Hui Ping Hsu

Predictors for Patterns of Failure after Pancreaticoduodenectomy in Ampullary Cancer

BackgroundAmpullary cancer has the best prognosis in periampullary malignancy but unpredicted early recurrence after resection is frequent. The current study tried to find the predictors for recurrence to be used as determinative for postoperative adjuvant therapy.MethodsInformation was collected from patients who underwent pancreaticoduodenectomy with regional lymphadenectomy for ampullary cancer in high-volume hospitals between January 1989 and April 2005. Recurrence patterns and survival rates were calculated and predictors were identified.ResultsA total of 135 eligible patients were included. The 30-day operative mortality was 3%. Median followup for relapse-free patients was 52 months. Disease recurred in 57 (42%) patients, including 31 liver metastases, 26 locoregional recurrences, 9 peritoneal carcinomatoses, 7 bone metastases, and 6 other sites. Pancreatic invasion (P = 0.04) and tumor size (P = 0.05) were the predictors for locoregional recurrence, while lymph node metastasis was the sole predictor for liver metastasis (P = 0.01). The 5-year disease-specific survival rate was 45.7%; 77.7% for stage I, 28.5% for stage II, and 16.5% for stage III; and 63.7% for node-negative versus 19.1% for node-positive patients. Pancreatic invasion and lymph node involvement were both predictors for survival of patients with ampullary cancer.ConclusionPancreaticoduodenectomy with regional lymphadenectomy is adequate for early-stage ampullary cancer but a dismal outcome can be predicted in patients with lymph node metastasis and pancreatic invasion. Lymph node metastasis and pancreatic invasion can be used to guide individualized, risk-oriented adjuvant therapy.

Loss of E-cadherin and β-catenin is correlated with poor prognosis of ampullary neoplasms

Distant metastasis resulting from carcinoma cell detachment from the primary tumor involves modification of adhesion molecules. This study was conducted to examine the correlation of E‐cadherin/β‐catenin expression with survival and recurrence in ampullary neoplasms.

Significance of intraoperative peritoneal culture of fungus in perforated peptic ulcer.

The incidence of postoperative fungal infection is increasing and the gastrointestinal tract is the major source, but antifungal therapy in perforated peptic ulcer (PPU) is still controversial. The aim of this study was to determine the significance of intraoperative peritoneal fluid culture of fungus and establish the indications for treatment.

Predictors of Recurrence After Pancreaticoduodenectomy in Ampullary Cancer: Comparison Between Non-, Early and Late Recurrence

BACKGROUND/PURPOSE Ampullary cancer is one of the periampullary cancers with a better prognosis, but relapse still occurs early in some patients. We sought to find predictors of recurrence to facilitate decisions about postoperative therapy. METHODS Between January 1989 and March 2006, information was gathered on a total of 127 patients undergoing pancreaticoduodenectomy with regional lymphadenectomy for ampullary cancer at National Cheng Kung University Hospital and Tainan Municipal Hospital. Clinical information, histopathologic results and long-term outcomes were collected and predictors for recurrence were identified. RESULTS Fifty-eight patients (46%) survived without evidence of recurrence (non-recurrence), while 32 patients (25%) suffered recurrent disease after 12 months (late recurrence) and 37 patients (29%) developed recurrent disease within 12 months (early recurrence). The median follow-up for non-recurrence was 65 months, 13 months for early recurrence, and 36 months for late recurrence. Patterns of recurrence were similar, without any significant difference between the early recurrence and late recurrence groups. The early and late recurrence patients had higher levels of microscopically (R1) or macroscopically (R2) positive margin of resection and more advanced disease (advanced tumor stage, numbers of lymph nodes involved, lymph node status, pancreatic invasion and TNM stage) than the non-recurrence group. After multivariate analysis, positive resection margin, pancreatic invasion and lymph node involvement were significant predictors for disease recurrence. Lymph node involvement was the main differentiating predictor between the late and early recurrence groups (odds ratio, 1.982; 95% confidence interval, 1.101-3.567; p = 0.022). CONCLUSION Positive resection margin, pancreatic invasion, and lymph node involvement were found to be predictors for disease recurrence and indicators for postoperative treatment.

Impact of Etiologic Factors and APACHE II and POSSUM Scores in Management and Clinical Outcome of Acute Intestinal Ischemic Disorders after Surgical Treatment

BackgroundAcute intestinal ischemic disorder (AIID) is an uncommon vascular disease with high mortality. According to etiology, it can be categorized into three groups: arterial occlusive mesenteric ischemia (AOMI), mesenteric venous thrombosis (MVT), and nonocclusive mesenteric ischemia (NOMI). This study analyzes the effect of classification on surgical outcome.Patients and MethodsAll AIID patients who underwent operative treatment at National Cheng Kung University Hospital between January 1989 and August 2003 were enrolled in this study. Preoperative information on these patients was compared to find predictors of outcome.ResultsData from 77 patients (49 men and 28 women, median age 70 years) were analyzed. The etiology was AOMI in 30 patients, MVT in 19 patients, and NOMI in 28 patients. Median age was younger in MVT (54 years) than in AOMI (70 years) or NOMI (72 years). In addition, MVT usually involved the jejunum (74%, versus 31% in AOMI and 46% in NOMI), whereas both AOMI and NOMI involved ileum and colon. The patients with AOMI had shorter duration of symptoms and higher ratio of underlying hypertension than those with MVT. The overall mortality rate was 53.2% (41/77). The day 1 and day 30 mortality were 0% and 10.5% in MVT, 16.7% and 30% in AOMI, and 42.9% and 67.9% in NOMI, respectively (P < 0.05). Both the etiology and the APACHE II scores were significant risk factors for day 30 and long-term mortality. The patients with NOMI had higher POSSUM physiologic scores than patients with MVT. The P-POSSUM regression equation can accurately predict mortality.ConclusionsPatients with MVT had a more favorable prognosis, whereas those with NOMI had the worst outlook. The APACHE II and POSSUM scoring systems are useful in predicting the clinical outcome. Early diagnosis and classification of AIID patients are useful for aggressive treatment to improve the clinical outcome.

Osteopontin-positive infiltrating tumor-associated macrophages in bulky ampullary cancer predict survival.

Purpose: Tumor-associated macrophages (TAMs) promote cancer cell proliferation and distant metastases. Osteopontin (OPN) is overexpressed in several human cancer cells and in TAMs. Therefore, we set out to determine the role of OPN-expressing macrophages in cancer. Experimental Design: Specimens from ampullary cancer patients at National Cheng Kung University Hospital were collected for immunohistochemistry. Plasma OPN was measured by enzyme-linked immunosorbent assay. Tumor and normal epithelial cells from fresh tissues were separated by laser-assisted microdissection for reverse-transcription polymerase chain reaction and quantitative real-time PCR analyses. Results: In 100 ampullary cancers, diffuse cytoplasmic positivity for OPN was found in infiltrating TAMs in 36 patients and marginal TAMs in 32 patients; OPN+ macrophages were absent in 32 patients. Expression patterns of OPN in TAMs were associated with pancreatic invasion, tumor stage, TNM stage, lymphovascular invasion and recurrence with peritoneal carcinomatosis. Patients were stratified according to a median tumor size of 2 cm. Patients with tumor sizes ≥2 cm and OPN+ infiltrating TAMs had a poorer disease-specific survival rate than those with OPN+ marginal TAMs. Macrophage-associated cytokine expression in ampullary cancer cells was also assessed; levels of macrophage migration inhibitory factor (MIF) in cancer cells were higher than in normal duodenal mucosa. Conclusions: Expression of OPN and location of TAMs in bulky ampullary cancer predict recurrence. In addition, cytoplasmic staining of MIF is enhanced in ampullary cancer cells. Patients with bulky tumor, OPN+ infiltrating TAMs and MIF expression had a worst disease-specific survival.

Puerperal mastitis requiring hospitalization during a nine-year period

OBJECTIVES To review the clinical and microbiologic features of isolates among patients with puerperal mastitis requiring hospitalization. STUDY DESIGN Between January 2000 and December 2008, postpartum patients who were hospitalized for mastitis were enrolled. The clinical characteristics, microbiologic results, management, and outcomes were reviewed. RESULTS One hundred twenty-seven cases were enrolled. Seventy-six patients (59.9%) underwent incision and drainage for abscess drainage, all of whom discontinued breastfeeding. Staphylococcus aureus and coagulase-negative staphylococci were the most common isolates. Among 81 isolates of S aureus, 52 (64.2%) were resistant to oxacillin. Patients undergoing incision and drainage were more likely to discontinue breastfeeding, had a longer duration of symptoms, a longer hospitalization, a higher platelet count and higher rates of infection caused by S aureus and oxacillin-resistant S aureus. CONCLUSION Oxacillin-resistant S aureus has emerged in patients with puerperal mastitis during the past decade, and often necessitates incision and drainage, which results in discontinuation of breastfeeding.

Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model.

Mucin 2 (MUC2) is the major secreted mucin of the large intestine and is expressed by adenomas and mucinous carcinomas. Since colon cancer is associated with a proinflammatory microenvironment and dysregulated MUC2 expression, the aim of this study was to characterize the effects of MUC2 gene expression in colon tumor progression using colonic cancer cells. CT26 colon cancer cells were stably transfected with MUC2 siRNA (MUC2 RNAi) or a control construct containing a nonspecific sequence (scrambled RNAi). Expression of MUC2 was significantly decreased in the MUC2 RNAi cell clones. Although MUC2 suppression did not affect the cell growth of colon cancer cells in vitro, MUC2 knockdown promoted tumor growth in an orthotopic colon cancer model in vivo. MUC2 silencing also increased interleukin (IL)-6 secretion by colon cancer cells. IL-6 neutralization attenuated tumor formation by MUC2 RNAi cells; it also increased CD8 T cell infiltration into the peritoneum. Taken together, to the best of our knowledge, this is the first study indicating that the immune response to cancer cells plays an important role in tumor growth regulated by MUC2. Furthermore, given the effects of MUC2 on IL-6 secretion, its targeting may represent a potentially useful strategy to treat colonic carcinomas.

Attenuation of Argininosuccinate Lyase Inhibits Cancer Growth via Cyclin A2 and Nitric Oxide

Arginine biosynthesis and nitric oxide (NO) production are important for cancer homeostasis. Degradation of arginine may be used to inhibit liver tumors with low argininosuccinate synthetase (ASS) expression. In this report, we investigated an alternative therapeutic approach by targeting argininosuccinate lyase (ASL). ASL is transcriptionally induced by endoplasmic reticulum stress and is overexpressed in some human liver tumors. Knockdown of ASL expression by short hairpin RNA (shRNA) in three liver cancer cell lines, ML-1, HuH-7, and HepG2, decreased colony formation in vitro and tumor growth in vivo. Furthermore, lentiviral infection of ASL shRNA inhibited tumor growth in a therapeutic animal tumor model. Analysis of ASL shRNA on the cell-cycle progression revealed a G2–M delay. Among cell-cycle regulatory molecules, cyclin A2 expression was reduced. Reintroduction of exogenous cyclin A2 restored the cell growth in ASL-knockdown cells. Autophagy was observed in the cells treated with ASL shRNA, as shown by an increase in LC3-II levels and autophagosome formation. The total cellular arginine level was not altered significantly. Inhibition of autophagy further attenuated cell growth, suggesting that autophagy induced by ASL shRNA plays a feedback prosurvival function. Knockdown of ASL reduced NO content, and addition of NO donor partially recovered the growth inhibition by ASL shRNA. In summary, downregulation of ASL attenuated tumor growth and the inhibition was mainly mediated by a decrease of cyclin A2 and NO. Mol Cancer Ther; 12(11); 2505–16. ©2013 AACR.

Hispolon promotes MDM2 downregulation through chaperone-mediated autophagy.

Amplification and overexpression of murine double minute (MDM2) has been observed in several human cancers. Some chemotherapeutic agents cause MDM2 ubiquitination and degradation in a proteasome-dependent system. In addition to the proteasome system, chaperone-mediated autophagy (CMA) is a lysosomal pathway for selective misfolded protein degradation. Molecular chaperone heat shock cognate 70 protein (Hsc70) recognizes the misfolded proteins, which are then delivered to lysosome-associated membrane protein type 2A (LAMP2A) for lysosomal degradation. Our previous study reported that hispolon was able to induce cell apoptosis and downregulate MDM2 expression. In this study, our results showed that the proteasome inhibitor, MG132, could not inhibit hispolon-induced MDM2 downregulation. In contrast, both inhibition of lysosomes with NH(4)Cl and inhibition of LAMP2A using siRNA partially attenuated hispolon-induced MDM2 downregulation. To determine whether Hsc70 recognizes MDM2 on amino acids 135-141, SMP14 antibody was used to compete with Hsc70 for interaction with MDM2. After Hsc70 knockdown, SMP14 antibody immunoprecipitated increased MDM2. We also found that hispolon induced increased association of Hsp70, Hsc70, Hsp90 and LAMP2A with MDM2. This association was inhibited in cells pretreated with geldanamycin (GA), an Hsp90 inhibitor. GA also attenuated hispolon-induced MDM2 downregulation. Meanwhile, inhibition of Hsc70 using siRNA attenuated hispolon-induced MDM2 downregulation. Our study provides the first example of the ability of hispolon to mediate MDM2 downregulation in lysosomes through the CMA pathway.