Dae-Seog Heo

Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer

PURPOSEnTo analyze the outcome of postoperative radiotherapy (RT) or chemoradiation for patients with extrahepatic bile duct cancer who had undergone either curative or palliative surgery, and to identify the prognostic factors for these patients.nnnMETHODS AND MATERIALSnBetween March 1982 and December 1994, 91 patients with extrahepatic bile duct cancer underwent RT at the Department of Therapeutic Radiology, Seoul National University Hospital. Of these patients, 84 were included in this retrospective study. The male/female ratio was 3.7:1 (66 men and 18 women). The median age of the patients was 58 years (range 33-76). Gross total surgical resection was performed in 72 patients, with pathologically negative margins in 47 and microscopically positive margins in 25. Twelve patients underwent surgical exploration and biopsy or subtotal resection with palliative bypass procedures. All the patients received >40 Gy of external beam RT after surgery. Concurrent 5-fluorouracil was administered during external beam RT in 71 patients, and maintenance chemotherapy was performed in 61 patients after RT completion. The minimal follow-up of the survivors was 14 months, and the median follow-up period for all the patients was 23 months (range 2-75).nnnRESULTSnThe overall 2- and 5-year survival rate was 52% and 31%, respectively. The 2- and 5-year disease-free survival rate was 48% and 26%, respectively. On univariate analysis using the Kaplan-Meier product limit method, the use of chemotherapy, performance status, N stage, size of residual tumor, stage, and tumor location were significant prognostic factors. However, on multivariate analysis using Coxs proportional hazard model, N stage (N0 vs. N1 and N2, p = 0.02) was the only significant prognostic factor.nnnCONCLUSIONnLong-term survival can be expected in patients with extrahepatic bile duct cancer who undergo radical surgery and postoperative chemoradiation. Regional lymph node metastasis is a poor prognostic factor for these patients.

The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines.

The overexpression of cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX‐2 in cancer cells. Therefore, we investigated the cross‐talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX‐2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2–20 times due to increased COX‐2 expression. This increase of COX‐2 expression by SNAP or PMA (potent inducer of both iNOS and COX‐2) was blocked to various degrees by NO scavengers and NOS inhibitors (L‐NAME and 1400W). Also, the expression of COX‐2 in resting cells was inhibited by NOS inhibitors. Moreover, COX‐2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl‐cGMP on COX‐2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX‐2 in HNSCC cell lines. We also observed that NO increased COX‐2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX‐2, and that NOS inhibitor may be also useful for cancer prevention.

Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines

We previously showed that nitric oxide (NO) induces overexpression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 in cancer cells. Here, we investigated the mechanisms by which NO induces COX-2 expression in cancer cells. We found that the cAMP-response element (CRE) is a critical factor in NO-induced COX-2 expression in all cells tested. We found that in cancer cells, three transcription factors (TFs) – cAMP response element-binding protein (CREB), activating transcription factor-2 (ATF-2) and c-jun, bound the CRE in the COX-2 promoter, and their activities were increased by addition of the NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). NO-induced activation of soluble guanylate cyclase (sGC), p38 and c-Jun NH2-terminal kinase (JNK) upregulated the three TFs, leading to COX-2 overexpression. Addition of dibutyryl-cGMP (db-cGMP) induced COX-2 expression in a manner similar to SNAP; this induction was blocked by a p38 inhibitor (SB202190), but not by a JNK inhibitor (SP600125). NO-induced cGMP was found to activate CREB and ATF-2 in a p38, but not c-jun-dependent manner, while NO induced JNK in a cGMP-independent manner, leading to subsequent activation of c-jun and ATF-2. These results suggest that the low concentrations of endogenous NO present in cancer cell may induce the expression of many genes, including COX-2, which promotes the growth and survival of tumor cells.

Class III β-tubulin, but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma

BACKGROUNDnRecent researches revealed that class III beta-tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in head and neck squamous cell carcinoma (HNSCC) is not defined yet. We analyzed the significance of TUBB3 expression along with p53 and ERCC1 in locally advanced HNSCC patients receiving cisplatin-based induction chemotherapy.nnnMATERIALS AND METHODSnRetrospective review of medical records at Seoul National University Hospital between 1998 and 2007 was carried out. Immunohistochemical stain of TUBB3, p53, and ERCC1 was done in paraffin-embedded tumor tissue. We assessed response to treatment, progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS).nnnRESULTSnEighty-five patients with oropharyngeal, hypopharyngeal, and laryngeal cancers received induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (n = 55), or 5-FU, cisplatin, and docetaxel (Taxotere) (n = 30). Eighty-three received definitive treatment after induction chemotherapy, where 62 received radiotherapy and 21 received surgery. TUBB3-positive patients showed lower response rate than TUBB3-negative patients (69% versus 88%, P = 0.039). Shorter median PFS was observed in TUBB3-positive group (12 versus 47 months, P = 0.001). Shorter median OS was observed in TUBB-positive group not reaching statistical significance (30 versus 59 months, P = 0.072). TUBB3 status significantly influenced CSS (35 months versus not reached, P = 0.017). Positive p53 status was related to poorer OS and CSS. ERCC1 showed no influence on chemotherapy response, PFS, OS, and CSS.nnnCONCLUSIONnTUBB3 is a predictive and prognostic marker along with well-known p53 in HNSCC patients receiving cisplatin-based induction chemotherapy. Clinical impact of ERCC1 is not evident in this setting.

Peripheral T‐cell lymphoma involving subcutaneous tissue

The peripheral T‐cell lymphomas, presumably derived from various immunocompetent peripheral T‐cell system components, form a heterogeneous group of non‐Hodgkins lymphomas. We describe two patients with peripheral T‐cell lymphoma primarily involving subcutaneous tissue. They presented with multiple subcutaneous nodules. Skin biopsy specimens in both patients demonstrated a lobular subcutaneous infiltrate. The infiltrate consisted of small and medium‐sized atypical lymphoid cells. Both patients had a protracted clinical course before they were diagnosed as having malignant lymphoma. We detected latent Epstein‐Barr virus infection in the skin lesions of case 2. Latent Epstein‐Barr virus infection might be related to the development of this variant of peripheral T‐cell lymphoma.

Celecoxib Can Prevent Tumor Growth and Distant Metastasis in Postoperative Setting

Much evidence suggests that an inflammatory condition provides a microenvironment favorable for tumor growth. One of the main components in the healing wound is the induction of cyclooxygenase-2 (COX-2) and prostaglandins, and many solid tumors have been known to overexpress COX-2. The present study investigated the relationship between surgical wounds and tumor growth and the roles of COX-2 and inflammatory reaction in this microenvironment. We created surgical wounds in syngeneic mice for the implantation of SCC VII murine cancer cell line. Accelerated tumor growth and increased angiogenesis by surgical wounds were clearly observed in C3H/HeJ mice with SCC VII tumor. The COX-2 expression of peritumoral tissues and leukocyte infiltration partly explained the accelerated tumor growth, especially in the early phase after surgical wounding. Celecoxib had a significantly suppressive effect on tumor growth, angiogenesis, and metastasis in tumor-implanted mice with surgical wounds. This tumor-suppressive action of celecoxib did not show any noticeable side effects on the late wound healing and on the gastrointestinal tracts. Prophylactic use of the drug can be advocated in many clinical situations, such as residual tumors or contamination of surgical fields by tumor cells.

Epstein–Barr virus-associated peripheral T-cell lymphoma in adults with hydroa vacciniforme-like lesions

We describe two Korean adult patients who had necrotizing papulovesicles mainly on their faces. Skin biopsy specimens showed perivascular and periadnexal infiltrate of atypical lymphoid cells with vasculitis in the dermis and subcutaneous tissue. In situ hybridization demonstrated a latent infection of Epstein–Barr virus in the majoriy of lymphoid cells in the dermis. These patients were diagnosed as having T‐cell lymphoma. Interestingly, large granular lymphocytosis was found in the peripheral blood of Case 2.

Increased quantity of tumor-infiltrating FOXP3-positive regulatory T cells is an independent predictor for improved clinical outcome in extranodal NK/T-cell lymphoma

BACKGROUNDnExtranodal natural killer/T-cell lymphoma (NKTCL) is a clinically heterogeneous disease with a poor prognosis, requiring risk-stratified management in affected patients. Recently, tumor microenvironment including regulatory T cells (Tregs) has been implicated as a prognostic marker in certain types of lymphoma.nnnPATIENTS AND METHODSnWe collected 64 NKTCL cases and numerically quantified the amount of tumor-infiltrating FOXP3-positive Tregs by automated slide scanning and image analysis program after immunohistochemical staining using anti-FOXP3 antibody.nnnRESULTSnPatients were able to be classified into two end groups by their level of Tregs. Twenty-eight (44%) patients had Tregs <50/0.40 mm(2), while 36 (56%) had Tregs > or =50/0.40 mm(2) within the tumor. The decreased number of Tregs (<50/0.40 mm(2)) was more common in patients with poor performance status or in those presented in non-upper aerodigestive tract. However, the level of Tregs was not associated with other prognostic factors, including stage, lactate dehydrogenase level, International Prognostic Index, and NKTCL Prognostic Index. Importantly, patients with increased numbers of Tregs (> or =50/0.40 mm(2)) showed prolonged overall and progression-free survival (P = 0.0005 and P = 0.0079, respectively). The number of FOXP3-positive Tregs was an independent prognostic factor (P = 0.001) by multivariate analysis.nnnCONCLUSIONnIncreased quantity of tumor-infiltrating Tregs predicted improved clinical outcome in NKTCL patients.

Effective second-line chemotherapy for extranodal NK/T-cell lymphoma consisting of etoposide, ifosfamide, methotrexate, and prednisolone

BACKGROUNDnMany patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy.nnnPATIENTS AND METHODSnThis was single-institutional, phase II study. The primary end point was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Patients with relapsed or refractory NTCL were eligible. They received the chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone and it was repeated every 3 weeks.nnnRESULTSnThirty-two patients were enrolled and 15 patients had achieved partial remission (PR) or complete remission (CR) after the front-line chemotherapy. The International Prognostic Index scores were 0-1 in thirteen, 2 in five, 3 in five, and 4-5 in nine patients. Twelve and two patients achieved CR and PR, respectively. Median OS and TTF of all patients were 8.2 and 3.7 months, respectively. Non-hematologic toxic effects were well tolerated, but grade 3/4 leukopenia occurred in 11.7% of all cycles. Four patients developed febrile neutropenia and one patient died due to pneumonia.nnnCONCLUSIONSnThis chemotherapy regimen was moderately effective for relapsed/refractory extranodal NTCL, nasal type. Toxic effects were moderate, but caution should be exercised to prevent severe infection.

The Effects of the Stromal Cell-Derived Cyclooxygenase-2 Metabolite Prostaglandin E2 on the Proliferation of Colon Cancer Cells

It is well known that tumor-surrounding stromal tissues support tumor development through secreting soluble factors such as various cytokines, chemokines, and growth factors. It has also been suggested that tumor-associated fibroblast and immune cells have a high expression of cyclooxygenase-2 (COX-2) and produce and secrete several prostaglandins (PGs) to adjacent cancer tissues. From these findings, we assumed that COX-2 inhibition might have an anticancer effect on cancer cells even without COX-2 expression in COX-2-dependent mechanisms through blocking the effect of stroma-derived PGs. Here, because of the complex involvement of various factors in vivo, we investigated this possibility with an in vivo-mimicking model using a Transwell system. To test our hypothesis, we used COX-2-transfected cell lines as stromal cells in our model. When we cocultured cancer cells (LS174T cells without COX-2 expression) with COX-2-high stromal cells in the Transwell membrane system, we observed that the proliferation of cancer cells was promoted and vascular endothelial growth factor synthesis was up-regulated significantly. These effects were blocked completely by COX-2 inhibitors and phosphoinositide-3-kinase inhibitors and partially by the PG E2 receptor 4 antagonist. Even if some cancer cells did not express COX-2, they were found to have expression of PG receptors and PG-related downstream signaling molecules associated with cell viability. Our observation suggests that these cells can be influenced by PGs derived from stromal tissues. These findings also suggest that COX-2 inhibitors can be used to control the interaction between cancer and surrounding stromal tissues and suppress the proliferation of cancer cells regardless of the expression of COX-2 in cancer cells.