Successful Treatment of Plaque Psoriasis with Allogeneic Gingival Mesenchymal Stem Cells: A Case Study.

Plaque psoriasis is the most common type of psoriasis that manifests as red scaly patches with white scales affecting body areas including scalp, elbows, knees, trunk, and buttocks. Although many treatment options are available including novel biologics, no cure is available. Mesenchymal stem cells (MSCs) have been safely used to treat a variety of human diseases. Allogeneic MSCs possess unique characteristics including hypoimmunogenicity, immunomodulatory, and anti-inflammatory properties, and they are currently being explored for potential therapeutic use for many systemic inflammatory diseases. The human gingival tissue is an easily accessible and obtainable source for the isolation of MSCs. MSCs from adult human gingiva are of fetal-like phenotype, multipotent, and easy to isolate and expand in vitro. Herein, we report a case of a 19-year-old man with a 5-year history of severe plaque psoriasis refractory to multiple topical and systemic therapies who was treated with allogeneic human gingival MSCs. Complete regression was achieved after 5 infusions with no adverse reaction occurred. The patient has been followed for three years and has remained disease free.

Efficacy and toxicity of pegylated liposomal doxorubicin-based chemotherapy in early-stage breast cancer: a multicenter retrospective case-control study.

AIM: PEGylated liposomal doxorubicin (PLD) has comparable efficacy and differing toxicity from conventional anthracyclines used to treat advanced breast cancer. This study compared disease-free survival and toxicity between PLD-based and conventional anthracycline-based regimens as adjuvant treatments for early-stage breast cancer. METHODS: We analyzed disease-free survival (DFS) rates, and adverse events in 102 women with early-stage (I-IIIa) breast cancer who received adjuvant PLD-based chemotherapy from 2002 to 2008. Each patient was matched for age, stage at diagnosis, HER-2 expression and hormone therapy use to a patient treated with an epirubicin-based regimen. Fisher's exact and Pearson's chi-square tests were used for categorical data analysis. Kaplan-Meier analysis and Cox regression models were used to analyze DFS. RESULTS: DFS at 5 years was 81.3% for PLD-based regimen and 82.3% for epirubicin-based regimen. This difference was not significant (p = 0.939). Stage IIIa disease was associated with a shorter DFS in univariate analysis (p = 0.048). In multivariate analysis that controlled for adjuvant treatment, age at diagnosis, stage, HER-2 expression, type of surgery and hormone and radiation therapy, stage IIIa disease (P = 0.023) and lack of hormone therapy (P = 0.024) were each independently associated with shorter DFS. Adverse events were evaluated, and with the exception of hand-foot syndrome, more grade 3 and 4 toxicities occurred in patients who received epirubicin-based regimens than in those given PLD-based regimens. CONCLUSION: For patients with early-stage breast cancer who received PLD-based adjuvant chemotherapy, 5-year DFS was comparable and toxicity was acceptable, yet different from those of patients who received epirubicin-based regimens.

Breast cancer quality of care in Taiwan in relation to hospital volume: a population-based cohort study.

AIM: To evaluate, compare and improve quality of care for patients with breast cancer at the institution and population level requires a standard set of core measures. We performed a population-based cohort study to examine the association between hospital volume and breast cancer core measures compliance in Taiwan. METHODS: Data were obtained from the Health Promotion Administration, Ministry of Health and Welfare, Taiwan. All women with a diagnosis of breast cancer between 2007 and 2011 were selected. Hospitals were divided into quartiles of hospital volume based on the total number of breast cancer surgery performed from 2007 to 2011. The core measure set that evaluates the quality of care for breast cancer included one preoperation and nine treatment-related indicators. RESULTS: Our final study population included 38 943 patients from 74 hospitals. An increase in hospital volume was associated with better core measures compliance as indicated by higher adherence rates. As compared with the lower quartiles (quartiles 1/2/3) of hospital volume, quartile 4 (high volume) showed significantly higher adherence rate in two indicators measured ("percentage of breast cancer patients whose diagnoses were histologically and cytologically confirmed before surgery" and "percentage of stage 1 and 2 patients with sentinel node sampling performed," P = 0.011 and 0.016, respectively). An increasing trend in compliance for "percentage of stage 1 patients who underwent breast conserving surgery" was observed in high-volume but not low-volume hospitals (P < 0.001). CONCLUSION: This institution and population-based study showed a certain degree of variation to core measures compliance among hospitals. In some aspects of pre- and postoperative care, high-volume hospitals demonstrated higher and more improved quality as supported by increased adherence rates. Further research is needed to determine whether better core measures compliance would result in better outcomes.

High chondroitin sulfate proteoglycan 4 expression correlates with poor outcome in patients with breast cancer.

Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified in melanoma cells, has been reported to be expressed in breast cancer cells. This study was performed to examine the expression and significance of CSPG4 in a cohort of breast cancer patients. Immunohistochemical analysis of CSPG4 was performed on tissue microarrays constructed from tissue specimens from 240 breast cancer patients. CSPG4 staining was correlated with clinical and pathological characteristics, overall survival (OS), and disease recurrence. Contradicting to a previous report, our results showed that high CSPG4 expression was not related to triple-negative status of breast cancer patients. The Kaplan-Meier method showed that high CSPG4 expression was significantly associated with shorter time to recurrence (TTR). Patients with high CSPG4 expression had poorer OS and shorter TTR in a multivariate survival analysis after adjustment for stage, tumor grade, expression of estrogen receptor and progesterone receptor, and HER2 overexpression. This study showed that high CSPG4 expression correlates with disease recurrence and OS in breast cancers.

Methylation of BRCA1 promoter region is associated with unfavorable prognosis in women with early-stage breast cancer.

BRCA1-associated breast cancers are associated with particular features such as early onset, poor histological differentiation, and hormone receptor negativity. Previous studies conducted in Taiwanese population showed that the mutation of BRCA1 gene does not play a significant role in the occurrence of breast cancer. The present study explored methylation of BRCA1 promoter and its relationship to clinical features and outcome in Taiwanese breast cancer patients. Tumor specimens from a cohort of 139 early-stage breast cancer patients were obtained during surgery before adjuvant treatment for DNA extraction. Methylation of BRCA1 promoter region was determined by methylation-specific PCR and the results were related to clinical features and outcome of patients using statistical analysis. Methylation of the BRCA1 promoter was detected in 78 (56%) of the 139 tumors. Chi-square analysis indicated that BRCA1 promoter methylation correlated significantly with triple-negative (ER-/PR-/HER2-) status of breast cancer patients (p = 0.041). The Kaplan-Meier method showed that BRCA1 promoter methylation was significantly associated with poor overall survival (p = 0.026) and disease-free survival (p = 0.001). Multivariate analysis which incorporated variables of patients' age, tumor size, grade, and lymph node metastasis revealed that BRCA1 promoter methylation was associated with overall survival (p = 0.027; hazard ratio, 16.38) and disease-free survival (p = 0.003; hazard ratio, 12.19) [corrected].Our findings underscore the clinical relevance of the methylation of BRCA1 promoter in Taiwanese patients with early-stage breast cancer.

Expression of Eps8 correlates with poor survival in oral squamous cell carcinoma.

AIMS: Epidermal growth factor receptor pathway substrate 8 (Eps8) is a signaling protein implicated in the development of many human cancers including oral squamous cell carcinoma (OSCC). This study examined the expression of Eps8 and assessed its significance in patients with OSCC. METHODS: Immunohistochemical staining for Eps8 was conducted in 205 cases of OSCC collected over 7 years. The results were analyzed and correlated with patients' clinical outcomes. RESULTS: We identified Eps8 expression in 186 of the 205 cases of OSCC (91%) and the aberrance occurred primarily in the cytoplasm of OSCC cells. Univariate analysis revealed that patients with Eps8 expression had significantly poorer 5-year overall survival (OS) than those without it (43% vs 74%, P = 0.014). Eps8 expression was also identified as an independent predictive factor for poorer OS by a multivariate analysis in regression modeling (P = 0.021, HR = 2.7). A Kaplan-Meier analysis showed that patients with positive Eps8 expression had a significantly poorer OS than patients with negative/low Eps8 expression (P = 0.038). The difference in disease-free survival between positive Eps8 expression and negative/low Eps8 expression nearly reached statistical significance (P = 0.051). CONCLUSION: Eps8 is frequently expressed in OSCC. The aberrant expression of Eps8 closely correlated with poor survival in patients with OSCC.

Overexpression of α-enolase correlates with poor survival in canine mammary carcinoma.

BACKGROUND: α-Enolase (ENO1) is a key glycolytic enzyme implicated in the development of many human cancers including breast cancer. Increased expression of ENO1 has recently been reported in estrogen (ER)-positive human breast cancer patients. The present study examined the expression of ENO1 and assessed its significance in canine mammary carcinoma. RESULTS: Immunohistochemical staining was employed to investigate the expression of ENO1 in 82 cases of canine mammary tumor (32 benign tumors and 50 carcinomas). Quantification of immunohistochemistry was carried out using Quick score and the results showed cytoplasmic ENO1 overexpression in 9 of the 50 carcinomas (18%). Overexpression of ENO1 correlated significantly with shorter cause-specific survival (P = 0.019), but was not associated with ER positivity in canine mammary carcinoma. CONCLUSIONS: Our findings suggest that overexpression of ENO1 may be used as a prognostic marker for poor outcome in canine mammary carcinoma.

Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients.

OBJECTIVE: We evaluated the analgesic efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablet, for the treatment of breakthrough pain in cancer patients. METHODS: This study was conducted at Changhua Christian Hospital, Changhua, Taiwan from January 2006 to February 2007. The single-center and open-label study enrolled 59 opioid-treated cancer patients with at least moderate breakthrough pain (visual analog scale [VAS] score ≥40mm on a 100-mm scale). The efficacy measures included VAS scores and adverse effect assessment 10, 30, and 60 minutes after the administration of tramadol/acetaminophen. Visual analog scale score at time of pain relief was reported. RESULTS: The mean VAS score when the breakthrough pain episode began (0 minute) was 77.8. Analysis showed significant better mean pain VAS scores at 10, 30, and 60 minutes after the administration of tramadol/acetaminophen (p≤0.001 versus 0 min for all 3 time points). The mean time to pain relief was 597.2 seconds and the mean VAS score at time of relief was 43.4. The effective rates, defined by more than 30% reduction of the VAS score, after 10 minutes of administration was 74.6%, 30 minutes 86.4%, and one hour 94.9% (p≤0.001 versus 0 minute for all 3 time points). Two cases of drowsiness were reported. CONCLUSION: Tramadol/acetaminophen might be efficacious and safe in the treatment of breakthrough pain in cancer.

Epigenetic alteration of the SOCS1 gene in hepatocellular carcinoma.

PRINCIPLES: It has been postulated that the induced suppressor of cytokine signalling (SOCS) protein inhibits the signalling pathway through the association with a variety of tyrosine kinase proteins, and decelerates or inhibits the progression of cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to investigate the expression of SOCS1 gene in HCC and explore the potential molecular mechanisms. METHODS: We investigated CpG island methylation status at the promoter region and the expression of the SOCS1 gene in 46 HCC tumour and paired non-tumour samples. RESULTS: This immuno-histochemical study demonstrated strong homogeneous or heterogeneous staining in the non-tumour liver tissue compared to a marked decreased heterogeneous staining in the HCC (p 0.001). Real-time quantitative (qRT)-PCR showed that SOCS1 mRNA was also down-regulated in tumour cells of HCC. The methylation analysis of CpG sites at the promoter region of SOCS1 disclosed hypermethylation in 39% of HCC samples and 41% of non-tumour tissue. Promoter methylation of SOCS1 was well correlated with HCC derived from liver cirrhosis (p = 0.044) and tumour size (p = 0.038). CONCLUSIONS: Our findings suggest a tumour suppressor-like role of SOCS1 in the hepatocarcinogenesis of human HCC.

Rapid detection of epidermal growth factor receptor mutations with multiplex PCR and primer extension in lung cancer.

Epidermal growth factor receptor (EGFR) kinase domain mutations hyperactivate the kinase and confer kinase addiction of the non-small-cell lung cancer (NSCLC) tumor cells. Almost all of these mutations are located within exons 18-21. The -216 single nucleotide polymorphism in the promoter region is associated with increased EGFR production. We present a method for detecting these common mutations in 81 cases of NSCLC. The protocol is based on the multiplex amplification of promoter region and exons 18-21 of the EGFR genes in a single tube, followed by primer extension of the PCR products using various sizes of primers to detect base changes at -216 promoter region and codons 719, 746-750, 790, 858 of the EGFR gene. We compared the results with that from direct sequencing for detecting EGFR mutations in 81 cases of NSCLC. The two methods identified the same 26 mutations, but our method is superior to direct sequencing in terms of the amount of work and time required. We presented a simple and fast method to detect mutations of EGFR genes in NSCLC.

Expression of protein kinase C family in human hepatocellular carcinoma.

Protein kinase Cs (PKCs) play important roles in signal transduction, cell regulation, and tumor formation. In the present study, we analyzed the expression of PKCs in human hepatocellular carcinoma (HCC) tissues and explored their roles in the development of HCC. Real-time quantitative PCR and immunohistochemistry showed that PKCbeta and PKCtheta were down-regulated in HCC tissues. Reduced expression of PKCtheta is well correlated with the grade of cancer cells (p = 0.009), and the down-regulated expression of PKCbetaII is associated with HBV infection (p = 0.035). Our findings suggest particular roles of the two PKC isoenzymes in the hepatocarcinogenesis of human HCC.

Detection of N-, H-, and KRAS codons 12, 13, and 61 mutations with universal RAS primer multiplex PCR and N-, H-, and KRAS-specific primer extension.

OBJECTIVES: Mutations of all three RAS genes, N-, H-, and KRAS, are identified mainly in codons 12, 13, and 61 of exons 2 and 3 in human cancers. DESIGN AND METHODS: DNA samples were isolated from 58 oral cancer and 106 colorectal cancer patients. Multiplex amplification of codons 12 and 13 of exon 2 and codon 61 of exon 3 of three RAS genes using two pairs of universal primers for exons 2 and 3 was performed in a single tube. The products were cleaned and split in three tubes. Each was subjected for primer extension using seven different-sized RAS primers for different RAS gene separately to detect base changes in codons 12, 13, and 61 of each RAS gene. RESULTS: We compared the results with that from direct sequencing for detecting N-, H-, and KRAS mutations in 58 oral cancers and 106 colorectal cancers. The two methods yield identical results, but our method is superior to direct sequencing in terms the amount of work and time required. CONCLUSIONS: We presented a rapid method to detect codons 12, 13, and 61 mutations of N-, H-, and KRAS genes in human cancers.

Analysing the expression of protein kinase C eta in human hepatocellular carcinoma.

AIMS: Protein kinase Cs (PKCs) play important roles in cell proliferation, differentiation, apoptosis, migration and tumorigenesis. In this report, we investigated the expression of PKCeta in human hepatocellular carcinoma (HCC) tissues and explored its role in the development of HCC. METHODS: We used real-time quantitative RT-PCR, mutation analysis, and immunohistochemical staining to analyse the expression of PKCeta in 50 pairs of human hepatocellular carcinoma (HCC) tissues. RESULTS: Expression of PKCeta was down-regulated in 82% of HCC tissues and the reduction of PKCeta was associated with poorer long-term survival of HCC patients. CONCLUSION: Reduced expression of PKCeta may represent a molecular lesion in the development of more aggressive disease of HCC.

Fast simultaneous detection of K-RAS mutations in colorectal cancer.

BACKGROUND: RAS genes acquire the most common somatic gain-of-function mutations in human cancer, and almost all of these mutations are located at codons 12, 13, 61, and 146. METHODS: We present a method for detecting these K-RAS hotspot mutations in 228 cases of colorectal cancer. The protocol is based on the multiplex amplification of exons 2, 3 and 4 in a single tube, followed by primer extension of the PCR products using various sizes of primers to detect base changes at codons 12, 13, 61 and 146. We compared the clinicopathological data of colorectal cancer patients with the K-RAS mutation status. RESULTS: K-RAS mutation occurred in 36% (83/228) of our colorectal cancer cases. Univariate analysis revealed a significant association between K-RAS mutation at codon 12 of exon 2 and poor 5-year survival (p = 0.023) and lymph node involvement (p = 0.048). Also, K-RAS mutation at codon 13 of exon 2 correlates with the size of the tumor (p = 0.03). Multivariate analysis adjusted for tumor size, histologic grade, and lymph node metastasis also indicated K-RAS mutations at codon 12 and 13 of exon 2 correlate significantly with overall survival (p = 0.002 and 0.025). No association was observed between codon 61 and 146 and clinicopathological features. CONCLUSION: We demonstrated a simple and fast way to identify K-RAS mutation.

Disturbance of circadian gene expression in breast cancer.

To explore the mechanism of the disruption of circadian rhythm in breast cancer, we examined the expression of nine circadian genes in 53 newly diagnosed breast cancers by immunohistochemical staining, mutational analysis, and methylation analysis of the promoter of circadian genes. Our results showed that 37 of the 53 breast cancer tissues had hypermethylation on the promoters of PER1, PER2, CRY1, or BMAL1. Twenty-five out of 53 paired noncancerous (normal) tissues had methylation on the promoter of PER1 or CRY1. Our results indicated a higher frequency of concurrent methylation of PER1 and CRY1 promoters in cancerous and normal tissues. Promoter methylation of the PER1 correlates with c-erbB2 immunohistochemical reaction of > or = 2+ (p = 0.012) and has a strong inverse correlation with estrogen receptor positivity (p = 0.016). We further analyzed the patterns of circadian gene expression by immunohistochemical methods and found that homogeneous expression of PER2 or BMAL1 is significantly associated with lymph node metastasis and poor prognosis. PER2 heterogeneous expression correlates with <2+ c-erbB2 immunohistochemical reaction. Heterogeneous expression of CLOCK is associated significantly with 3-year survival. In conclusion, the expression pattern of circadian genes might be a biomarker for the prognosis of breast cancer.

Expression of CD80 and CD86 costimulatory molecules are potential markers for better survival in nasopharyngeal carcinoma.

BACKGROUND: B7 Costimulatory signal is essential to trigger T-cell activation upon the recognition of tumor antigens. This study examined the expression of B7-1 (CD80) and B7-2 (CD86) costimulatory molecules along with HLA-DR and the presence of infiltrating lymphocytes and dendritic cells to assess their significance in patients with nasopharyngeal carcinoma (NPC). METHODS: Expression of CD80, CD86, HLA-DR, S-100 protein and the presence of infiltrating lymphocytes and follicular dendritic reticulum cells were immunohistochemically examined on the paraffin-embedded tissue blocks from newly diagnosed NPC patients (n = 50). The results were correlated with clinical outcome of patients. RESULTS: CD80 and CD86 were each expressed in 10 of 50 cases in which they co-expressed in 9 cases. Univariate analysis revealed that patients with CD80/CD86 expression had significantly better overall survival than those without it (P = 0.017), but after adjustment for stage, nodal status, and treatment, the expression of CD80/CD86 did not significantly correlate with overall survival. Expression of HLA-DR and the presence of infiltrating lymphocytes and dendritic cells did not appear to have impact on the survival of patients. CONCLUSION: Expression of CD80 and CD86 costimulatory molecules appears to be a marker of better survival in patient with NPC.

Expression of c-kit protooncogene in human hepatocellular carcinoma.

The expression of the c-kit protooncogene in human hepatocellular carcinoma (HCC) was investigated. Immunohistochemical staining (IHC) and RT-PCR were employed to examine the protein and mRNA expression of c-kit protooncogene, respectively. IHC results demonstrated that 22 of 86 (25.6%) HCC tissue sections expressed c-kit protein. The c-kit mRNA transcript was further confirmed in all 22 IHC c-kit positive HCC tissue samples by RT-PCR. Moreover, the relationship between c-kit expression in HCC and prognosis of patients was statistically analyzed and a correlation was established. The group of patients whose HCC specimens showed positive c-kit staining exhibited better survival as compared to those patients with negative c-kit expression (p=0.021). These results suggest that c-kit expression may be a good prognostic indicator for HCC.

Corticosteroid administration depresses circulating dendritic cells in ITP patients.

Idiopathic or immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count resulting from antibody-mediated destruction of platelets. The production of these IgG anti-platelet autoantibodies is critically governed by T-lymphocytes which can be activated by antigen-presenting cells (APC) such as dendritic cells. We hypothesized that one of the mechanisms by which corticosteroid administration can suppress the immune system is to depress the number of circulating dendritic cells production in ITP patients. Dendritic cell population was measured in peripheral blood of three ITP patients before and after the administration of prednisone. Both counts of myeloid and lymphoid dendritic cells in the blood of ITP patients were greatly reduced after the administration of prednisone. The decrease in circulating dendritic cells is associated with the increase of platelets in circulation with the treatment of prednisone. These results suggest that corticosteroid therapy may decrease the effects of the autoantibody on platelets in ITP patients by reduce the number of circulating dendritic cells.

Successful treatment for multiple cerebral hemorrhage in a newly diagnosed patient with acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by severe bleeding associated with coagulation abnormalities. High incidence of disseminated intravascular coagulation (DIC) in APL often causes early hemorrhagic death. We report a case of APL with massive cerebral hemorrhage and respiratory failure in a 24-year old woman. A combination of all-trans retinoic acid (ATRA) differential therapy and blood component therapy was given to control DIC and stop bleeding. In order to minimize the severity of DIC during chemotherapy induced acute cytolysis, ATRA was started 8 days before the induction chemotherapy which consisted of idarubicin (IDA) and cytosine arabinoside (Ara-C). Complete clinical remission was achieved in this APL patient despite of the severity of the hemorrhage.