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Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, anti-angiogenesis, and apoptosis. This phase II trial evaluated the efficacy and toxicity profile of conventional FOLFIRI chemotherapy plus simvastatin in metastatic colorectal cancer patients. Patients received irinotecan 180 mg/m2 as a 90-min infusion followed by leucovorin 200 mg/m2 in a 2-h infusion, and then 5-FU 400 mg/m2 bolus injection followed by 2,400 mg/m2 as a 46-h continuous infusion. Treatment cycles were repeated every 2 weeks until documented disease progression, unacceptable toxicity, or patient’s refusal. Simvastatin 40 mg tablet was given once daily per oral everyday during the period of chemotherapy without a rest. From October 2005 to June 2006, 49 patients were enrolled. The overall response rate (ORR) was 46.9% (95% CI, 31.0–58.8) by intent-to-treat analysis and 45.8% (95% CI, 33.3–62.8) by per-protocol analysis. There were one complete response (CR) and 22 partial responses (PRs). Both CR and PRs were confirmed at least 4 weeks later. The disease-control rate was 83.7% (95% CI, 73.4–94.0). The median follow-up duration was 25.6 months (range, 20.9–28.8 months). The median survival of all patients was 21.8 months (95% CI, 14.4, 29.2). The median TTP was 9.9 months (95% CI, 6.4, 13.3). No patients experienced additional adverse effect that was definitely caused by simvastatin drug therapy in this trial. The combination of simvastatin plus FOLFIRI was a feasible regimen with promising antitumor activity. [ABSTRACT FROM AUTHOR]

Aims: The MOSAIC trial showed that FOLFOX4 improves overall survival as compared to 5-FU/LV and is feasible and safe in early stage colon cancer patients worldwide. Based on these positive results, the present study MASCOT (Multicenter Asia Study in adjuvant treatment of Colon cancer with Oxalipla Tin/5-FU/LV), aimed to evaluate the safety and tolerability of FOLFOX4 in postoperative adjuvant treatment of colon cancer in Asian patients. Methods: In this open-label, non-randomized, single arm feasibility study, stage II/III colon cancer patients who had undergone complete resection of a primary tumor were treated using the FOLFOX4 regimen (2 weeks/cycle, 12 cycles) and followed up for 12 months. Results: A total of 159 patients (28.3% stage II and 71.7% stage III) from 17 hospitals in five Asian countries were included in the study. Overall 130 (81.8%) patients completed all 12 planned treatment cycles. There were 60% and 11% patients who experienced ≥ grade 3 pre-listed and non pre-listed toxicities, respectively. The incidences of grade 3 and 4 neuropathy were 5.7% and 0%, respectively. A total of 25 serious adverse events (SAE) were experienced by 21 (13%) patients, with one life-threatening SAE. At 12 months follow-up two patients were known to be dead due to disease relapse or recurrence. Conclusion: The MASCOT study demonstrates a favorable safety profile of FOLFOX4 in Asian patients. Based on these results and the safety and efficacy results from MOSAIC, FOLFOX4 may be considered a standard for the adjuvant treatment of colon cancer in the Asian population. [ABSTRACT FROM AUTHOR]

Objectives: This prospective, multicenter, phase 2 study evaluated the efficacy and safety of imatinib mesylate and assessed KIT and PDGFRA gene mutation status in Korean patients with gastrointestinal stromal tumors (GISTs). Methods: Forty-seven patients with pathologically proven KIT-positive metastatic or unresectable GISTs were accrued from eight institutions in Korea. Imatinib was administered orally at 400 mg once daily. In case of disease progression, the dose was escalated to 600 mg once daily, then 400 mg twice daily. KIT and PDGFRA mutations were analyzed in 29 of the 47 patients. Results: Imatinib produced partial responses in 30 patients (63.8%; 95% confidence interval, 50.1–77.6%) and stable disease in 13 patients (27.7%). The median time to response was 2.6 months (range, 1.0–6.2 months). With a median follow-up of 62 months (range, 32–67 months), 4-year progression-free survival and overall survival rates were 50 and 65%, respectively. The most common adverse events were anemia, neutropenia, edema, and skin rash (predominantly of grade 1–2). There were no treatment-related deaths. In the subset evaluated for mutational status, 24 patients (82.8%) had KIT exon 11 mutations and 1 (3.4%) had a KIT exon 9 mutation. Conclusions: Imatinib is effective and safe in Korean patients with metastatic or unresectable GIST. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose. This study analyzed the relationship between treatment outcome and kinase mutational status in Korean patients with advanced gastrointestinal stromal tumors (GISTs). Experimental Design. Clinical data were collected from 113 consecutive patients with metastatic or unresectable GISTs treated with imatinib from June 2001 through June 2005 at five institutions in Korea. KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were examined. Results. The median patient age was 57 years (range, 31-82 years). The overall response rate was 67.2%. KIT mutations were found in exon 11 (n = 92, 81.4%) and exon 9 (n = 10, 8.8%). One patient had a PDGFRA exon 18 mutation. The overall mutation rate was 91.2%. Response rates were 68.4%, 50.0%, and 80.0% in patients with KIT exon 11 mutations, KIT exon 9 mutations, and no kinase mutations, respectively. With a median follow-up of 49.0 months, the median progression-free survival (PFS) time was 42.0 months and median overall survival (OS) time was not reached. PFS and OS times did not differ significantly according to KIT genotype. Conclusion. This study was unable to find an association between KIT mutational status and clinical outcome of imatinib in Korean patients with advanced GISTs. There was a trend toward better outcomes for patients with wild-type KIT or exon 11 mutations compared with exon 9 mutations, although this was not statistically significant. Compared with previous studies in western populations, these results suggest that ethnic differences may influence the relationship between KIT genotype and clinical outcome to imatinib. [ABSTRACT FROM AUTHOR]

We designed a phase II trial of the combination with oxaliplatin and doxorubicin for patients with unresectable HCC to evaluate the overall response rate (ORR) and the toxicity. Forty patients with inoperable, systemic chemotherapy naive HCC were enrolled. Finally, 32 patients received oxaliplatin (130 mg/m2) and doxorubicin (60 mg/m2) every 3 weeks. Eighty-two treatment cycles were administered (median 2 cycles, range 1–6). There was no treatment-related mortality. The ORR was 15.6% (95% CI, 3.3–28.7) with five partial responses. The median overall survival and median overall progression free survival were 31 weeks (95% CI, 22–40 weeks) and 12 weeks (95% CI, 5-19 weeks). Nausea and peripheral neuropathy were most frequent non-hematologic toxicities (nausea, n = 15; peripheral neuropathy, n = 10). The most frequent grade 3–4 hematologic adverse event was neutropenia (14 of 82 cycles) including three cases of febrile neutropenia. The combination of oxaliplatin and doxorubicin showed modest activity and a tolerable toxicity profile in advanced HCC patients. [ABSTRACT FROM AUTHOR]

Background: Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy. Methods: The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival. Results: At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61-0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52-0.83) were independent negative prognostic factors for overall survival. Conclusion: Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC. [ABSTRACT FROM AUTHOR]

Background and Aim: The resection of synchronous or metachronous pulmonary and liver metastasis is an aggressive treatment option for patients with stage IV colorectal cancer and has been shown to yield acceptable long-term survival. We reviewed our experience with colorectal cancer patients with both liver and lung resections to determine the efficacy of surgical resections. Methods: We performed a single institution, retrospective analysis of all patients who underwent surgical hepatic and pulmonary resection for metastatic colorectal cancer between 1995 and 2004. Results: A total of 32 patients underwent resection of both hepatic and pulmonary metastases secondary to colorectal cancer. The 5-year overall survival from initial operation was 60.8%. The disease-free interval was 44.3 months (95% confidence interval: 24.7 and 63.8, respectively). Neither the number of pulmonary lesions nor the time interval between the primary surgery and the metastasectomy had a significant impact on survival ( P = 0.134). Conclusion: An aggressive surgical treatment of selected colorectal cancer patients with lung and liver metastases resulted in prolonged survival. The 5-year survival rate of 60.8% with no perioperative mortality was observed in our study. [ABSTRACT FROM AUTHOR]

Biliary tract cancer is one of the most aggressive and chemotherapy-refractory tumors. Although only curative treatment modality is surgery, most patients are not suitable for surgery due to advanced stage of the disease at diagnosis. Thus most patients with biliary tract cancer are possible candidates for palliative chemotherapy. The standard chemotherapeutic regimen is still to be defined, however. We performed a phase II study of combination chemotherapy with capecitabine and cisplatin in these patients to evaluate efficacy and toxicity of the regimen. Patients with previously untreated metastatic, recurrent, or inoperable biliary tract cancer were enrolled. Eligible patients were screened as following: (1) histologically confirmed, (2) age between 18 and 75 years, (3) at least one measurable lesion according to RECIST criteria, (4) ECOG performance status ≤2, (5) a life expectancy of at least 3 months, and (6) adequate laboratory values. Patients received capecitabine (2,500 mg/m2/day, days 1 to 14) and cisplatin (60 mg/m2, day 1) every 3 weeks. Response was assessed for every two cycles of chemotherapy and treatment was stopped when tumor had progressed or stable with no further response. Thirty-two patients were enrolled, 20 (62.5%) were male and 12 (37.5%) were female and the median age was 54 years (33–71 years). Fifteen patients (46.9%) had gallbladder cancer, 13 (40.6%) had intrahepatic cholangiocarcinoma, and 4 (12.5%) had extrahepatic biliary cancer. The most frequent metastatic sites were lymph nodes (20/32, 62.5%) and liver (28/32, 56.3%). No complete response was observed and partial response was observed in 13/32 patients. By the intent-to-treat analysis, the overall response rate was 40.6% (95% CI, 23.7–59.4) with 0 CR and 13 PRs. Stable disease was observed in 3 patients (9.4%), and 11 patients (34.4%) had progressive disease. The median time to progression was 3.5 months (95% CI, 1.3–5.8), and the median overall survival was 12.4 months (95% CI, 6.3–18.5) after the median follow-up duration of 9.5 months (4.8–26.1 months). A total of 108 cycles of chemotherapy was delivered. Grade 3 hematologic toxicities included neutropenia (5, 15.6%), anemia (1, 3.1%), and thrombocytopenia (1, 3.1%) per patient, and no grade 4 hematologic toxicities were observed. Grade 3 non-hematologic toxicities included hyperbilirubinemia (2, 6.3%), increase of alkaline phosphatase (2, 6.3%), hand–foot syndrome (2, 6.3%), anorexia, and diarrhea (1, 3.1%) per patient, respectively. There was no treatment-related death. The combination chemotherapy of capecitabine and cisplatin demonstrated a promising antitumor activity with mild toxicity profile in patients with advanced biliary tract cancer. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the therapeutic value and safety of third-line treatment with mitomycin-C (MMC) and capecitabine (Xeloda) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5-FU), folinic acid (FA) and irinotecan (CPT-11) or 5-FU, FA and oxaliplatin (L-OHP). Patients and methods: A total of 21 patients (M/F 16/5, median age 60.0 years) with advanced colorectal cancer, all of whom had developed progressive disease while receiving or within 6 months of discontinuing two sequential chemotherapy lines with 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP, were accrued to this study. At the time of their relapse or progression, cytotoxic chemotherapy, consisting of intravenous MMC 7 mg/m² on therapeutic day 1 plus oral capecitabine 1000 mg/m² twice daily on days 1-14, was initiated. After rest for 7 days, capecitabine 1000 mg/m² twice daily was administered on days 22-35 followed by 7 days rest. Treatment courses were repeated every 6 weeks unless there was evidence of progressive disease, unacceptable toxicity or patient refusal of treatment. Results: All the patients were assessable for toxicity and 19 for response. The median number cycles of chemotherapy was two (range one to four). Only 1 patient (4.8%) had a partial response, 4 patients (19.0%) had stable disease, and 14 patients (66.7%) progressed. The median follow-up period was 7.3 months and median time to progression was 2.6 months. The median overall survival was 6.8 months. No toxic deaths occurred. Toxicities of third-line treatment were mild and manageable. As NCI/NIH common toxicity criteria, grade 3/4 anemia, neutropenia and thrombocytopenia occurred in two, one and one patients, respectively. Conclusion: Our findings suggest that the combination of MMC and capecitabine in patients with advanced colorectal cancer pretreated with combination regimens including 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP is safe. However, this regimen had a poor response rate and no definitive contribution to increasing patients' overall survival time. Further evaluation of other salvage regimens seems to be warranted. [ABSTRACT FROM AUTHOR]

Objective: The outcome of systemic chemotherapy in metastatic hepatocellular carcinoma (HCC) patients had been disappointing. Based on the demonstrated activities and different mechanisms of action and toxicity profiles, we designed a phase II trial of combination therapy with doxorubicin and cisplatin in metastatic HCC patients anticipating a synergistic interaction of the combination. Methods: From January 1998 to January 2003, 42 consecutive patients with metastatic HCC were accrued. The regimen consisted of doxorubicin 60 mg/m2 delivered as an intravenous infusion over 30 min on day 1, followed by cisplatin 60 mg/m2 infused over 1 h on day 1. The cycle was repeated every 28 days. The objective tumor response was evaluated after two or three courses of chemotherapy. The serum alpha-fetoprotein level was measured at the start of every cycle. Results: In total, 122 cycles of the regimen were administered, with a median of three cycles per patient (range one to eight cycles). The median age of the patients was 45 years (range 19–61 years), and 37 were evaluable for treatment response. The objective response rate was 18.9% (95% CI 8.0-35%) with one complete response and six partial responses. Six patients (16.2%) had stable disease and 24 patients (64.9%) had progression. Median overall survival of 37 patients was 7.3 months (95% CI 5.9–8.6 months). The median time to progression of all evaluable patients was 6.6 months (95% CI 5.4–7.8 months). Of 37 evaluable patients, 12 32.4%, 95% CI 18.0-49.8%) showed more than 50% decrease in AFP level from their baseline AFP and the median time to decrease in AFP by more than 50% was 1.8 months with a range of 0.7–4.7 months. The chemotherapy was well tolerated and the most common grade ¾ side effects were neutropenia (14.3%), thrombocytopenia (11.9%), and diarrhea (9.5%). Conclusion: Combination chemotherapy with doxorubicin and cisplatin in metastatic HCC patients showed modest antitumor activity with relatively tolerable adverse effects. The objective response rate of the regimen was comparable to those found in other phase II trials, but the search for the optimal chemotherapy should be continued. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the psychometric properties of the Korean version of the European Organization for Research and Treatment of Cancer Breast-Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23). A total of 153 patients with breast cancer and 153 normal subjects completed three questionnaires of the Korean version of the EORTC QLQ-BR23. Multitrait scaling analyses demonstrated that all scales met multidimensional conceptualization criteria in terms of convergence and discrimination validity. Cronbach?s alpha coefficients for five multiple-item scales were greater than 0.70 (range, 0.72?0.91). In known-group comparisons, there were marked group differences between patients differing in disease stage. In breast cancer patients, performance on the questionnaires was in the expected direction for almost all functioning and symptom scores. In addition, comparison between the patient and control groups showed that almost all variables discriminated between patients and normal individuals. In conclusion, the Korean version of the EORTC QLQ-BR23 was found to be a reliable and valid measure of quality of life in breast cancer patients, indicating that it should be used in clinical and epidemiological cancer research. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate efficacy and safety of the combination chemotherapy with irinotecan plus capecitabine in patients with advanced colorectal adenocarcinoma. Methods: Patients with histologically proven advanced colorectal adenocarcinoma received a first-line chemotherapy with irinotecan 240 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day as an intermittent regimen of 2 weeks of treatment followed by a 1-week rest. Treatment was repeated every 3 weeks. Results: Thirty-nine patients were registered, and 36 were assessable for responses. Sixteen objective responses (44%) were observed with a median response duration of 6.9 months. Stable disease was documented in 14 cases (39%). The median time to progression was 6.7 months. The median overall survival was not reached at the time of analysis, and the 1-year survival rate was 67%. Two patients died: 1 due to sepsis not complicating myelosuppression, and 1 patient, known as a hepatitis B virus carrier prior to chemotherapy, died of hepatic failure, the cause of which was not clinically verified. Frequently encountered therapy-related events were leukopenia and gastrointestinal side effects including diarrhea. Severe hand-and-foot syndrome was observed in only 1 patient. Conclusions: The combination chemotherapy of irinotecan and capecitabine is an active and tolerable regimen for advanced colorectal adenocarcinoma, but the observed deaths suggest a future randomized trial that requires a cautious patient selection. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Presents a phase II study of etoposide (VP-16)-ifosfomide-cisplatin(VIP) combination chemotherapy plus early concurrent thoracic irradiation for patients with untreated small cell lung cancer to assess the improvement in the response rate and toxicity. Effects of early and late thoracic irradiation; Comparison of the response rate and survival of the patients.

Purpose: Peritoneal carcinomatosis (PC) presents a major challenge in the treatment of late-stage, solid tumors, with traditional therapies limited by poor drug penetration. We evaluated a novel hyperthermic pressurized intraperitoneal aerosol chemotherapy (HPIPAC) system using a human abdominal cavity model for its efficacy against AGS gastric cancer cells. Materials and Methods: A model simulating the human abdominal cavity and AGS gastric cancer cell line cultured dishes were used to assess the efficacy of the HPIPAC system. Cell viability was measured to evaluate the impact of HPIPAC under 6 different conditions: heat alone, PIPAC with paclitaxel (PTX), PTX alone, normal saline (NS) alone, heat with NS, and HPIPAC with PTX. Results: Results showed a significant reduction in cell viability with HPIPAC combined with PTX, indicating enhanced cytotoxic effects. Immediately after treatment, the average cell viability was 66.6%, which decreased to 49.2% after 48 hours and to a further 19.6% after 120 hours of incubation, demonstrating the sustained efficacy of the treatment. In contrast, control groups exhibited a recovery in cell viability; heat alone showed cell viability increasing from 90.8% to 94.4%, PIPAC with PTX from 82.7% to 89.7%, PTX only from 73.3% to 74.8%, NS only from 90.9% to 98.3%, and heat with NS from 74.4% to 84.7%. Conclusions: The HPIPAC system with PTX exhibits a promising approach in the treatment of PC in gastric cancer, significantly reducing cell viability. Despite certain limitations, this study highlights the system’s potential to enhance treatment outcomes. Future efforts should focus on refining HPIPAC and validating its effectiveness in clinical settings. [ABSTRACT FROM AUTHOR]

Purpose: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. Materials and Methods: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of =50.4 Gy were defined as the non-boost group, while =54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. Results: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). Conclusion: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed. [ABSTRACT FROM AUTHOR]

Background/Aims: Synchronous multiple gastric cancer (SMGC) accounts for approximately 6% to 14% of gastric cancer (GC) cases. This study aimed to identify risk factors for SMGC. Methods: A total of 14,603 patients diagnosed with GC were prospectively enrolled. Data including age, sex, body mass index, smoking, alcohol consumption, family history, p53 expression, microsatellite instability, cancer classification, lymph node metastasis, and treatment were collected. Risk factors were analyzed using logistic regression analysis between a single GC and SMGC. Results: The incidence of SMGC was 4.04%, and that of early GC (EGC) and advanced GC (AGC) was 5.43% and 3.11%, respectively. Patients with SMGC were older (65.33 years vs 61.75 years, p<0.001) and more likely to be male. Lymph node metastasis was found in 27% of patients with SMGC and 32% of patients with single GC. Multivariate analysis showed that SMGC was associated with sex (male odds ratio [OR], 1.669; 95% confidence interval [CI], 1.223 to 2.278; p=0.001), age (≥65 years OR, 1.532; 95% CI, 1.169 to 2.008; p=0.002), and EGC (OR, 1.929; 95% CI, 1.432 to 2.600; p<0.001). Survival rates were affected by Lauren classification, sex, tumor size, cancer type, distant metastasis, and venous invasion but were not related to the number of GCs. However, the survival rate of AGC with SMGC was very high. Conclusions: SMGC had unique characteristics such as male sex, older age, and EGC, and the survival rate of AGC, in which the intestinal type was much more frequent, was very good, [ABSTRACT FROM AUTHOR]

Purpose Bone metastasis (BM) adversely affects the prognosis of gastric cancer (GC). We investigated molecular features and immune microenvironment that characterize GC with BM compared to GC without BM. Materials and Methods Targeted DNA and whole transcriptome sequencing were performed using formalin-fixed paraffin-embedded primary tumor tissues (gastrectomy specimens) of 50 GC cases with distant metastases (14 with BM and 36 without BM). In addition, immunohistochemistry (IHC) for mucin-12 and multiplex IHC for immune cell markers were performed. Results Most GC cases with BM had a histologic type of poorly cohesive carcinoma and showed worse overall survival (OS) than GC without BM (p < 0.05). GC with BM tended to have higher mutation rates in TP53, KDR, APC, KDM5A, and RHOA than GC without BM. Chief cell-enriched genes (PGA3, PGC, and LIPF), MUC12, MFSD4A, TSPAN7, and TRIM50 were upregulated in GC with BM compared to GC without BM, which was correlated with poor OS (p < 0.05). However, the expression of SERPINA6, SLC30A2, PMAIP1, and ITIH2 were downregulated in GC with BM. GC with BM was associated with PIK3/AKT/mTOR pathway activation, whereas GC without BM showed the opposite effect. The densities of helper, cytotoxic, and regulatory T cells did not differ between the two groups, whereas the densities of macrophages were lower in GC with BM (p < 0.05). Conclusion GC with BM had different gene mutation and expression profiles than GC without BM, and had more genetic alterations associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

Purpose: According to the American Joint Committee on Cancer cancer staging system, positive peritoneal washing cytology (PWC) indicates stage IV gastric cancer. However, rapid intraoperative diagnosis of PWC has no established reliable method. This study evaluated and compared the diagnostic accuracy of the Shorr and the modified ultrafast Papanicolaou (MUFP) methods for intraoperative PWC. Materials and Methods: This study included patients with gastric cancer who were clinically diagnosed with stage cT3 or higher. The Shorr and MUFP methods were performed on all PWC specimens, and the results were compared with those of conventional Papanicolaou (PAP) staining with carcinoembryonic antigen immunohistochemistry. Sensitivity, specificity, and partial likelihood tests were used to compare the 2 methods. Results: Forty patients underwent intraoperative PWC between November 2019 and August 2021. The average time between specimen reception and slide preparation using Shorr and MUFP methods was 44.4±4.5 minutes, and the average time between specimen reception and pathologic diagnosis was 53.9±8.9 minutes. Eight patients (20.0%) had positive cytology in PAP staining. The Shorr method had a sensitivity of 75.0% and specificity of 93.8%; the MUFP method had 62.5% sensitivity and 100.0% specificity. The area under the curve was 0.844 for Shorr and 0.813 for MUFP. In comparing the C-indices of each method with overall survival, no difference was found among the Shorr, MUFP, and conventional PAP methods. Conclusions: The Shorr and MUFP methods are acceptable for the intraoperative diagnosis of PWC in advanced gastric cancer. [ABSTRACT FROM AUTHOR]

Background/Aims: There are few reports regarding mixed carcinoma, defined as a mixture of glandular and poorly cohesive components, in patients with gastric cancer (GC). The aim of this study was to evaluate the proportion and characteristics of mixed carcinoma in GC patients. Methods: A total of 7,215 patients diagnosed with GC at Seoul National University Bundang Hospital were enrolled from March 2011 to February 2020. GC was divided into four groups (wellmoderately differentiated GC, poorly differentiated GC, poorly cohesive carcinoma, and mixed carcinoma). The proportion of each GC type and the clinicopathological features were analyzed and divided into early GC and advanced GC. Results: The proportion of mixed carcinoma was 10.9% (n=787). In early GC, submucosal invasion was the most common in poorly differentiated (53.7%), and mixed carcinoma ranked second (41.1%). Mixed carcinoma showed the highest proportion of lymph node metastasis in early GC (23.0%) and advanced GC (78.3%). In advanced GC, the rate of distant metastasis was 3.6% and 3.9% in well-moderately differentiated GC and mixed carcinoma, respectively, lower than that in poorly differentiated GC (6.4%) and poorly cohesive carcinoma (5.7%), without statistical significance. Conclusions: Mixed carcinoma was associated with lymph node metastasis compared to other histological GC subtypes. And it showed relatively common submucosal invasion in early GC, but the rates of venous invasion and distant metastasis were lower in advanced GC. Further research is needed to uncover the mechanism underlying these characteristics of mixed carcinoma. [ABSTRACT FROM AUTHOR]

Background: To investigate the optimal approach for laparoscopic splenic hilum lymph node dissection in proximal advanced gastric cancer, we compared the operative outcomes between laparoscopic spleen-preserving total gastrectomy (sp-LTG) and laparoscopic total gastrectomy with splenectomy (sr-LTG). Methods: A retrospective case-cohort study was conducted between February 2006 and December 2012. The operative outcomes, the number of retrieved splenic hilum lymph node, complication, and patients' survivals were analyzed. Results: 112 patients who underwent laparoscopic total gastrectomy with or without splenectomy for advanced gastric cancer were enrolled (68 sp-LTGs and 44 sr-LTGs). The mean operation time (227 min vs. 224 min, p = 0.762), estimated blood loss (157 ml vs. 164 ml, p = 0.817), and complication rate (17.6% vs. 13.6%, p = 0.572) were not different between two groups. Regarding splenic lymph node dissection, there were significantly differences in the mean number of retrieved lymph nodes between sp-LTG and sr-LTG (LN no.10; 1.78 vs. 3.21, p = 0.033, LN no.11d; 1.41 vs. 2.76, p = 0.004). The 5-year survivals were 77.3% in sp-LTG and 65.9% in sr-LTG (p = 0.240). The hazard ratio of splenectomy was 1.139 (95% confidence interval 0.514-2.526, p = 0.748). Conclusion: In laparoscopic total gastrectomy for proximal advanced gastric cancer, spleen-preserving hilar dissection showed comparable short-term and long-term outcomes. [ABSTRACT FROM AUTHOR]

Purpose: In this study, polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing was comprehensively analyzed and compared with immunohistochemistry (IHC) for mismatch repair (MMR) protein expression in patients with gastric cancer (GC). Materials and Methods: In 5,676 GC cases, PCR-based MSI testing using five microsatellites (BAT-26, BAT-25, D5S346, D2S123, and D17S250) and IHC for MLH1 were performed. Re)evaluation of MSI testing/MLH1 IHC and additional IHC for MSH2, MSH6, and PMS2 were performed in discordant/indeterminate cases. Results: Of the 5,676 cases, microsatellite stable (MSS)/MSI-low and intact MLH1 were observed in 5,082 cases (89.5%), whereas MSI-high (MSI-H) and loss of MLH1 expression were observed in 502 cases (8.8%). We re-evaluated the remaining 92 cases (1.6%) with a discordant/ indeterminate status. Re-evaluation showed 1) 37 concordant cases (0.7%) (18 and 19 cases of MSI-H/MMR-deficient (dMMR) and MSS/MMR-proficient (pMMR), respectively), 2) 6 discordant cases (0.1%) (3 cases each of MSI-H/pMMR and MSS/dMMR), 3) 14 MSI indeterminate cases (0.2%) (1 case of dMMR and 13 cases of pMMR), and 4) 35 IHC indeterminate cases (0.6%) (22 and 13 cases of MSI-H and MSS, respectively). Finally, MSI-H or dMMR was observed in 549 cases (9.7%), of which 47 (0.8%) were additionally confirmed as MSI-H or dMMR by re-evaluation. Sensitivity was 99.3% for MSI testing and 95.4% for MMR IHC. Conclusions: Considering the low incidence of MSI-H or dMMR, discordant/indeterminate results were occasionally identified in GCs, in which case complementary testing is required. These findings could help improve the accuracy of MSI/MMR testing in daily practice. [ABSTRACT FROM AUTHOR]

Background/Aims: The incidence and prognosis of gastric cancer (GC) shows sex difference. This study aimed to evaluate the effect of body mass index (BMI) on GC survival depending on sex. Methods: The sex, age, location, histology, TNM stages, BMI, and survival were analyzed in GC patients from May 2003 to February 2020 at the Seoul National University Bundang Hospital. Results: Among 14,688 patients, there were twice as many males (66.6%) as females (33.4%). However, under age 40 years, females (8.6%) were more prevalent than males (3.1%). Cardia GC in males showed a U-shaped distribution for underweight (9.6%), normal (6.4%), overweight (6.1%), obesity (5.6%), and severe obesity (9.3%) but not in females (p=0.003). Females showed decreased proportion of diffuse-type GC regarding BMI (underweight [59.9%], normal [56.8%], overweight [49.5%], obesity [44.8%], and severe obesity [41.7%]), but males did not (p<0.001). Both sexes had the worst prognosis in the underweight group (p<0.001), and the higher BMI, the better prognosis in males, but not females. Sex differences in prognosis according to BMI tended to be more prominent in males than in females in subgroup analysis of TNM stages I, II, and III and the operative treatment group. Conclusions: GC-specific survival was affected by BMI in a sex-dependent manner. These differences may be related to genetic, and environmental, hormonal factors; body composition; and muscle mass (Trial registration number: NCT04973631). [ABSTRACT FROM AUTHOR]

Background: With a 15% incidence, KRAS is one of the most common mutations in biliary tract cancer (BTC) and is a poor prognostic factor. Immune checkpoint inhibitors (ICIs) as salvage therapy have modest activity in BTC. Objectives: There are limited data on the efficacy of ICIs according to KRAS mutation in BTC. We evaluated the efficacy of ICIs in BTC patients with or without KRAS mutations. Design: Retrospective observational study. Methods: We conducted molecular profiling in BTC patients who received ICIs as salvage therapy. The expression of programmed death ligand 1 (PD-L1) on tumor cells was assessed using immunohistochemistry. The TruSight™ Oncology 500 assay from Illumina was used as a cancer panel. We analyzed overall survival (OS) and progression-free survival (PFS) of ICI in BTC patients according to KRAS mutation and PD-L1 expression. Results: A total of 62 patients were included in this analysis. The median age was 68.0years; 47 patients (75.8%) received pembrolizumab and 15 (24.2%) received nivolumab as salvage therapy. All patients received gemcitabine plus cisplatin as the frontline therapy, and 53.2% received fluoropyrimidine plus oxaliplatin (FOLFOX) before ICI. The median number of lines of prior chemotherapy was 2.5. The KRAS mutation was found in 13 patients (19.1%), and 28 patients (45.2%) showed 1% or more of tumor cells out of visible tumor cells positive for PD-L1. There was no statistical correlation between KRAS mutation and PD-L1 expression. The median OS and PFS with ICI were 5.6 [interquartile range (IQR): 3.3–8.0] and 3.8 (IQR: 3.0–4.5) months, respectively. There were no statistically significant differences in PFS with ICIs according to KRAS mutation (mutant type versus wild type) and PD-L1 expression (positive versus negative). In subgroup analysis, patients with both KRAS mutation and PD-L1 positivity had longer PFS compared with patients with KRAS mutation and PD-L1 negativity (10.1 versus 2.6months, 푝=0.047). This finding was not shown in patients with wild-type KRAS. Conclusion: Our analysis suggested that PD-L1 expression might be a useful biomarker for ICIs in BTC patients with KRAS mutation but not in those with wild-type KRAS. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC). Materials and Methods Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity. Results Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin. Conclusion The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity. [ABSTRACT FROM AUTHOR]

Purpose Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. Materials and Methods We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. Conclusion Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor. [ABSTRACT FROM AUTHOR]

Background: Continuous glucose monitoring (CGM) has been widely used in the management of diabetes. However, the usefulness and detailed data during perioperative status were not well studied. In this study, we described the immediate changes of glucose profiles after metabolic surgery using intermittently scanned CGM (isCGM) in individuals with type 2 diabetes mellitus (T2DM). Methods: This was a prospective, single-center, single-arm study including 20 participants with T2DM. The isCGM (FreeStyle Libre CGM) implantation was performed within 2 weeks before surgery. We compared CGM metrics of 3 days before surgery and 3 days after surgery, and performed the correlation analyses with clinical variables. Results: The mean glucose significantly decreased after surgery (147.0±40.4 to 95.5±17.1 mg/dL, P<0.001). Time in range (TIR; 70 to 180 mg/dL) did not significantly change after surgery in total. However, it was significantly increased in a subgroup of individuals with glycosylated hemoglobin (HbA1c) =8.0%. Time above range (>250 or 180 mg/dL) was significantly decreased in total. In contrast, time below range (<70 or 54 mg/dL) was significantly increased in total and especially in a subgroup of individuals with HbA1c <8.0% after surgery. The coefficient of variation significantly decreased after surgery. Higher baseline HbA1c was correlated with greater improvement in TIR (rho=0.607, P=0.005). Conclusion: The isCGM identified improvement of mean glucose and glycemic variability, and increase of hypoglycemia after metabolic surgery, but TIR was not significantly changed after surgery. We detected an increase of TIR only in individuals with HbA1c =8.0%. [ABSTRACT FROM AUTHOR]

Background/Aims: Less invasive surgical treatment is performed in East Asia to preserve postoperative digestive function and reduce complications such as post gastrectomy syndromes, but there is an issue of metachronous gastric cancer (GC) in the remaining stomach. This study aimed to analyze the incidence of metachronous GC and its risk factors in patients who had undergone partial gastrectomy. Methods: A total of 3,045 GC patients who had undergone curative gastric partial resection at Seoul National University Bundang Hospital were enrolled and analyzed retrospectively for risk factors, including age, sex, smoking, alcohol, Helicobacter pylori status, family history of GC, histological type, and surgical method. Results: Metachronous GC in the remaining stomach occurred in 35 of the 3,045 patients (1.1%): 23 in the distal gastrectomy group (18 with Billroth-I anastomosis, five with Billroth-II anastomosis), seven in the proximal gastrectomy (PG) group, and five in the pylorus-preserving gastrectomy (PPG) group. Univariate and multivariate Cox regression analyses showed that age ≥60 years (p=0.005) and surgical method used (PG or PPG, p<0.001) were related risk factors for metachronous GC, while male sex and intestinal type histology were potential risk factors. Conclusions: Metachronous GC was shown to be related to older age and the surgical method used (PG or PPG). Regular and careful follow-up with endoscopy should be performed in the case of gastric partial resection, especially in patients with male sex and intestinal type histology as well as those aged ≥60 years undergoing the PG or PPG surgical method. [ABSTRACT FROM AUTHOR]

Background: Single-incision laparoscopic surgery is gaining more attention due to advancements in surgical devices and techniques. Ten years have passed since the first report of single-incision distal gastrectomy. This study aims to analyze the long-term oncological safety of single-incision distal gastrectomy by comparing it with multiport distal gastrectomy.Study Design: Patients diagnosed with gastric cancer who underwent laparoscopic distal gastrectomy from January 2010 to December 2017 were enrolled. Palliative surgery, history of other malignancy, preoperative chemotherapy, and distant metastasis were excluded. The 5-year overall survival and 5-year disease-free survival were set as coprimary endpoints. Operative time, blood loss, postoperative outcome, and risk factors for survival were secondary endpoints. Propensity score matching of 1:1 ratio was performed to adjust for age, sex, body mass index, comorbidities, tumor size, operation history, and clinical stage.Results: A total of 3,097 patients were enrolled. After propensity score matching, 378 patients were allocated to each group. There was no difference in patient demographics after matching. Operation time was faster (170.8 ± 65.3 minutes vs 147.2 ± 44.1 minutes, p < 0.001), with less blood loss in the single-port group (84.1 ± 87.6 mL vs 34.9 ± 49.9 mL, p < 0.001). Administration of additional intravenous analgesics was less frequent in the single-port group (p = 0.043). There was no difference in long-term survival (5-year overall survival: multiport 94.2%, single-port 95.8%, p = 0.43; 5-year disease-free survival: multiport 94.1%, single-port 95.8%, p = 0.32).Conclusions: Single-incision distal gastrectomy is safe and feasible with good long-term outcomes and less use of additional analgesics for patients diagnosed with early gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose The present study aimed to evaluate atypical lymph node metastasis rates according to tumor depth, size, and location in patients with gastric cancer. Methods A total of 727 gastric adenocarcinoma patients, with metastasis to 1 or 2 lymph nodes, who underwent radical gastrectomy with curative intent from May 2003 to May 2017, were enrolled in this study. The characteristics of atypical (skip or transversal) metastases were evaluated according to the following risk factors: longitudinal versus circumferential location, size, and T stage of the tumor. Results The rates of skip and transversal metastases were 8.4% and 15.5%, respectively. Skip metastases were present throughout, regardless of the primary tumor location. On the contrary, transversal metastases of gastric cancer were most frequently observed in the lower third region (19.5%, P=0.002). When the size of the tumor is large (>4 cm), transversal metastasis was found to be significantly more common (P=0.035), compared with skip metastasis, which was less common (P=0.011). There was no significant correlation between atypical metastases and tumor depth. Conclusion Lower and larger tumors were more likely to have transversal metastases compared with others; however, skip metastases were less common in large tumors.

Purpose Trifluridine/tipiracil (TAS-102) was effective in patients with metastatic colorectal cancer (mCRC) in a phase II Japanese trial. This regional trial evaluated the efficacy and safety of trifluridine/tipiracil in Asian patients with mCRC with or without exposure to biologic therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase III trial was conducted at 30 sites in China, the Republic of Korea, and Thailand. Patients ≥ 18 years old with histologically or cytologically confirmed adenocarcinoma of the colon or rectum and known KRAS status who were refractory or intolerant to two or more prior chemotherapy regimens were enrolled. Eligible patients were randomly assigned (2:1 ratio; minimization method) to receive trifluridine/tipiracil (twice per day orally; 5 days on and 2 days off for 2 weeks, followed by 14 days off per cycle) or placebo. The primary end point was overall survival (intent-to-treat population). Results Between October 16, 2013, and June 15, 2015, 406 patients were randomly assigned to receive trifluridine/tipiracil (n = 271) or placebo (n = 135). Risk of death was significantly lower in the trifluridine/tipiracil arm than in the placebo arm (hazard ratio for death, 0.79; 95% CI, 0.62 to 0.99; log-rank P = .035). Median overall survival was significantly longer in the trifluridine/tipiracil than in the placebo arm (7.8 months [95% CI, 7.1 to 8.8 months] v 7.1 months [95% CI, 5.9 to 8.2 months], respectively), for a median survival follow-up time of 13.8 months (95% CI, 13.1 to 15.3 months) compared with 13.4 months (95% CI, 11.6 to 17.3 months), respectively. The incidence of serious adverse events was similar between the arms (trifluridine/tipiracil, n = 63 [23.2%]; placebo, n = 32 [23.7%]). No treatment-related deaths were reported. Conclusion Trifluridine/tipiracil has a statistically significant survival benefit compared with placebo in Asian patients with mCRC refractory or intolerant to standard chemotherapies, regardless of exposure to biologic therapy. The safety profile is similar to previous reports.