Vitamin D3 Supplementation Promotes Regulatory T-Cells to Maintain Immune Homeostasis After Surgery for Early Stages of Colorectal Cancer.

BACKGROUND/AIM: Vitamin D3 (VD3) affects the regulation of the immune system, including the differentiation and function of regulatory T-cells (Tregs). Tregs play an important role in maintaining immune homeostasis in patients with colorectal cancer (CRC). The effects of VD3 on Treg-associated immune function were investigated in Thai patients in the early stages of CRC. MATERIALS AND METHODS: Twenty-eight patients were randomized to one of two groups: Untreated or treatment with VD3 for 3 months. Whole blood samples were collected at baseline, and at 1 and 3 months. Peripheral blood mononuclear cells were isolated and the populations of forkhead box P3-positive Treg cells was analyzed by flow cytometry. The levels of Treg-associated cytokines, interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-ß1), were measured by enzyme-linked immunosorbent assays. RESULTS: Serum VD3 levels of the VD3-treated group were significantly increased at 1 (p=0.017) and 3 months (p<0.001) compared to the untreated control group. The mean percentage of Tregs was maintained between 1 and 3 months in the VD3-treated group. At 3 months, the untreated group had significantly lower Treg levels than the VD3-treated group (p=0.043). Serum IL-10 levels of the VD3-treated group were statistically increased at 1 month compared to the control group (p=0.032). No significant difference in serum TGF-ß1 levels was observed between the two groups. However, the TGF-ß1 level in the VD3-treated group at 1 month was lower than that of the control. CONCLUSION: Our findings suggest that VD3 supplementation can maintain immune responses in the early stages of CRC, helping to control Treg function. Therefore, VD3 should be supplemented to maintain immune homeostasis, especially in patients with vitamin D deficiency.

Validation of the Scored Patient-Generated Subjective Global Assessment (PG-SGA) in Thai Setting and Association with Nutritional Parameters in Cancer Patients

Background: The Scored Patient-Generated Subjective Global Assessment (PG-SGA) is a multidimensional tool to assess malnutrition and risk factors. The objectives of this study are to determine the validity of the Thai version of the Scored PG-SGA (Thai PG-SGA) and examine the correlations with selected nutritional parameters. Methods: This observational analytic study included 195 cancer patients aged greater than 18 years at a university-affiliated hospital in Bangkok, Thailand. All patients were assessed for nutritional status by Thai PG-SGA in comparison to subjective global assessment (SGA). Anthropometry, body composition, and hand grip strength were evaluated. Results: According to PG-SGA global assessment categories, 39% (75) of 195 cancer patients were well nourished, 27% (53) were moderately malnourished and 34% (67) of patients were severely malnourished. Thai PG-SGA had a sensitivity of 99.1% and a specificity of 86.0% at predicting SGA classification. PG-SGA numerical scores were significantly different between well-nourished and malnourished groups (4.2 ± 2.4 Vs 16.3 ± 4.9; p < 0.001). The PG-SGA scores, nutritional status assessed by PG-SGA, and nutritional status assessed by SGA were correlated with weight, % weight loss in one month, body mass index, body fat, and hand grip strength (p < 0.001) respectively. Conclusions: Thai PG-SGA showed high sensitivity and good specificity in predicting malnutrition in Thai cancer patients. This tool demonstrated the correlations with anthropometric parameters, body composition, and muscle strength.

Antianemic effect of once weekly regimen of epoetin alfa 40,000 units in anemic cancer patients receiving chemotherapy.

BACKGROUND: Anemia is a common problem in the cancer population that is the result of clinical consequences. It also has adverse effects on patients' perceived quality of life. Good management of anemia in the cancer population is therefore essential. A recent published clinical trial has demonstrated statistically significant increases in hemoglobin levels and significantly increased QOL assessment following the administration of recombinant erythropoietin. OBJECTIVE: To evaluate the effectiveness, the safety, and the quality of life by using once weekly dosing of Epoetin alfa (Eprex, Janssen-cilag) 40,000 units in the treatment of anemia in cancer patients receiving chemotherapy. SETTING: Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University Bangkok, Thailand. MATERIAL AND METHOD: This was an open label, non-randomized study, in 41 adult male and female anemic cancer patients who had non-myeloid malignancies in the upper area of the body part and hemoglobin ranging from 9-11 g/dL receiving chemotherapy at least 8 weeks with or without concurrent radiotherapy. The subjects were treated with Epoetin alfa 40,000 units once a week subcutaneously. If, the hemoglobin did not increase by > 1.0 g/dl after 4 weeks of treatment, the dose of Epoetin alfa was then increased to 60,000 units per dose subcutaneously at week 5. The Epoetin alfa treatment would continue for a total of 16 weeks. Clinical outcome was evaluated based on quality of life by using the linear analog scale assessment (LASA) and the functional assessment of cancer therapy-anemia (CU-QOL) instrument. Analyses were performed to determine the incremental change in QOL associated with hemoglobin increases. RESULTS: Seventy six percent of patients receiving Epoetin alfa subcutaneously showed good response with hemoglobin increases of > or = 1 g/dL (Hb level before and after = 9.82 +/- 0.78 g/dL and 12.56 +/- 1.49 g/dL, respectively; p < 0. 001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level and ability to do daily activities evaluated from LASA and fatigue assessed from CU-QOL, were significantly greater (p < 0.01) for week 16 (233.94 +/- 56.01 and 18.45 +/- 13.07) compared to the baseline (202.58 +/- 36.74 and 25.09 +/- 11.00). Epoetin alfa was well tolerated in all patients. CONCLUSION: Once weekly dosing of Epoetin alfa 40,000 units therapy is safe and effective in remodeling anemia and significantly improves the quality of life in cancer patients receiving chemotherapy. Therefore, the physician should maintain hemoglobin concentration of cancer patients in normal level to improve their quality of life through the chemotherapy period.

Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis.

Genome-wide losses of DNA methylation have been regarded as a common epigenetic event in malignancies and may play crucial roles in carcinogenesis. Limited information is available on the global methylation status in normal tissues and other cancer types beyond colonic carcinoma. Here we applied the combined bisulfite restriction analysis PCR to evaluate the methylation status of LINE-1 repetitive sequences in genomic DNA derived from microdissected samples from several human normal and neoplastic tissues. We found that methylation of LINE-1 in leukocytes was independent of age and gender. In contrast, normal tissues from different organs showed tissue-specific levels of methylated LINE-1. Globally, most carcinomas including breast, colon, lung, head and neck, bladder, esophagus, liver, prostate, and stomach, revealed a greater percentage of hypomethylation than their normal tissue counterparts. Furthermore, DNA derived from sera of patients with carcinoma displayed more LINE-1 hypomethylation than those of noncarcinoma individuals. Finally, in a colonic carcinogenesis model, we detected significantly greater hypomethylation in carcinoma than those of dysplastic polyp and histological normal colonic epithelium. Thus, the methylation status is a unique feature of a specific tissue type and the global hypomethylation is a common epigenetic process in cancer, which may progressively evolve during multistage carcinogenesis.

Global gene expression profile of nasopharyngeal carcinoma by laser capture microdissection and complementary DNA microarrays.

A number of genetic and epigenetic changes underlying the development of nasopharyngeal carcinomas have recently been identified. However, there is still limited information on the nature of the genes and gene products whose aberrant expression and activity promote the malignant conversion of nasopharyngeal epithelium. Here, we have performed a genome-wide transcriptome analysis by probing cDNA microarrays with fluorescent-labeled amplified RNA derived from laser capture microdissected cells procured from normal nasopharyngeal epithelium and areas of metaplasia-dysplasia and carcinoma from EBV-associated nasopharyngeal carcinomas. This approach enabled the identification of genes differentially expressed in each cell population, as well as numerous genes whose expression can help explain the aggressive clinical nature of this tumor type. For example, genes indicating cell cycle aberrations (cyclin D2, cyclin B1, activator of S-phase kinase, and the cell cycle checkpoint kinase, CHK1) and invasive-metastatic potential (matrix metalloproteinase 11, v-Ral, and integrin beta(4)) were highly expressed in tumor cells. In contrast, genes underexpressed in tumors included genes involved in apoptosis (B-cell CLL/lymphoma 6, secretory leukocyte protease inhibitor, and calpastatin), cell structure (keratin 7 and carcinoembryonic antigen-related cell adhesion molecule 6), and putative tumor suppressor genes (H-Ras-like suppressor 3, retinoic acid receptor responder 1, and growth arrested specific 8) among others. Gene expression patterns also suggested alterations in the Wnt/beta-catenin and transforming growth factor beta pathways in nasopharyngeal carcinoma. Thus, expression profiles indicate that aberrant expression of growth, survival, and invasion-promoting genes may contribute to the molecular pathogenesis of nasopharyngeal carcinoma. Ultimately, this approach may facilitate the identification of clinical useful markers of disease progression and novel potential therapeutic targets for nasopharyngeal carcinoma.

Phase II trial of ramosetron plus dexamethasone in the prevention of cisplatin-induced nausea and vomiting.

OBJECTIVE: To evaluate the clinical efficacy of ramosetron hydrochloride in the combination with dexamethasone for the prevention of nausea and vomiting induced by cisplatin. MATERIAL AND METHOD: Thirty in-patients with malignant tumor being treated with cisplatin at a dose of 70 mg/m2 or more for a total of 94 cycles were scheduled to receive ramosetron 0. 3 mg IV given 30 minutes before chemotherapy and dexamthasone 20 mg IV on day 1 for the prevention of acute emesis and continued with ramosetron tablet 0.1 mg one tablet orally one hour before chemotherapy or in the morning in case of no chemotherapy scheduled and dexamethasone capsule 5 mg 2 capsules twice daily on day 2 to day 5 for the prevention of delayed emesis. The evaluation period started concomitantly with the start of chemotherapy (hour 0) and continued until 24 hours after completion of chemotherapy. The antiemetic efficacy of ramosetron plus dexamethasone was analyzed according to the occurrence of nausea and vomiting within 24 hours of treatment cycle. The study emphasized both on acute and delayed emesis control. ASSESSMENT: The degree of severity of nausea was determined according to the following criteria: 0: None: nausea does not occur, 1: Mild: slight nausea but no disruption to daily acitivites, 2: Moderate: nausea and some disruption to daily activities, 3: Severe: extreme nausea and severe disruption to daily activities. The control of vomiting episodes was determined according to the frequency of vomiting (including retching) as the following criteria: Complete: 0 emesis episode, Major: 1-2 emesis episodes, Minor: 3-5 emesis episodes, Failure: > 5 emesis episodes. RESULTS: The result of all 94 cycles of the first day of treatment on acute emesis (0-24 hours) were none 80.9%, mild 18.1%, and moderate 1.1% for nausea episode. For the vomiting control were complete 81.9%, major 16%, minor 1.1% and failure 1.1% respectively. The efficacy of the prevention of delayed emesis (day 2 to day 5) for nausea episode were 67%, 66%, 70.2%, and 75.5% no nausea respectively. For the vomiting control were 75.5%, 74.5%, 86.2%, and 88.3% complete control on day 2 to day 5. No serious adverse events occurred. Hiccups, constipation, and dull headache were reported as the common side effects of ramosetron. CONCLUSION: Ramosetron combined with dexamethasone is effective for the prevention of both acute and delayed emesis associated with cisplatin. The prevention of acute emesis seems to be more effective than the prevention of delayed emesis. Adverse events were mild. No serious side effects occurred in the present study.

Clinical benefits of epoetin alfa (Eprex) 10,000 units subcutaneously thrice weekly in Thai cancer patients with anemia receiving chemotherapy.

BACKGROUND: Recently the American society of clinical oncology and the American society of hematology have jointly launched the clinical practice guideline of epoetin usage in cancer related anemia patients The recommended starting dose is 150-300 unit/kg thrice weekly. The clinical outcome of epoetin alfa 10,000 units subcutaneously thrice weekly regimen has not been evaluated in Thai cancer patients with anemia yet. OBJECTIVES: To determine the clinical benefits and safety of epoetin alfa (Eprex) 10,000 units subcutaneously thrice weekly in anemic cancer patients receiving chemotherapy PATIENTS: The present study was an open label, non-randomized study. Adult patients were eligible for inclusion aged >18 years with a confirmed diagnosis of non-myeloid malignancy in the upper area of the body and scheduled to receive chemotherapy regardless of the concurrent radiotherapy. All patients had hemoglobin (Hb) level less than 11 g/dL, serum ferritin more than 100 ng/dL and had a life expectancy of at least 6 months. MATERIAL AND METHOD: All patients were initially treated with Epoetin alfa 10,000 units subcutaneously thrice weekly. The dose was up to 20,000 units after 4 weeks of therapy, if Hb level did not increase by > 1.0 g/dL. Treatment time was 16 weeks. Target Hb was 12 g/dL Blood transfusion and iron supplement was permitted. Efficacy Assessments: The primary efficacy end point was the proportion of responders (patients with an increase in Hb > or =1 g/dL). Secondary efficacy evaluation was change in Quality of life (QOL) scores by the Linear Analog Scale Assessment (LASA) and Quality of life-Chula (QOL-CU) scale. Statistical Analysis was t-tests, P < 0.05 was considered significant. RESULTS: Forty patients (21 men and 19 women) were enrolled. Twenty five patients (62.5%) had stage of disease in grade III or IV The mean Hb levels at baseline were 8.46 +/- 1.28 g/dL. Eight patients (20%) refused to complete the course during the study. Reasons for refusing to participate included lack of time, changing the resident area or disease progression. Twenty three of 32 patients (71.8%) were responders. These patients completed the study course and showed good response. Their mean Hb levels increased gradually and reach approximately 11 g/dl by week 4 and were maintained through week 16. The significant difference in mean Hb level of baseline was initially found at week 4 of the study (10.26 +/- 1.95 g/dl; p = 0.001 vs baseline). The LASA score increased in all of three items including level of energy, ability to do daily activities, and overall QOL but not statistical significance. However, the improvement of quality of life of cancer patients, evaluated by QOL-CU, was significantly apparent after treatment, (p < 0.05). The most common adverse events were grade I flu like symptoms (17.5%) and recovered the next day. CONCLUSION: Epoetin alfa (Eprex) 10,000 units thrice weekly significantly increased the hemoglobin levels, achieving the target hemoglobin and sustained the level in cancer patients with anemia receiving chemotherapy. Clinical benefits on functional status and quality of life were also improved. The treatment was well tolerated.

Histopathologic characteristics of pulmonary adenocarcinomas with and without EGFR mutation.

UNLABELLED: EGFR mutation played crucial role for responsiveness of non-small cell lung cancers to EGFR tyrosine kinase inhibitors. Almost the mutations were present in adenocarcinomas. Few had studied on histopathologic correlation with EGFR mutation in pulmonary adenocarcinomas. To obtain better view on pathobiology of pulmonary adenocarcinomas, we correlated exons 19 and 21 mutations with various histopathologic features by dissecting particular histological patterns from 60 surgically resected adenocarcinomas. RESULTS: Gland-forming pattern, including bronchiloloalveolar carcinoma (BAC), well-formed acinar, and poorly-formed acinar patterns more frequently contains EGFR mutations than solid pattern (72.7% vs. 23.1%, p = 0.002). EGFR mutations of each within the gland-forming pattern are not significantly different. Micropapillary pattern revealed less exon 19 mutations than the gland-forming pattern (12.5% vs. 66.7%, p = 0.018), but tended to have more Exon 21 mutations than the others (33.3% vs. 11.9%, p = 0.10). Tumors predominated by BAC pattern more commonly had exon 19 mutations than non-BAC predominated tumors (68.8% vs. 39.5%, p = 0.046). EGFR-mutated tumors comprised less proportion of papillary pattern than tumors without mutation (mean = 1.5% vs. 11.2%, p = 0.049). Terminal respiratory unit (TRU) histology was associated with more EGFR mutations (72.4% vs. 42.1%, p = 0.036). Tumors smaller than 3.5 cm had more EGFR mutations than larger tumors (73.1% vs. 41.9%, p = 0.018). CONCLUSION: High frequency of the mutation does not present only in BAC pattern, but also in well-formed and poorly-formed acinar patterns, suggesting them as usual spectrum of EGFR mutated adenocarcinomas. Other characteristics of EGFR-mutated adenocarcinomas include TRU-type histology, smaller size, and less solid phenotype.

Polymeric immunoglobulin receptor polymorphisms and risk of nasopharyngeal cancer.

BACKGROUND: Epstein-Barr virus (EBV) associated nasopharyngeal cancer (NPC) is an important squamous cell cancer endemic in Southeast Asia and the Far East and can be considered a multifactorial genetic disease. This research explores potential associations between nasopharyngeal epithelial EBV receptor and NPC susceptibility. To prove the hypothesis, we evaluated two candidate genes, complement receptor 2 (CR2) and polymeric immunoglobulin receptor (PIGR) by using 4 SNPs, CR2IVS2-848C-->T, PIGRIVS3-156G-->T, PIGR1093G-->A and PIGR1739C-->T, to genotype 175 cases and 317 controls, divided into Thai, Chinese and Thai-Chinese based on their respective ethnic origins. RESULTS: The results obtained indicated that PIGR is an NPC susceptibility gene. The risk association pertaining to each ethnic group was detected for homozygous PIGR1739C with a significant ethnic group adjusted OR (95%CI) of 2.71(1.72-4.23) and p < 0.00001. Haplotype of the two missense PIGR SNPs, 1093G-->A and 1739C-->T, and sequence analyses have confirmed the role of the nucleotide PIGR1739 and excluded possibility of an additional significant nonsynonymous NPC susceptibility SNP. CONCLUSIONS: We present genetic evidence leading to hypothesize a possibility of PIGR to function as the EBV nasopharyngeal epithelium receptor via IgA-EBV complex transcytosis failure. The PIGR1739C-->T is a missense mutation changing alanine to valine near endoproteolytic cleavage site. This variant could alter the efficiency of PIGR to release IgA-EBV complex and consequently increase the susceptibility of populations in endemic areas to develop NPC.

Pattern of local-regional recurrence in patient with early breast cancer after mastectomy: an analysis of 357 cases at King Chulalongkorn Memorial Hospital.

A retrospective review was performed on 357 patients with early stage I-IIIA operable breast cancer who were treated with mastectomy and referred to the clinic at the Division of Radiation Therapy, Department of Radiology, King Chulalongkorn Memorial Hospital between Jan 1991 and Dec 2001. Patients characteristics, treatment modalities and pattern of local and regional failure were evaluated. The median and mean age in the present study were 49 and 50.2 years, respectively. Stage I, II and IIIA were 10.9%, 79.6% and 9.5%, respectively. One hundred and ninety-seven patients (55.2%) received postoperative radiation therapy (RT). Adjuvant chemotherapy was given in 247 patients (69.2%) while 122 patients (34.2%) received adjuvant hormonal therapy. Sixty one patients (17.1%) received both adjuvant chemotherapy and hormonal therapy. However, 12.6% (45/357) did not receive any adjuvant treatment. Median follow up time was 42.6 months (range 6-136 months). Ipsilateral supraclavicular node and chest wall were the most common sites of local-regional recurrence. The chest wall recurrence rate was 10.4% (37/357), which was 16.9% (27/160) in the non postoperative radiation (No RT) group and 5.1% (10/197) in the postoperative radiation (RT) group. For ispilateral supraclavicular node, the recurrence rate was 10.6% (38/357), which was 15.6% (25/160) and 6.6% (13/197) for non RT and RT groups, respectively. The incidence of ipsilateral axilla, ipsilateral internal mammary node and ipsilateral infraclavicular node recurrence rate were 4.2%, 3.6% and 0.8%, respectively. Overall, chest wall and ipsilateral supraclavicular node were the most common sites of local-regional recurrence in early stage operable breast cancer who underwent mastectomy Postoperative adjuvant radiation therapy decreased the risk of local-regional recurrence.

Retrospective review of extra-pulmonary small cell carcinoma at King Chulalongkorn memorial hospital cases during 1998-2005.

OBJECTIVE: The aim of this study was to review cases of extra-pulmonary small cell carcinoma (EPSCC), including their clinical manifestations and treatment outcomes. METHODS: We retrospectively reviewed the medical records and pathological reports of patients who were diagnosed with EPSCC from 1998 to 2005. RESULTS: Overall 21 EPSCC patients were eligible for this study. The most common primary sites were the gastrointestinal organs and the nasal cavity. Eleven patients (52.3%) had limited disease (LD) and 10 patients (47.7%) had extensive disease (ED). Nine patients underwent radical surgery alone, four received only radical radiation and two received only palliative chemotherapy. Two patients received adjuvant radiation or chemotherapy following surgical resection and one received a combination of all three treatment modalities. Three patients declined specific treatment and were treated with best supportive care. The median overall survival in the ED group was only 3 months (range 1-16 months), compared to 30 months (range 20-61 months) for LD. EPSCC of pancreas demonstrated a favorable clinical outcome with treatment, whereas primary EPSCC of the liver, esophagus and rectum had an aggressive natural history and a poor response to treatment. CONCLUSION: Our report suggests that EPSCC may have a different biology from that of pulmonary small cell carcinoma. When detected at an early stage, EPSCC may have an excellent prognosis with treatment. Additional studies involving more patients with EPSCC are warranted to further define the optimal roles of each treatment modality.