Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.

Anti-heparan sulfate antibody and functional loss of glomerular heparan sulfate proteoglycans in lupus nephritis.

Background The purpose of this study was to evaluate the features of heparan sulfate proteoglycans (HSPGs) as agrins of the glomerular basement membrane (GBM) and circulating anti-heparan sulfate (HS) antibodies in lupus nephritis, comparing titers among the following groups: lupus nephritis (LN), non-renal lupus, non-lupus nephritis, and healthy controls. Methods The stage of nephritis was determined based on the kidney biopsy. Alcian blue staining and immunohistochemical (IHC) staining for agrin were performed for histological evaluation of GBM HSPGs in normal glomeruli, non-lupus membranous glomerulonephritis (MGN), and lupus MGN. The results were used for measurement of the serum anti-HS antibody titers using an enzyme-linked immunosorbent assay (ELISA) in the following groups: 38 healthy controls, 38 non-lupus nephritis, 37 non-renal lupus, and 38 LN. Results Glomerulus HSPGs were stained bluish-green along the GBM with Alcian blue. However, IHC staining against agrin was almost completely negative in the lupus MGN group compared with the normal and non-lupus MGN groups, which showed brown staining of GBM. A higher level of anti-HS IgG was detected in LN compared with other groups, respectively. Higher titers were associated with the presence of SLE and nephritis. A higher degree of proteinuria normalized to glomerular filtration rate (eGFR) was observed in association with higher anti-HS antibody titers in LN. Conclusion This study demonstrated a functional loss of GBM HSPGs and higher levels of circulating anti-HS antibodies as a characteristic feature of lupus nephritis, suggesting their involvement in the pathogenesis of lupus nephritis and proteinuria.

Late anastomotic leakage after low anterior resection in rectal cancer patients: clinical characteristics and predisposing factors.

AIM: The purpose was to examine the clinical characteristics and predisposing factors of late anastomotic leakage following low anterior resection for rectal cancer. METHOD: We retrospectively evaluated the clinicopathological features of patients who experienced anastomotic leakage after low anterior resection for rectal cancer. Patients were divided into two groups according to the time to leakage: early leakage (within 30 days postoperatively) and late leakage (after 30 days postoperatively). Clinicopathological characteristics were compared between the two groups. RESULTS: Anastomotic leakage occurred in 141 patients. Anastomotic leakage was diagnosed at a median of 17 (range 0-886) days postoperatively; 85 (60.3%) and 56 (39.7%) were categorized as the early and late leakage groups, respectively. Radiotherapy (hazard ratio 5.007; 95% CI 2.208-11.354; P < 0.0001) was the only significant independent predisposing factor for late leakage. Diverting stoma did not protect against late leakage. The late leakage group more frequently had the fistula type (46.4% vs. 10.6%; P < 0.001) and less frequently needed laparotomy (55.4% vs. 78.8%; P = 0.001). The rate of long-term stoma over 1 year was greater in the late leakage than the early leakage group (51.8% vs. 29.4%; P = 0.009). CONCLUSION: Late anastomotic leakages that develop after 30 days following low anterior resection are not uncommon and may be associated with the use of radiotherapy. Late leakage should be a different entity from early leakage in terms of the type of leakage, methods of management and subsequent sequelae.

The outcomes of instrumented posterolateral lumbar fusion in patients with rheumatoid arthritis.

AIMS: The aims of this study were to evaluate the clinical and radiological outcomes of instrumented posterolateral fusion (PLF) performed in patients with rheumatoid arthritis (RA). METHODS: A total of 40 patients with RA and 134 patients without RA underwent instrumented PLF for spinal stenosis between January 2003 and December 2011. The two groups were matched for age, gender, bone mineral density, the history of smoking and diabetes, and number of fusion segments. The clinical outcomes measures included the visual analogue scale (VAS) and the Korean Oswestry Disability Index (KODI), scored before surgery, one year and two years after surgery. Radiological outcomes were evaluated for problems of fixation, nonunion, and adjacent segment disease (ASD). The mean follow-up was 36.4 months in the RA group and 39.1 months in the non-RA group. RESULTS: Both groups had significant improvement in symptoms one year after surgery, while the RA group showed some deterioration of outcome scores owing to complications during the second year after surgery. Complications occurred at a higher rate in the group with RA (19 patients, 47.5%) than in those without RA (23 patients, 17.1%) (p < 0.001). A total of 15 patients in the RA group (37.5%) required revision surgery, mainly for implant failure and post-operative infection. DISCUSSION: Multimodal approaches should be considered when performing instrumented PLF in patients with RA to reduce the rate of complications, such as problems of fixation, post-operative infection and nonunion. TAKE HOME MESSAGE: Specific strategies should be undertaken in order to optimise outcomes in patients with rheumatoid arthritis.

Ferritin is associated with neural differentiation of bone marrow-derived mesenchymal stem cells under extremely low-frequency electromagnetic field.

Extremely low-frequency electromagnetic field (ELFEF) is a well-known mechanical stimulation that induces neural differentiation. It is potentially an effective treatment for neurodegenerative diseases. In a previous study, ferritin light chain was upregulated in ELFEF-exposed human bone marrow-derived mesenchymal stem cells (BM-MSCs). Ferritin light chain is a component of ferritin, a highly conserved iron-binding protein. In this study, to identify molecules associated with ferritin during neural differentiation of BM-MSCs, we performed reverse transcription polymerase chain reaction (RT-PCR), western blotting, and ATP analysis. Our data indicated that ELFEF triggers the upregulation of ferritin light chain (FLC) and ferritin heavy chain (FHC) in BM-MSCs. The elevated levels of FLC and FHC correlated positively with the differentiation of BM-MSCs into neural cells. Moreover ELFEF induced the activation of iron regulatory protein-1 (IRP-1) and cofilin, which are downstream targets of ferritin. These results suggest that ELFEF induces neural differentiation through activation of a ferritin-regulated mechanism.

Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer.

AIM: Colorectal cancer (CRC) with microsatellite instability (MSI) is characterized by frequent poor differentiation or mucinous histology. The purpose of this study was to evaluate the association of MSI with clinicopathological features and the oncological outcome in patients with a mucinous component. METHOD: CRC tissue samples were analysed for histology and MSI. Patients were grouped according to the mucinous content of the tumour, as follows: > 50%, mucinous adenocarcinoma (MA); ≤ 50%, adenocarcinoma with mucinous component (AMC); none, nonmucinous adenocarcinoma (NMA). Clinicopathological parameters and survival were compared between patient groups. RESULTS: Of 2025 patients, 84 (4%) had MA and 124 (6%) had AMC. In addition, 202 (10%) had MSI. Patients with MA and AMC tended to have a younger age of onset, right-colon predilection, large-sized tumour and high frequency of MSI compared with those with NMA (P < 0.001). MA and AMC patients with MSI showed a trend towards right-colon predilection and infrequent lymph-node metastasis compared with those with microsatellite stability (MSS; P = 0.005-0.03). There were no survival differences between the three groups, but patients with MSI-MA demonstrated lower 4-year recurrence and better overall survival rates than those with MSS-MA (P = 0.018 and P = 0.046, respectively). CONCLUSION: Clinicopathological features of AMC and MA were similar and closely associated with MSI status. Although the prognoses of AMC and MA were no different from that of NMA, survival of patients with an MSI-MA tumour was significantly better than for those with MSS-MA tumours.

Evaluation of in vivo antitumor effects of ANT2 shRNA delivered using PEI and ultrasound with microbubbles.

Gene therapy using RNA interference can be directed against tumors through various strategies, but has been hindered owing to the inefficiency of non-viral delivery. To evaluate the antitumor effects of adenine nucleotide translocase-2 (ANT2) short hairpin RNA (shRNA) by intraperitoneal injection using the polyethylenimine (PEI) and an ultrasound gene delivery method, human breast carcinoma MDA-MB-231 cells were injected subcutaneously into NOG (NOD/Shi-scid/IL-2Rγ(null)) mice. The results showed greater tumor regression (*P<0.05) as well as an increased survival rate in the group receiving ANT2 shRNA+two types of enhancer relative to the groups receiving ANT2 shRNA without enhancer. These findings demonstrate that the introduction of PEI and ultrasound with SonoVue exerted enhanced antitumor effects in vivo. Although the combination of jet-PEI and ultrasound provided the best results with respect to tumor regression, the antitumor effects from the individual enhancers were approximately equivalent. In addition, we confirmed that there was no toxicity on aspartate aminotransferase and alanine aminotransferase levels in the liver and albumin, blood urea nitrogen or creatine kinase levels in the kidney following the various gene delivery methods.

Robotic rectal surgery: what are the benefits?

Robotic rectal surgery is not a rare event for colorectal surgeons any more. Even patients with colorectal diseases obtain information through the mass media and are asking surgeons about robotic surgery. Since laparoscopic rectal surgery has proved to have some benefits compared to open rectal surgery, many surgeons became interested in robotic rectal surgery. Some of them have reported the advantages and disadvantages of robotic rectal surgery over the last decade. This review will report on the outcomes of robotic rectal surgery. Robotic rectal surgery requires a longer operation time than laparoscopic or open surgery, but many authors reduced the gap as they were accustomed to the robotic system and used various additional techniques. The high cost for purchasing and maintaining the robotic system is still a problem, though. However, except for this reason, robotic rectal surgery shows comparable and even superior results in some parameters than laparoscopic or open surgery. They include pathologic and functional outcomes as well as short-term outcomes such as complication rates, length of hospital stay, time to recover normal bowel function or first flatus, time to start diet, and postoperative pain. Moreover, studies on oncologic outcomes show acceptable results. Robotic rectal surgery is safe and feasible and has a number of benefits. Therefore, it can be an alternative option to conventional laparoscopic and open surgery with strict indications.

Serum biomarker panels for the diagnosis of gastric adenocarcinoma.

BACKGROUND: Currently, serum biomarkers, which are sufficiently sensitive and specific for early detection and risk classification of gastric adenocarcinoma do not exist. Therefore, this study identified a panel of serum biomarkers for the diagnosis of gastric adenocarcinoma. METHODS: A 29-plex array platform with 29 biomarkers, consisting of 11 proteins discovered through proteomics and 18 previously known to be cancer-associated, was constructed. A test/training set consisting of 120 gastric adenocarcinoma and 120 control samples were examined. After 13 proteins were selected as candidate biomarkers, multivariate classification analyses were used to identify algorithms for diagnostic biomarker combinations. These algorithms were independently validated using a set of 95 gastric adenocarcinoma and 51 control samples. RESULTS: Epidermal growth factor receptor (EGFR), pro-apolipoprotein A1 (proApoA1), apolipoprotein A1, transthyretin (TTR), regulated upon activation, normally T-expressed and presumably secreted (RANTES), D-dimer, vitronectin (VN), interleukin-6, α-2 macroglobulin, C-reactive protein and plasminogen activator inhibitor-1 were selected as classifiers in the two algorithms. These algorithms differentiated between the majority of gastric adenocarcinoma and control serum samples in the training/test set with high accuracy (>88%). These algorithms also accurately classified in the validation set (>85%). CONCLUSION: Two panels of combinatorial biomarkers, including EGFR, TTR, RANTES, and VN, are developed, which are less invasive method for the diagnosis of gastric adenocarcinoma. They could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy.

Impact of BMI on the incidence of metabolic abnormalities in metabolically healthy men.

OBJECTIVES: Although the existence of metabolically healthy obese (MHO) individuals has been recognized, little is known regarding metabolic health status in these subjects over time. Thus, we evaluated longitudinal changes in metabolic parameters among MHO subjects compared with metabolically healthy, normal-weight (MHNW) subjects. METHODS: A cohort study was performed on 2599 Korean men, 30-59 years of age, with no evidence of fatty liver disease on ultrasound and no traits of metabolic syndrome at baseline. BMI was categorized based on criteria for Asian population. Study participants were followed annually or biennially between 2002 and 2009. At each visit, the fatty liver on ultrasound was assessed and metabolic abnormalities were measured. Parametric Cox models and a pooled logistic regression models were used to evaluate the relationships of BMI with incident metabolic abnormalities. RESULTS: During 9647.1 person-years of follow-up, 1673 participants developed metabolic abnormalities. After adjusting for age, smoking, alcohol intake and exercise, higher baseline BMI categories predicted increased incidences of metabolic abnormalities in a dose-response manner. The hazard ratios (95% confidence intervals) for hypertriglyceridemia, prediabetes, pre-hypertension, low high-density lipoprotein-cholesterol, fatty liver, elevated high sensitivity-C reactive protein, elevated homeostasis model assessment of insulin resistance, any metabolic abnormality and metabolic syndrome among the MHO subjects compared with the MHNW subjects were 1.51 (1.23-1.85), 1.43 (1.19-1.72), 1.79 (1.45-2.22), 1.80 (1.30-2.49), 2.69 (2.19-3.31), 1.39 (1.16-1.67), 2.90 (2.31-3.62), 1.68 (1.45-1.93) and 1.84(1.02-3.30), respectively. CONCLUSION: In this study, MHO individuals showed higher incidences of metabolic abnormalities compared with MHNW individuals. This suggests that initially MHO individuals undergo adverse metabolic changes associated with obesity over time.

Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway.

Although the hyper-glycosylated transmembrane protein Mucin 1 (MUC1) is aberrantly overexpressed in human breast carcinoma, the biological significance of MUC1 overexpression is unclear. This study showed that MUC1 expression promoted the synthesis and secretion of vascular endothelial growth factor (VEGF) through the AKT signaling pathway. Increase VEGF production through MUC1 expression had a number of effect. First, MUC1 transfection increased expression of VEGF in breast cancer cells. Second, MUC1-mediated VEGF induction was attenuated by a chemical inhibitor of AKT or MUC1 knock-down by MUC1 siRNA. Third, MUC1 expression led to the activation of insulin-like growth factor-1 receptor, which correlated with VEGF expression. In addition, when MDA-MB-231 human breast cancer cells were directly injected into NOD/SCID mice, MUC1 expression accelerated xenograft tumor growth in vivo. Finally, MUC1 expression enhanced tumor growth and angiogenesis in a PyMT-MMTV/hMUC1 transgenic mouse model. Concurrent with these results, analysis of a human tissue microarray identified a high correlation between MUC1 and VEGF expression in human breast carcinoma. The current report is the first to demonstrate that MUC1 expression promotes angiogenesis in human breast cancer in vivo and in vitro.

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt.

BACKGROUND AND PURPOSE: Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and function of these microdomains. The ginsenoside Rh2 exhibits anti-tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti-tumour effect by modulating rafts and caveolae. EXPERIMENTAL APPROACH: A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over-expression of Akt and active-Akt on Rh2-induced cell death. KEY RESULTS: Rh2 induced apoptosis concentration- and time-dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Akt-dependent phosphorylation of Bad, a pro-survival protein, was decreased whereas the pro-apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2-mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2-induced cell death. Rh2-induced cell death was attenuated in MDA-MB-231 cells over-expressing either wild-type or dominant-active Akt. CONCLUSIONS AND IMPLICATIONS: Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti-cancer therapy.

The current status of HIV screening laboratories in Korea assessed by a questionnaire survey of participants in the KCDC HIV EQAS (2006).

Using a questionnaire, we assessed the current status of the quality management systems at HIV screening laboratories in Korea. The Korea Centres for Disease Control and Prevention HIV external quality assurance scheme (EQAS) questionnaire includes 18 items divided into five groups related to HIV testing: personnel, HIV test processes, participation in the Quality Assurance programme and HIV testing equipment. Five hundred and sixty-one HIV screening laboratories participated in this questionnaire investigation; data were collected from 233 public health centres, 309 hospitals or clinics, eight blood centres and 11 commercial laboratories. The total number of HIV screening tests was about 5.5 million in 2005. The average number of HIV tests per institution was highest in blood centres (308 561), followed by commercial laboratories (56 084), hospital or clinic laboratories (6756), and public health centres (1751). Equipment and HIV test methods varied between HIV screening laboratories, and, to manage the quality of their HIV testing, most laboratories participated in several evaluation programmes such as EQAS or a laboratory accreditation programme. This study is the first questionnaire survey of HIV testing laboratories in Korea. The results could be used to evaluate and promote the quality management of HIV testing laboratories.

Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells.

The expression of hypoxia-inducible factor-1 (HIF-1) correlates with poor clinical outcomes and confers resistance to the apoptosis of the tumor cells that are exposed to hypoxia. Presently, the mechanism underlying this phenomenon is poorly understood. In this study we provide evidence that transglutaminase 2 (TG2), an enzyme that catalyses protein crosslinking reactions, is a transcriptional target of HIF-1 to enhance the survival of hypoxic cells. We found that hypoxia induces TG2 expression through an HIF-1 dependent pathway and concurrently activates intracellular TG2. The hypoxic cells overexpressing TG2 showed resistance to apoptosis. Conversely, the hypoxic cells treated with either TG2 inhibitor or small interfering RNA (siRNA) became sensitive to apoptosis. Activation of TG2 in response to hypoxic stress inhibited caspase-3 activity by forming crosslinked multimer, resulting in insoluble aggregates. TG2 also activates nuclear factor (NF)-kappaB pathway after hypoxic stress, and thereby induces the expression of cellular inhibitor of apoptosis 2. The anti-apoptotic role of TG2 was further confirmed in vivo using xenografts in athymic mice. Our results indicate that TG2 is an anti-apoptotic mediator of HIF-1 through modulating both apoptosis and survival pathways and may confer a selective growth advantage to tumor cells. These findings suggest that the inhibition of TG2 may offer a novel strategy for anticancer therapy.

Benefit of downsizing hepatocellular carcinoma in a liver transplant population.

BACKGROUND: Long-term results after downstaging hepatocellular carcinoma (HCC) prior to liver transplantation (LT) remain unknown. AIMS: To investigate dropouts and post-transplant outcome among patients with downstaged HCC by transarterial chemo-lipiodolization (TACL). METHODS: Between 2000 and 2007, 386 patients with HCC initially exceeding Milan criteria underwent TACL for tumour downstaging and were consecutively enrolled. RESULTS: Overall, 160 (41.5%) patients achieved successful downstaging of HCC to within Milan criteria. During the follow-up, 82 eventually dropped off the waiting list for LT, with estimated dropout rates at 1, 2 and 5 years of 46.7%, 70.2%, and 87.2%, respectively. The overall post-transplant survival rates at 1, 2 and 5 years were 89.2%, 70.3% and 54.6% and the corresponding rates for recurrence-free survival were 74.7%, 71.8% and 66.3% respectively. Multivariate analysis indentified alpha-fetoprotein (AFP) levels > or = 100 ng/mL at LT (P = 0.003), maximum tumour size > or = 7 cm (P = 0.002) and the lack of complete necrosis by TACL (P = 0.048) as independent predictors of HCC recurrence after LT. Patients with none of these risk factors had an excellent post-transplant outcome, with an 87.5% probability of recurrence-free survival up to 6 years. CONCLUSIONS: These long-term results may contribute to the database for optimizing management of LT candidates with downstaged HCC. Based on our data, patients with a maximum tumour size <7 cm who achieve complete necrosis together with AFP levels <100 ng/mL at LT may be the best candidates for LT following downstaging using TACL.

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

BACKGROUND: Extranodal 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. PATIENTS AND METHODS: We 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. RESULTS: Patients 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. CONCLUSION: Increased quantity of tumor-infiltrating Tregs predicted improved clinical outcome in NKTCL patients.

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

BACKGROUND: Recent 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. MATERIALS AND METHODS: Retrospective 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). RESULTS: Eighty-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. CONCLUSION: TUBB3 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.

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

BACKGROUND: Many patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy. PATIENTS AND METHODS: This 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. RESULTS: Thirty-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. CONCLUSIONS: This 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.