with xerostomia according to its aetiology. One hundred and forty patients (24 men and 116 women, mean age, 58.1 +/- 13.3 years) with a chief complaint of xerostomia were included. The patients were divided into five groups; Sjögren's syndrome (n = 34), post-radiation therapy in the head and neck region (n = 16), antipsychotic medications (n = 30), systemic diseases or medications affecting salivary flow (n = 35), and unknown aetiology (n = 25). The patients were asked a standardized series of questions concerning dry mouth, and their whole salivary flow rates were measured. Patients with a history of radiation therapy displayed the most decreased values of salivary flow rates and the most severe associated symptoms and behaviours while patients with unknown aetiology displayed the least decreased values of salivary flow rates and relatively favourable symptoms and behaviours. A burning sensation in the mouth was the most prevalent in patients with systemic diseases or those who were taking medications while altered taste perception was the most prevalent in patients taking antipsychotics. In conclusion, patients with xerostomia displayed various degrees of discomfort related to the quality of life according to the aetiology of their conditions.

Inflammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint.

OBJECTIVE: Dysregulated Wnt signaling appears to modulate chondrocyte fate and joint disorders. Dickkopf-1 (DKK1) regulates the pathogenesis of skeletal tissue by inhibiting Wnt actions. This study examined whether DKK1 expression is linked to chondrocyte fate in osteoarthritis (OA). METHOD: Articular cartilage specimens harvested from nine patients with knee OA and from six controls with femoral neck fracture were assessed for DKK1, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), Bad, Bax, Bcl2 and caspase-3 expression by real time-polymerase chain reaction (RT-PCR) and immunohistochemistry. Apoptotic chondrocytes were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labelling (TUNEL) and 4', 6-dianidino-2-phenylindole dihydrochloride (DAPI) staining. Human chondrocyte cultures were treated with recombinant IL-1beta and monoclonal DKK1 antibody to determine whether DKK1 impairs chondrocyte survival. RESULTS: Expression of DKK1 correlated with inflammatory cytokine levels (IL-1beta and TNF-alpha expressions), proapoptosis regulators (Bad and caspase-3 expressions) and TUNEL staining in OA cartilage tissues. The IL-1beta induced expressions of DKK1, Bax, Bad and caspase-3-dependent apoptosis of chondrocyte cultures. Neutralization of DKK1 by monoclonal DKK1 antibody significantly abrogated IL-1beta-mediated caspase-3 cleavage and apoptosis and reversed chondrocyte proliferation. Recombinant DKK1 treatment impaired chondrocyte growth and promoted apoptosis. By suppressing nuclear beta-catenin accumulation and Akt phosphorylation, DKK1 mediated IL-1beta promotion of chondrocyte apoptosis. CONCLUSION: Chondrocyte apoptosis correlates with joint OA. Expression of DKK1 contributes to cartilage deterioration and is a potent factor in OA pathogenesis. Attenuating DKK1 may reduce cartilage deterioration in OA.

Role of ultrasound-guided fine needle aspiration in assessing the impalpable cervical node with increased 18F-fluorodeoxyglucose uptake on positron emission tomography scanning: preliminary communication.

OBJECTIVES: 18F-Fluorodeoxyglucose positron emission tomography can detect cervical metastases before they are palpable. However, false positive results are not uncommon. This paper reports the use of ultrasound-guided fine needle aspiration to determine the nature of impalpable cervical nodes that are positive on positron emission tomography scanning. METHODS: Ultrasound-guided fine needle aspiration was performed in 10 cancer patients with suspicious cervical nodes revealed by positron emission tomography scan. Clinical data were retrospectively reviewed. RESULTS: The underlying cancers included lung cancer (three patients), nasopharyngeal carcinoma (two), oesophageal cancer (two), buccal cancer (one), bladder cancer (one) and Langerhan's histiocytosis (one). The lymph nodes were located in the supraclavicular region in four patients, the level II region in four, the level IV region in one and the accessory chain in one. Cytological examination was positive for malignant cells in eight patients, all of whom received salvage treatment. Two of these patients died of distant metastases. Cytological examination revealed a benign or reactive lesion in two patients, who at the time of writing were alive and well, 19 and 36 months after examination. CONCLUSIONS: Ultrasound-guided fine needle aspiration is a minimally invasive procedure which enables cytological examination of suspicious cervical lymph nodes detected by positron emission tomography scanning, allowing further treatment to be planned.

Extracorporeal shockwave therapy shows regeneration in hip necrosis.

OBJECTIVES: The effect of shockwave in osteonecrosis of the femoral head (ONFH) is poorly understood. The purpose of this study was to investigate the regeneration effects of shockwave in ONFH. METHODS: This study consisted of 14 femoral heads from 14 patients undergoing total hip arthroplasty for ONFH. Seven patients with seven hips who received shockwave prior to surgery were designated as the study group, whereas, seven patients with seven hips who did not receive shockwave were assigned to the control group. Both groups showed similar demographic characteristics. The femoral heads were investigated with histopathological examination and immunohistochemical analysis with von Willebrand factor (vWF), VEGF, platelet endothelial cell adhesion molecule-1 (PECAM-1) also referred to as (CD 31) and vascular cell adhesion molecule (VCAM) for angiogenesis, and with proliferation cell nuclear antigen (PCNA), Dickkopf-1 (DKK1) and Winless 3a (Wnt 3) for bone remodelling and regeneration. RESULTS: In histopathological examination, the study group showed significantly more viable bone and less necrotic bone, higher cell concentration and more cell activities including phagocytosis than the control group. In immunohistochemical analysis, the study group showed significant increases in vWF (P < 0.01), VEGF (P = 0.0012) and CD 31 (P = 0.0023), Wnt3 (P = 0.008) and PCNA (P = 0.0011), and decreases in VCAM (P = 0.0013) and DKK1 (P = 0.0007) than the control group. CONCLUSIONS: Shockwave treatment significantly promotes angiogenesis and bone remodelling than the control. It appears that application of shockwave results in regeneration effects in hips with ONFH.

Induction chemotherapy with mitomycin, epirubicin, cisplatin, fluorouracil, and leucovorin followed by radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Survival in advanced nasopharyngeal carcinoma (NPC) is compromised by distant metastasis. Because mitomycin is active against hypoxic and G0 cells, which may help to eradicate micrometastasis, we investigated the effect of mitomycin-containing cisplatin-based induction chemotherapy. PATIENTS AND METHODS: Recruited for this study were American Joint Committee on Cancer (AJCC) 1992 staging system stage IV NPC patients with the following adverse features: obvious intracranial invasion, supraclavicular or bilateral neck lymph node metastasis, large neck node (> 6 cm), or elevated serum lactate dehydrogenase (LDH) level. Patients were given three cycles of chemotherapy before radiotherapy. The chemotherapy comprised a 3-week cycle of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL). RESULTS: From January 1994 to December 1997, 111 patients were recruited. The median follow-up period was 43 months. The actuarial 5-year overall survival rate was 70% (95% confidence interval [CI], 60% to 80%; n = 111). For patients having completed radiotherapy (n = 100), the 5-year locoregional control rate was 70% (95% CI, 55% to 84%) and the distant metastasis-free rate was 81% (95% CI, 73% to 89%). The 5-year distant metastasis-free rate of N3a and N3b disease of AJCC 1997 staging system were 79% (95% CI, 62% to 95%) and 74% (95% CI, 60% to 89%), respectively. By Cox multivariate analysis, high pretreatment serum LDH level (P = .04) and neck nodal enlargement before radiotherapy (P = .001) were adverse prognostic factors of survival. CONCLUSION: The good 5-year survival of N3 disease supports the effectiveness of induction MEPFL in the primary treatment of advanced NPC. Further investigation to incorporate concurrent chemoradiotherapy is warranted.

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.