Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers.

BACKGROUND: Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). However, it is unclear whether MSI affects the prognosis of recurrent CRCs. METHODS: This study included 2940 patients with stage I-III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed. RESULTS: A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results. CONCLUSIONS: Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis.

Bone alkaline phosphatase as a surrogate marker of bone metastasis in gastric cancer patients.

BACKGROUND: Bone metastasis is relatively uncommon in gastric cancer patients, but its incidence has been rising. Early detection of bone metastasis is important in preventing complications related to bone metastasis such as pain, fracture and the compromise of chemotherapy. In this pilot study, we investigated the feasibility of bone turnover markers as surrogate markers of bone metastasis in gastric cancer patients. METHODS: Fifty-eight patients with gastric cancer were included in this study. Serum levels of bone alkaline phosphatase (ALP), parathyroid hormone (PTH), 25(OH) D, osteocalcin (OC) and C terminal telopeptide were measured and compared between patients with bone metastasis and those without. Student's t-test and Mann-Whitney U test were used in comparing two groups, and Spearman's rank order correlation coefficient was calculated to quantify the strength of the associations. RESULTS: Fifty eight age- and sex-matched patients were evaluated for bone turnover markers, among whom 29 patients had bone metastasis and 29 patients with no bone metastasis. The median age was 62 and there were 20 (68.9 %) males and 9 (31.1 %) females in each group. Bone ALP was significantly higher in the patient group (57.32 ± 46.83 vs. 34.57 ± 21.57, P = 0.037) than control group. Bone ALP was positively associated with ALP, osteocalcin, CA19-9, CA 72-4 and negatively associated with 25(OH) D. According to ROC-curve analysis, at the threshold value of 29.60 µg/L, the sensitivity of bone ALP was 76.7 % and the specificity was 59.4 %. CONCLUSION: Bone ALP may be a surrogate marker of bone metastasis in gastric cancer patients. More prospective studies are warranted to determine the optimal bone turnover markers in the evaluation of bone metastasis.

Risk factors for incomplete resection and complications in endoscopic mucosal resection for lateral spreading tumors.

AIM: Lateral spreading tumors (LST) are relatively large flat lesions with diameters exceeding 10 mm in length. Endoscopic mucosal resection (EMR) is a commonly used technique for removing LST. We aimed to evaluate the risk factors for incomplete resection and complications of EMR for LST. METHOD: Between January 2004 and December 2010, 497 patients who underwent EMR for LST were retrospectively reviewed. Risk factors for endoscopic and histopathological complete resection, complications, and clinical outcomes were investigated. RESULTS: Risks for incomplete resection by piecemeal resection and en bloc resection of a lesion ≥ 30 mm were higher than for en bloc resection of a lesion <30 mm (OR=2.688, CI 1.036-6.993; OR=4.982, CI 1.894-13.101). Risks of post-EMR bleeding for piecemeal resection and en bloc resection for a lesion ≥ 40 mm were higher than for en bloc resection of a lesion <40 mm (OR=15.231, CI 1.816-127.744; OR=43.043, CI 4.306-430.314). CONCLUSION: We found risk factors of EMR for LST and tentatively suggest a protocol for EMR adapted to the size of LST and resection methods. (i) Following piecemeal resection and en bloc resection for LST ≥ 40 mm, hospitalize patients for 36 h and note risk for incomplete resection and delayed bleeding. (ii) After en bloc resection for 40 mm>LST ≥ 30 mm, hospitalize patients for 12 h and note risk for incomplete resection. (iii) Following en bloc resection for LST<30 mm, hospitalize the patient for 12 h and expect complete resection.

The effect of autologous serum eye drops on the conjunctivalization over exposed porous polyethylene orbital implant (Medpor(®)) in the rabbit model.

PURPOSE: To assess the efficacy of autologous serum eye drops (AS) in enhancing conjunctivalization over a scleral patch graft on exposed porous polyethylene orbital implant (Medpor(®)). METHODS: Eighteen rabbits were underwent evisceration, implantation of Medpor(®) and homologous scleral patch graft. The conjunctival edge was sutured leaving 5 mm-diameter circular defect. In group A, 20% AS were applied 8 times a day and only balanced salt solution was applied in group B. Digital anterior segment photography was obtained 1, 3, 7, 10, 14, and 21 days after surgery and analyzed with Image Pro Plus(®) software. RESULTS: In the early postoperative period, the average conjunctival growth rate (mm(2)/day) was faster in group A, but failed to show statistical significance (3.79 vs. 3.03, p = 0.26 in 1~3days, 2.39 vs. 1.80, p = 0.59 in 4- days, 0.03 vs. -0.02, p = 0.94 in 7-10 days, Mann-Whitney test). The complete healing rate was higher (67% vs. 56%, p = 0.5, Fisher's exact test) and the mean elapsed time for complete healing (days) was shorter in group A (17.3 vs. 18.2, p = 0.83, Mann-Whitney test), but did not show a statistically significant difference. CONCLUSION: In a rabbit model, 20% AS did not appear to facilitate the healing of small conjunctival defects of exposed porous orbital implant.

Efficacy of Polytetrafluoroethylene/Polylactide-co-glycolide (PTFE/PLGA) Laminate and PTFE/PLGA Laminate Containing Slow-Releasing Thalidomide in Delayed Adjustable Strabismus Surgery in a Rabbit Model.

Purpose: To evaluate the efficacy of polytetrafluoroethylene/polylactide-co-glycolide (PTFE/PLGA) laminate containing sustained-release thalidomide for delayed adjustable strabismus surgery. Methods: This is a prospective, masked-observer, controlled study using 50 eyes of 25 rabbits. After superior rectus muscle (SRM) recession, a PTFE/PLGA laminate containing thalidomide (group PT, 20 eyes), PTFE/PLGA laminate alone (group P, 20 eyes), or no barrier (group C, 10 eyes) were applied around the SRM. Delayed adjustment was performed at postoperative 3 or 5 weeks. Adjustability, adjustment lengths, adjustment forces, and degrees of adhesion were evaluated. Results: Both groups PT and P showed significantly better adjustability compared to group C at both 3 weeks (100%, 80%, and 0%, respectively) and 5 weeks (100%, 90%, and 0%, respectively). Between groups PT and P, adjustability, adjustment lengths, and forces were not significantly different at 3 and 5 weeks. Group PT showed a significantly lower grade of adhesion between SRM and sclera (SRM/S) compared to group C at both 3 weeks (p = 0.007) and 5 weeks (p = 0.001, respectively). Group P showed no significant difference in adhesion between SRM/S compared to group C at 3 weeks (p= 0.302) but had a lower grade of adhesion after 5 weeks (p = 0.007). There was no significant difference between groups PT and P at 3 weeks (p= 0.143) and 5 weeks (p= 0.716). Conclusions: PTFE/PLGA laminate containing sustained-release thalidomide was effective in reducing adhesion and allowed delayed adjustment in all eyes. However, PTFE/PLGA laminate alone was also equally effective in reducing adhesion compared to controls.

A Phase II Study to Evaluate the Safety and Efficacy of Pegteograstim in Korean Breast Cancer Patients Receiving Dose-Dense Doxorubicin/Cyclophosphamide.

PURPOSE: Dose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT. MATERIALS AND METHODS: Patients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability. RESULTS: Of 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%). CONCLUSION: Dose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.

Randomised phase II trial comparing four front-line doublets in Asian patients with metastatic gastric cancer.

INTRODUCTION: Consensus has not been reached regarding the standard regimen for front-line chemotherapy of recurrent/metastatic gastric cancer. In this randomised phase II study, we compared four doublet regimens: S-1 and cisplatin (SP); oxaliplatin and 5-FU (FOLFOX); docetaxel and 5-FU (DF) and paclitaxel and 5-FU (PF). PATIENTS AND METHODS: Patients without prior history of chemotherapy for recurrent/metastatic gastric cancer were randomised evenly to each regimen. The primary end-point was progression-free survival (PFS). The secondary end-points were overall survival (OS), response rate (RR) and safety profile. RESULTS: A total of 179 Korean patients were enrolled from March 2010 to May 2015. The study was prematurely terminated because of slow accrual. At data cut-off, the median PFS was 8.4 months for SP, 5.8 months for FOLFOX, 5.7 months for DF and 4.2 months for PF (P = 0.023). The median OS was 14.7 months for SP, 11.3 months for FOLFOX, 11.7 months for DF and 10.8 months for PF (P = 0.143). RR was 18%, 23%, 16% and 32% for SP, FOLFOX, DF and PF, respectively. The platinum group displayed a longer PFS trend than the taxane group (7.2 versus 4.9 months, P = 0.058), but no significant difference in OS was found. Notably, 105 patients were exposed to all three drugs (platinum, taxane and fluoropyrimidine) throughout the treatment course, and OS was identical whether starting with platinum or taxane (13.3 versus 13.3 months, P = 0.997). All regimens were well tolerated. CONCLUSION: SP showed the most favourable results in PFS, whereas a significant difference in OS was not observed among the four regimens.

STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade.

The stimulator of interferon genes (STING) signaling pathway is a critical link between innate and adaptive immunity, and induces anti-tumor immune responses. STING is expressed in vasculatures, but its role in tumor angiogenesis has not been elucidated. Here we investigated STING-induced tumor vascular remodeling and the potential of STING-based combination immunotherapy. Endothelial STING expression was correlated with enhanced T-cell infiltration and prolonged survival in human colon and breast cancer. Intratumoral STING activation with STING agonists (cGAMP or RR-CDA) normalized tumor vasculatures in implanted and spontaneous cancers, but not in STING-deficient mice. These were mediated by upregulation of type I/II interferon genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in non-hematopoietic cells is as important as STING in hematopoietic cells to induce a maximal therapeutic efficacy of exogenous STING agonist. Vascular normalizing effects of STING agonists were dependent on type I interferon signaling and CD8+ T cells. Notably, STING-based immunotherapy was maximally effective when combined with VEGFR2 blockade and/or immune checkpoint blockade (αPD-1 or αCTLA-4), leading to complete regression of immunotherapy-resistant tumors. Our data show that intratumoral STING activation can normalize tumor vasculature and the tumor microenvironment, providing a rationale for combining STING-based immunotherapy and anti-angiogenic therapy.

Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade.

PURPOSE: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy. EXPERIMENTAL DESIGN: The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses. RESULTS: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8+ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival. CONCLUSIONS: Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immune-checkpoint blockades by overcoming resistance to immunotherapy.

Real-world efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin in patients with metastatic pancreatic adenocarcinoma: a study by the Korean Cancer Study Group.

BACKGROUND: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) was effective and well-tolerated in patients with metastatic pancreatic adenocarcinoma (mPAC) that progressed on gemcitabine-based therapy in the global NAPOLI-1 trial. Real-world data may further clarify the outcomes and safety profile of nal-IRI + 5-FU/LV in clinical practice. METHODS: This retrospective analysis included patients with mPAC who received nal-IRI + 5-FU/LV following gemcitabine-based therapy under a Managed Access Program in Korea. RESULTS: From January 2017 to April 2018, 86 patients across 10 institutions received nal-IRI + 5-FU/LV (median age, 61 years; 60% male; ECOG performance status, 0-1). A total of 35 (41%) and 51 (59%) patients had received less than two and two or more lines of chemotherapy before inclusion, respectively. At a median follow up of 6.4 months, median overall survival (OS) was 9.4 months (95% confidence interval [CI] 7.4-11.4) and median progression-free survival (PFS) was 3.5 months (95% CI 1.3-5.7). Six-month OS and PFS rates were 65.1% and 37.5%, respectively. Objective response and disease control rates were 10% and 55%, respectively. Most common grade 3-4 toxicities were neutropenia (37.2%), nausea (10.5%), vomiting (9.3%), anorexia (8.1%) and diarrhoea (4.7%). CONCLUSION: Real-life data for Korean patients indicate that, consistent with NAPOLI-1, nal-IRI + 5-FU/LV is effective and well-tolerated in patients with mPAC that progressed on gemcitabine-based therapy.

A Prediction Model of Tumor Progression and Survival in HER2-Positive Metastatic Gastric Cancer Patients Treated with Trastuzumab and Chemotherapy.

The effects of different patient factors and dose levels of chemotherapeutic agents on clinical outcomes in advanced gastric cancer are not as yet fully characterized. We aimed at developing an integrative model that incorporates dose and covariate information to predict tumor growth and patient survival in advanced gastric cancer patients treated with trastuzumab (T), 5-FU(F)/capecitabine (X) (F or X), and cisplatin (P). Sixty-nine patients (training dataset) were used for model building and a separate 86 patients (test dataset) for model validation. A fraction of tumor cells sensitive to each drug was incorporated as a model parameter, and T was assumed as cytostatic and X/F and P as cytotoxic. Cox proportional hazards analyses were performed on model parameters and patient covariates. The model well described the time course of observed tumor size changes, and revealed that the pretreatment tumor growth rate constant k g , which was formulated as a function of pretreatment disease duration and baseline tumor size, was positively correlated with baseline tumor size (p = 0.0084) and histologic grade (p = 0.034), and the efficacy of 5-FU with body weight (p < 2e-16) and that of cisplatin with histologic grade (p = 0.00013). Prior gastrectomy and Eastern Cooperative Oncology Group scores were significant prognostic factors for progression-free survival (PFS). For hazards analysis, a unit increase of k g was associated with a relative risk of 3.19 for PFS (p = 0.00055) and 4.45 for OS (p = 2e-04) in the test dataset, with a similar trend observed in the training dataset. Dose-response simulations showed that, for small baseline tumor size or low histologic grade, a maximum cytotoxic effect was attainable with a dose smaller than the current recommended dose.

PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer.

BACKGROUND: Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. RESULTS: Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index (<5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). CONCLUSION: In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. METHODS: HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.

Rho GTPase RhoJ is Associated with Gastric Cancer Progression and Metastasis.

Rho GTPases play a pivotal role in tumor progression by regulating tumor cell migration and invasion. However, the role of Rho GTPases in gastric cancer (GC) remains unexplored. This study aimed to investigate the clinical implications of RhoJ, which is an uncharted member of Rho family. RhoJ expression in human GC cell lines and surgical specimens from GC patients were analyzed. Moreover, in vitro gain-of-function analysis was performed to evaluate the malignant phenotypes of RhoJ-overexpressing GC cells. The extent of RhoJ expression varied among GC cell lines and GC patients. YCC-9 cell line displayed the strongest expression, while YCC-10, -11, and -16 showed scant expressions. Of the 70 GC patients, 34 (48.6%) had RhoJ expression in their GC tissue, and patients with high RhoJ expression had more diffuse type GC (73.5% vs. 41.7%), were at more advanced stages (stage III, IV: 85.3% vs. 58.4%), and had more frequent metastasis (47.1% vs. 11.1%), denoting that RhoJ has a potential role in GC progression and metastasis. High RhoJ expression significantly correlated with poor overall survival and recurrence-free survival after surgical resection of gastric cancer. Finally, In vitro gain-of-function experiments showed 41.3% enhanced motility and 60.4% enhanced invasiveness in RhoJ-overexpressing GC cells compared to control, with negligible difference in cell proliferation. Collectively, high RhoJ expression is an independent negative prognostic factor for the survival outcome of GC and correlated with the increased cell motility and invasiveness.

Efficacy and Toxicity of Mammalian Target Rapamycin Inhibitors in Patients with Metastatic Renal Cell Carcinoma with Renal Insufficiency: The Korean Cancer Study Group GU 14-08.

PURPOSE: We evaluated the efficacy and toxicity of mammalian target rapamycin inhibitors in Korean patients with metastatic renal cell carcinoma (mRCC) with chronic renal insufficiency not requiring dialysis. MATERIALS AND METHODS: Korean patients with mRCC and chronic renal insufficiency not requiring dialysis treated with everolimus or temsirolimus between January 2008 and December 2014 were included. Patient characteristics, clinical outcomes, and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) durations were evaluated according to the degree of renal impairment. RESULTS: Eighteen patients were considered eligible for the study (median age, 59 years). The median glomerular filtration rate was 51.5 mL/min/1.73 m2. The best response was partial response in six patients and stable disease in 11 patients. The median PFS and OS durations were 8 months (95% confidence interval [CI], 0 to 20.4) and 32 months (95% CI, 27.5 to 36.5), respectively. The most common non-hematologic and grade 3/4 adverse events included stomatitis, fatigue, flu-like symptoms, and anorexia as well as elevated creatinine level. CONCLUSION: Mammalian target rapamycin inhibitors were efficacious and did not increase toxicity in Korean patients with mRCC and chronic renal insufficiency not requiring dialysis.

A Rapid and Simple Liquid-Chromatography-Tandem Mass Spectrometry Method for Measuring 25-Hydroxyvitamin D2 and 25-Hydroxyvitamin D3 in Human Serum: Comparison with Two Automated Immunoassays.

BACKGROUND: Total 25-hydroxyvitamin D (25(OH)D) is well-known to be a reliable biomarker of human vitamin D status, with the recognition of widespread vitamin D insufficiency in general populations. The aims of this study are to validate a fast and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying 25(OH)D2 and 25(OH)D3 in serum and to compare two automated immunoassays with the LC-MS/MS method. METHODS: Samples were prepared by protein precipitation with ethanol including 25(OH)D3-d6, followed by a liquid-liquid extraction with hexane. The analytes were separated within a total run time of 3 min. Accuracy was evaluated with standard reference materials (SRM) 972a. Using 150 samples, the LC-MS/MS method was compared with the LIAISON® assay and ADVIA Centaur® assay. RESULTS: The LC-MS/MS method had a limit of quantitation of 1 ng/mL for the 25(OH)D2 and 25(OH)D3 with linear responses between 1 and 100 ng/mL. Intra- and inter-assay precision were <8.8% and <13.2%, respectively. It also showed a smallest mean difference (+0.9%) for the SRM level 1 to 3, compared to the two immunoassays. Compared to the LC-MS/MS, the mean biases of the RIAISON and ADVIA were +2.4 and +7.9 ng/mL, respectively. Also, the agreement of the LC-MS/MS with the RIAISON was better than that with the ADVIA. CONCLUSION: This study suggests that the LC-MS/MS method traceable to the SRM can be reliably applied in routine quantification of 25(OH)D2 and 25(OH)D3.

Incidence of Febrile Neutropenia in Korean Female Breast Cancer Patients Receiving Preoperative or Postoperative Doxorubicin/Cyclophosphamide Followed by Docetaxel Chemotherapy.

PURPOSE: Doxorubicin/cyclophosphamide followed by docetaxel chemotherapy (AC-D) is an intermediate risk factor (incidence of 10%-20%) for febrile neutropenia (FN) in breast cancer. However, the reported incidence of FN while using this regimen was obtained mostly from Western breast cancer patients, with little data available from Asian patients. This study aimed to assess the incidence of FN in Korean breast cancer patients and to describe clinical variables related to FN. METHODS: From September 2010 to February 2013, data from the Yonsei Cancer Center registry of breast cancer patients who received neoadjuvant or adjuvant chemotherapy with four cycles of AC-D (60 mg/m(2) doxorubicin, 600 mg/m(2) cyclophosphamide every 3 weeks for four cycles followed by 75 mg/m(2) or 100 mg/m(2) docetaxel every 3 weeks for four cycles) were analyzed. The incidence of FN, FN associated complications, dose reduction/delays, and relative dose intensity (RDI) were investigated. RESULTS: Among the 254 patients reported to the registry, the FN incidence after AC-D chemotherapy was 29.5% (75/254), consisting of 25.2% (64/254) events during AC and 4.7% (12/254) during docetaxel chemotherapy. Dose reductions, delays, and RDI less than 85.0% during AC were observed in 16.5% (42/254), 19.5% (47/254), and 11.0% (28/254) of patients, respectively. Patients with FN events frequently experienced dose reduction/delays, which eventually led to a decreased RDI. CONCLUSION: The incidence of FN during AC-D neoadjuvant or adjuvant chemotherapy was higher than expected in Korean breast cancer patients. Whether these patients should be classified as a high-risk group for FN warrants future prospective studies.

Prognostic implications of PIK3CA amplification in curatively resected liposarcoma.

BACKGROUND: We investigated the epidemiologic characteristics and prognostic significance of PIK3CA mutations/amplifications in curative resected liposarcoma. PATIENTS AND METHODS: A total of 125 liposarcoma tissue samples were collected over a 12-year period. PIK3CA mutations and gene copy number amplifications were analyzed by pyrosequencing and fluorescence in situ hybridization (FISH). RESULTS: Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation. PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043). In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification. In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005). By multivariate analysis, PIK3CA copy number gain was an independent prognostic factor for worse DFS (P=0.027; hazard ratio, 2.400; 95% confidence interval 1.105 to 5.213). PIK3CA mutation was not associated with DFS and overall survival. CONCLUSIONS: We demonstrated PIK3CA mutation and amplification in liposarcoma. PIK3CA copy number gain was an independent poor prognostic factor for DFS. Further studies are needed to evaluate the potential diagnostic and therapeutic role of PIK3CA mutations and amplifications in liposarcoma.

¹8F-FDG PET/CT in hepatocellular carcinoma: detection of bone metastasis and prediction of prognosis.

OBJECTIVE: The purpose of this study was to assess the diagnostic accuracy and prognostic value of 18F-fluorodeoxyglucose PET/computed tomography (CT) in bone metastases from hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Of 3912 consecutive HCC patients, 67 patients who had undergone both PET/CT and bone scintigraphy (BS) within a 3-month interval were evaluated. RESULTS: Bone metastases were most frequently found in the pelvis (20%), followed by the lumbar spine (14%) and long bones (13%). PET/CT was significantly more sensitive than BS in region-based analyses, with 273 confirmed bone metastases (96.7 vs. 52.7%, respectively; P<0.001), and in patient-based analyses (99 vs. 85%; P=0.042). The median survival period was 5 (range, 0.4-18) months. On univariate analysis, poor prognostic factors included age (<60 years), multiple bone metastases, lymph node metastasis, high serum α-fetoprotein (≥400 IU/ml), Child-Pugh class B, and high maximum standardized uptake value (SUVmax) of bone metastasis (>5.0). Large metabolic volume (≥200 cm3) of bone metastasis was another poor prognostic factor. On Cox regression analysis, high α-fetoprotein was the only poor prognostic factor with statistical significance. CONCLUSION: PET/CT was more sensitive than BS in bone metastasis from HCC by both patient-based and region-based analyses, and offered additional information on survival. PET/CT can be helpful in early diagnosis and opportune treatment of bone metastasis from HCC.

The role of second-look endoscopy in endoscopic submucosal dissection for early gastric cancer.

BACKGROUND/AIMS: Delayed bleeding is a major complication of endoscopic submucosal dissection. Second-look endoscopy is routinely performed in most hospitals to reduce the possibility of delayed bleeding without solid evidence to support this practice. The aim of this study was to evaluate whether second-look endoscopy prevents delayed bleeding, and to verify clinicopathological features of delayed bleeding in order to identify lesions that may benefit from a second-look endoscopy. MATERIALS AND METHODS: We investigated 392 lesions in 388 patients who underwent endoscopic submucosal dissection for early gastric cancer from January 2006 to July 2011. Clinically evident bleeding from mucosal defects 24 hours after endoscopic submucosal dissection was considered delayed bleeding. Data including characteristics of patients, lesions, and procedures were reviewed. Furthermore, the rate of delayed bleeding before and after second-look endoscopy, performed within three days of endoscopic submucosal dissection, was investigated to determine the utility of second-look endoscopy. RESULTS: Delayed bleeding was evident in 12 of 392 lesions (3,1%), all of which achieved endoscopic hemostasis. The only significant factor predicting delayed bleeding was a resected specimen size of over 40 mm (OR=6,200, 95% CI=1,912 - 20,108). Delayed bleeding occurred more frequently prior to the second-look endoscopy (p=0,022). CONCLUSIONS: In our endoscopic submucosal dissection data about early gastric cancer, it is too early to conclude that second-look endoscopy is not a valuable procedure, and second-look endoscopy may be useful for preventing post-endoscopic submucosal dissection bleeding, especially in resected specimens greater than 40 mm in size.