Sequential Lateral Lymphatic Metastasis Shows Similar Oncologic Outcomes to Upward Spread in Advanced Rectal Cancer After Preoperative Chemoradiotherapy.

BACKGROUND: Whether lateral pelvic node metastasis should be considered as a regional or systemic disease is a long-standing debate. Although previous Japanese studies have considered it to be locoregional disease, Western countries consider it a systemic disease and do not perform lateral pelvic node dissection after preoperative chemoradiotherapy. OBJECTIVE: To evaluate whether lateral pelvic node metastasis is a systemic or regional disease that is amenable to curative resection. DESIGN: Retrospective analysis of a prospectively collected database. SETTING: This study was conducted at a tertiary cancer center. PATIENTS: There were 616 consecutive patients who underwent curative total mesorectal excision alone or with lateral pelvic node dissection after preoperative chemoradiotherapy for locally advanced rectal cancer between 2011 and 2019. MAIN OUTCOME MEASURES: Three-year disease-free and overall survival. RESULTS: A total of 360 patients underwent total mesorectal excision, and 160 patients underwent total mesorectal excision with lateral pelvic node dissection. There was no difference in the 3-year disease-free survival (DFS; p = 0.844) or overall survival rates ( p = 0.921) between the groups. Patients with lateral pelvic node metastasis showed DFS similar to those with perirectal lymph node metastasis in the total mesorectal excision group. In a subgroup analysis, patients with internal iliac pelvic node metastasis showed a disease-free survival comparable to those with perirectal node involvement, and patients with other lateral pelvic node metastasis showed a DFS similar to those with intermediate node involvement. In the lateral pelvic node dissection group, the lateral pelvic node metastatic rate was 32.5%. On multivariate analysis, fewer than 8 of the unilateral harvested lateral pelvic nodes and advanced ypT stage were significantly associated with poor disease-free survival. LIMITATION: The retrospective design. CONCLUSIONS: Lateral lymphatic metastasis showed oncologic outcomes similar to those of upward spread, especially perirectal lymph nodes metastasis. Large cohort studies with long-term follow-up are required to confirm these results. See Video Abstract . LAS METSTASIS LINFTICAS SECUENCIALES LATERALES MUESTRAN RESULTADOS ONCOLGICOS SIMILARES EN LA PROPAGACIN ASCENDENTE DEL CNCER RECTAL AVANZADO DESPUS DE LA RADIOQUIMIOTERAPIA PREOPERATORIA: ANTECEDENTES:Es un debate muy antiguo si las metástasis en los ganglios pélvicos laterales deben considerarse una enfermedad regional o sistémica. Si bien estudios japoneses anteriores las consideran como una enfermedad locorregional, en los países de occidente se las considera como una enfermedad sistémica por la cual no se realiza disección de ganglios pélvicos laterales después de una radioquimioterapia preoperatoria.OBJETIVOS:Evaluar si la metástasis en los ganglios pélvicos laterales se consideran como enfermedad sistémica o enfermedad regional susceptible de resección curativa.DISEÑO:Análisis retrospectivo de una base de datos recopilada prospectivamente.AJUSTE:Este estudio se realizó en un centro oncológico terciario.PACIENTES:616 pacientes consecutivos se sometieron a excisión total del mesorrecto curativa sola o con disección de los ganglios pélvicos laterales después de radioquimioterapia preoperatoria en casos de cáncer de recto localmente avanzado entre 2011 y 2019.PRINCIPALES MEDIDAS DE RESULTADO:Sobrevida global y libre de enfermedad a 3 años.RESULTADOS:Un total de 360 pacientes se sometieron a excisión total del mesorrecto y 160 pacientes se sometieron a excisión total del mesorrecto con disección de ganglios pélvicos laterales.No hubo diferencias en la sobrevida libre de enfermedad a 3 años (p = 0,844) ni en las tasas de sobrevida general (p = 0,921) entre los grupos. Los pacientes con metástasis en los ganglios pélvicos laterales mostraron una sobrevida libre de enfermedad similar a aquellos con metástasis en los ganglios linfáticos perirrectales que se encontraban en el grupo de excisión total del mesorrecto.En el análisis de subgrupos, los pacientes con metástasis en los ganglios pélvicos ilíacos internos mostraron una sobrevida libre de enfermedad comparable a aquellos con afección de los ganglios perirrectales y los pacientes con otras metástasis en los ganglios pélvicos laterales mostraron una sobrevida libre de enfermedad similar a aquellos con afección de los ganglios intermedios.En el grupo de disección de los ganglios pélvicos laterales, la tasa de metástasis en dichos ganglios fué del 32,5%. En el análisis multivariado, < de 8 ganglios pélvicos laterales resecados unilateralmente y el estadio ypT avanzado se asociaron significativamente con una menor sobrevida libre de enfermedad.LIMITACIÓN:El diseño retrospectivo del estudio.CONCLUSIONES:Las metástasis linfáticas laterales mostraron resultados oncológicos similares a la diseminación ascendente, especialmente las metástasis en los ganglios linfáticos perirrectales. Se requieren grandes estudios de cohortes con seguimiento a largo plazo para confirmar estos resultados. (Traducción-Dr. Xavier Delgadillo ).

Preoperative sequential short-course radiation therapy and FOLFOX chemotherapy versus long-course chemoradiotherapy for locally advanced rectal cancer: a multicenter, randomized controlled trial (SOLAR trial).

BACKGROUND: Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). METHODS: A multicenter randomized phase II trial involving 364 patients with LARC (cT3-4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45-50.4 Gy in 25-28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2-5 weeks from the last cycle of chemotherapy in the experimental arm and 6-8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. DISCUSSION: This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. TRIAL REGISTRATION: This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

Oncological impact of intraperitoneal chemotherapy after cytoreductive surgery for patients with colorectal peritoneal metastasis: A bi-institutional retrospective analysis.

BACKGROUND AND OBJECTIVES: There is a paucity of evidence on the value of intraperitoneal chemotherapy (IPC) following cytoreductive surgery (CRS) for colorectal peritoneal metastasis. This study aimed to evaluate the association between mitomycin C-IPC and survival outcomes following CRS. METHODS: The institutional databases of two tertiary hospitals were reviewed to identify patients who underwent CRS for colorectal peritoneal metastasis. The outcomes of patients who underwent CRS without IPC were compared with those of patients who underwent CRS plus early postoperative intraperitoneal chemotherapy (EPIC) or CRS plus hyperthermic intraperitoneal chemotherapy (HIPEC). The primary endpoints were cancer-specific survival (CSS), progression-free survival (PFS), and peritoneal PFS (P-PFS). RESULTS: In 149 patients with peritoneal metastasis alone, EPIC and HIPEC use was significantly associated with better CSS, PFS, and P-PFS in the multivariate analysis. CSS was also significantly associated with perioperative systemic chemotherapy. Among 42 patients with both peritoneal and extraperitoneal metastases, CSS was independently related to the completeness of cytoreduction score, location of extraperitoneal metastasis, and grade 3-4 complications. CONCLUSIONS: Mitomycin C-IPC after CRS was associated with better survival outcomes than CRS alone in patients with resectable peritoneal metastasis of colorectal cancer. This study found that IPC had beneficial effects regarding P-PFS in patients with both peritoneal and extraperitoneal metastases.

Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study.

BACKGROUND: The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin. METHODS: This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m2 for 90 min) plus intravenous leucovorin (400 mg/m2 for 30 min) and intravenous fluorouracil (2400 mg/m2 for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete. FINDINGS: Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7-18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6-8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2-1·5; hazard ratio 0·56, 95% CI 0·39-0·81; p=0·0019). The most common grade 3-4 adverse events were neutropenia (21 [24%] of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one [1%] of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 [13%] vs three [3%]). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths. INTERPRETATION: Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer. FUNDING: Servier and HK inno. N TRANSLATION: For the Korean translation of the abstract see Supplementary Materials section.

Initial experience of preoperative short-course radiotherapy followed by oxaliplatin-based consolidation chemotherapy for locally advanced rectal cancer.

PURPOSE: We analyzed the safety and feasibility of preoperative short-course radiotherapy (SCRT) followed by consolidation chemotherapy for patients with locally advanced rectal cancer (LARC). METHODS: From April 2018 to May 2019, 19 patients with LARC were treated with SCRT followed by three cycles of consolidation chemotherapy with leucovorin, fluorouracil, and oxaliplatin (FOLFOX6) before surgery. Adjuvant chemotherapy relied on oxaliplatin. Tumor response, patient compliance, and toxicities were analyzed. RESULTS: The median age was 60 years (range 44-71), and 16 of the patients were male. The median tumor height was 5 cm (range 0-9) from anal verge. All patients received a total dose of 25 Gy in five fractions. The number of cycles of FOLFOX6 before surgery was three in 17, four in one, five in one. Five patients required dose reductions in consolidation chemotherapy. The median interval between initiation of SCRT and surgery was 10.6 weeks (range 8.6-16.4). A pathologic complete response was seen in two patients (11%). Grade III toxicities to the preoperative treatment were seen in five patients (26%): diarrhea in two, a decreased white blood cell count in one, and anemia in two. Postoperative complications arising within 30 days developed in five patients (26%). During the median follow-up period of 20.4 months, there was no tumor recurrence. CONCLUSION: Preoperative SCRT followed by oxaliplatin-based consolidation chemotherapy showed acceptable toxicity and feasibility in patients with LARC. Prospective randomized trials are warranted to verify the efficacy and safety of this treatment strategy compared with conventional long-course concurrent chemoradiotherapy.

Impact of Anatomic Extent of Nodal Metastasis on Adjuvant Chemotherapy Outcomes in Stage III Colon Cancer.

BACKGROUND: An oxaliplatin-based chemotherapy regimen improves the survival outcomes of patients with stage III colon cancer. However, its complications are well-known. OBJECTIVE: The purpose of this study was to distinguish between the survival outcomes of patients who underwent curative resection for stage III colon cancer with oxaliplatin chemotherapy and those who underwent such resection without oxaliplatin chemotherapy. DESIGN: This was a retrospective analytical study based on prospectively collected data. SETTINGS: This study used data on patients who underwent surgery at our hospital between January 2010 and December 2014. PATIENTS: A cohort of 254 consecutive patients who underwent curative resection for stage III colon cancer was included in this study. The patients were divided into 2 groups: patients with isolated pericolic lymph node metastasis (n = 175) and those with extrapericolic lymph node metastasis (n = 79). MAIN OUTCOME MEASURES: Clinicopathologic features and 3-year survival outcomes were analyzed with and without oxaliplatin therapy in the pericolic lymph node group. RESULTS: The pericolic lymph node group showed significantly improved overall survival compared with the extrapericolic lymph node group at a median follow-up of 48.5 months (95.8% vs 77.8%; p < 0.001). In contrast, there was no significant difference in overall survival (99.0% vs 92.0%; p = 0.137) and disease-free survival (89.1% vs 88.2%; p = 0.460) between the oxaliplatin and nonoxaliplatin subgroups of the pericolic lymph node group. Multivariate analysis showed that the administration of oxaliplatin chemotherapy to the pericolic lymph node group did not lead to a significant difference in the overall survival (p = 0.594). LIMITATIONS: The study was limited by its retrospective design and single institutional data analysis. CONCLUSIONS: This study suggests that the anatomic extent of metastatic lymph nodes could affect patient prognosis, and the effect of oxaliplatin-based adjuvant chemotherapy may not be prominent in stage III colon cancer with isolated pericolic lymph node metastasis.

Treatment with intravenous busulfan, melphalan, and etoposide followed by autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a multicenter study from the consortium for improving survival of lymphoma.

Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.

Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma.

Cordyceps species are known to contain numerous bioactive compounds, including cordycepin. Extracts of Cordyceps militaris (CME) are used in diverse medicinal purposes because of their bioactive components. Cordycepin, one of the active components of CME, exhibits anti-proliferative, pro-apoptotic, and anti-inflammatory effects. Cordycepin structurally differs from adenosine in that its ribose lacks an oxygen atom at the 3' position. We previously reported that cordycepin suppresses Epstein⁻Barr virus (EBV) gene expression and lytic replication in EBV-associated gastric carcinoma (EBVaGC). However, other studies reported that cordycepin induces EBV gene expression and lytic reactivation. Thus, it was reasonable to clarify the bioactive effects of CME bioactive compounds on the EBV life cycle. We first confirmed that CME preferentially induces EBV gene expression and lytic reactivation; second, we determined that adenosine in CME induces EBV gene expression and lytic reactivation; third, we discovered that the adenosine A1 receptor (ADORA1) is required for adenosine to initiate signaling for upregulating BZLF1, which encodes for a key EBV regulator (Zta) of the EBV lytic cycle; finally, we showed that BZLF1 upregulation by adenosine leads to delayed tumor development in the EBVaGC xenograft mouse model. Taken together, these results suggest that adenosine is an EBV lytic cycle inducer that inhibits EBVaGC development.

Quercetin Synergistically Inhibit EBV-Associated Gastric Carcinoma with Ganoderma lucidum Extracts.

Mycotherapy has been shown to improve the overall response rate during cancer treatment and reduce some chemotherapy-related adverse events. Ganoderma lucidum is a traditional mushroom used for pharmaceutical purposes. G. lucidum extracts (GLE) showed potential antitumor activities against several cancers. These tumor inhibitory effects of GLE were attributed to the suppression of the proliferation and metastasis of cancer cells. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is defined as the monoclonal proliferation of carcinoma cells with latent EBV infection. The inhibitory effects of GLE against EBVaGC are questionable. The aim of this study was to investigate GLE as potential antitumor agents and a counterpart of quercetin (QCT) for the cotreatment in suppressing EBVaGC development. Therefore, this study conducted antitumor assays using a EBVaGC xenograft mice model and found that GLE could suppress tumor development. These inhibitory effects were significantly augmented by the low concentration of the quercetin (QCT) cotreatment in the xenograft mice. The addition of GLE in low concentrations synergistically reinforced QCT-induced apoptosis and EBV lytic reactivation. GLE contains various polysaccharides and triterpenes, such as ganoderic acid. Interestingly, the addition of ganoderic acid A (GAA) could produce similar bioactive effects like GLE in QCT-mediated antitumor activity. The GAA addition in low concentrations synergistically reinforced QCT-induced apoptosis and EBV lytic reactivation. GAA was sufficiently effective as much as GLE. Therefore, our results suggested that QCT-supplemented GLE could be a potential food adjunct for the prevention of EBVaGC development.

Phase II study of oxaliplatin, irinotecan and S-1 therapy in patients with advanced gastric cancer: the Korean Cancer Study Group ST14-11.

BACKGROUND: Doublet chemotherapy of platinum and 5-fluorouracil is a standard first-line treatment for patients with unresectable gastric cancer. Although the addition of taxane or irinotecan to this regimen has yielded promising efficacy, its use has been limited due to severe toxicities. To overcome this limitation, we evaluated the efficacy and safety of the combination of irinotecan, oxaliplatin, and S-1 (OIS) for the treatment of advanced gastric cancer. METHODS: Chemotherapy-naïve patients with pathologically proven advanced gastric adenocarcinoma were assessed for eligibility. Irinotecan (135 mg/m2) and oxaliplatin (65 mg/m2) were administered intravenously on day 1, and S-1 (80 mg/m2/day) was administered orally on days 1-7 of every 2-week cycle. RESULTS: Forty-four patients (median age 57 years) were enrolled and all but one patient had a good performance status (ECOG 0 or 1). A total of 529 cycles were administered, with a median of 9.5 (range 1-31) cycles per patient. The overall response rate was 61.4% (95% confidence interval [CI] 46.6-74.3). The median progression-free survival and overall survival were 10.8 months (95% CI 7.6-14.0) and 15.4 months (95% CI 12.6-18.2), respectively. Major toxicities included grade 3/4 neutropenia (38.6%), febrile neutropenia (13.6%), abdominal pain (9.1%), and diarrhea (9.1%). CONCLUSION: These data suggest that the OIS regimen is effective and relatively well tolerated in patients with advanced gastric cancer. Given that all the patients treated, but one, had a good performance status, these results must be confirmed in a patient population more representative of regular clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02527785.

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer.

BACKGROUND: This study investigated the clinical relevance and prognostic impact of the overall expression of programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-2 (PD-L2), in patients with Epstein-Barr virus-associated gastric cancer (EBVaGC). METHODS: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, the expression status of PD-L1 and PD-L2 in 120 patients with EBVaGC identified by EBV-encoded RNA in situ hybridisation was retrospectively analysed using immunohistochemistry (IHC). For each IHC marker, positivity was separately in intraepithelial tumour cells (iTu-) and immune cells in the tumour stroma area (str-). RESULTS: Among 116 eligible patients, 57 (49.1%) and 66 patients (56.9%) were determined as iTu-PD-L1-positive and str-PD-L1-positive, respectively, whereas 23 (21.6%) and 45 patients (38.8%) were determined as iTu-PD-L2 positive and str-PD-L2 positive, respectively. Intraepithelial tumour cell PD-L1 positivity was found to be significantly associated with lymph node (LN) metastasis (P=0.012) and a poor disease-free survival (DFS) (P=0.032), yet not overall survival (P=0.482). In a multivariate analysis, iTu-PD-L1 positivity was independently associated with a poor DFS (P=0.006, hazard ratio=12.085). In contrast, str-PD-L2-positivity was related to a lower T category (P=0.003), absence of LN metastasis (P=0.032) and perineural invasion (P=0.028). Intraepithelial tumour cell and str-PD-L2 positivity showed a trend towards an improved DFS, although not significant (P=0.060 and P=0.073, respectively). CONCLUSIONS: Intraepithelial tumour cells PD-L1 expression can be used to predict a poor outcome in patients with EBVaGC and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.

AQP5 Variants Affect Tumoral Expression of AQP5 and Survival in Patients with Early Breast Cancer.

BACKGROUND: Our previous study showed the association of AQP5 upregulation with cancer proliferation and migration in breast cancer cell lines and with unfavorable prognosis in patients with early breast cancer (EBC). In the current study, we analyzed the association of AQP5 variants or their haplotypes with AQP5 expression and their prognostic impact for survival in patients with EBC. METHODS: Three AQP5 polymorphisms (rs74091166, rs3736309, and rs1964676) were selected based on the SNP database and genotyped using the Sequenom MassARRAY in 374 out of 447 patients with EBC in whom AQP5 expression had been investigated in our previous study. RESULTS: The allele frequencies of the selected variants in the current study were similar to those from Asian data previously reported. In a univariate analysis, both rs74091166 and rs1964676 were statistically associated with survival as a dominant model of minor allele. Moreover, a multivariate survival analysis revealed that the CC genotype of rs1964676 is an independent prognostic marker of survival in EBC patients, regardless of stage, tumor subtype, and adjuvant treatment [hazard ratio = 0.399, 0.384, and 0.205; p = 0.021, 0.027, and 0.016 for disease-free survival (DFS), distant DFS, and disease-specific survival, respectively]. In particular, the CT/TT genotype of rs1964676 showed an association with strong expression of AQP5 (58.6 vs. 26.0%; p = 0.001), without any associations with clinical or pathological characteristics including tumor subtype, stage, or histologic grade. CONCLUSION: The current study suggests AQP5 rs1964676 as a new potential prognostic marker in patients with EBC involved in AQP5 expression.

Efficacy of Early Postoperative Intraperitoneal Chemotherapy After Complete Surgical Resection of Peritoneal Metastasis from Colorectal Cancer: A Case-Control Study from a Single Center.

BACKGROUND: Early postoperative intraperitoneal chemotherapy (EPIC) is a type of intraperitoneal chemotherapy for patients with colorectal cancer and peritoneal metastasis. However, there is a paucity of clinical studies evaluating the efficacy of EPIC after complete cytoreductive surgery. This study was designed to evaluate the efficacy of EPIC in patients who underwent complete surgical resection of peritoneal metastasis from colorectal cancer. METHODS: A 1:2 matched case-control study was conducted in patients undergoing complete surgical resection of peritoneal metastases from colorectal cancer at our institution between January 2000 and November 2013. The operative and survival outcomes of patients receiving EPIC (EPIC group) and those who did not (no EPIC group) were compared. RESULTS: Thirty patients who were treated with EPIC were matched with 15 patients who did not receive EPIC. The 3-year overall survival (OS) and disease-free survival (DFS) were 74.3 and 53.0 % in the EPIC group and 34.7 and 7.5 % in the no EPIC group (EPIC group vs. no EPIC group: OS, P = 0.016; DFS, P = 0.002). Multivariate analysis identified EPIC and adjuvant systemic chemotherapy as independent prognostic factors for OS, whereas only EPIC was prognostic factor for DFS. For peritoneal-DFS, EPIC was the only significant variable in the univariate analysis (hazard ratio, 2.70; 95 % confidence interval 1.17-6.21; P = 0.020). CONCLUSIONS: EPIC is a safe and efficacious option for intraperitoneal chemotherapy to prevent peritoneal recurrence and prolong survival after complete resection of peritoneal metastasis from colorectal cancer.

Pilot Study of Neoadjuvant Chemoradiotherapy with Three Cycles of 5-Fluorouracil Plus Leucovorin for Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Neoadjuvant concurrent chemoradiotherapy combined with total mesorectal excision is the main treatment for patients with locally advanced rectal cancer (LARC). However, because distant metastasis remains the major challenge in the management of LARC, we proposed an additional one cycle of chemotherapy before surgery to improve systemic control. METHODS: One hundred sixty-eight patients with clinical stage II and III rectal cancer were enrolled at Kyungpook National University Medical Center (Daegu, Korea) between January 2011 and December 2013 and were considered the study group. In addition, 160 patients were retrospectively reviewed as the historical control group. All the patients underwent total mesorectal excision at 8 weeks after completing the radiotherapy and receiving a total of six cycles of 5-fluorouracil plus leucovorin. RESULTS: Overall, 155 (96.9%) of the 168 patients completed their planned six cycles of study treatment. Dose modification at any cycle was observed in 18 patients (10.7%). The grade 3 to 4 treatment-related toxicity rate was 27.3%, and the most common grade 3 to 4 hematologic adverse event was neutropenia. With a median follow-up duration of 38 months, the estimated 3-year disease-free survival and OS rates were 79.5 and 86.9%, respectively. CONCLUSIONS: Adding one cycle of chemotherapy during the resting period between chemoradiotherapy and surgery was found to be feasible in patients with LARC in terms of the chemotherapy-related adverse events and postoperative complications. These results warrant further investigation in future prospective randomized trials.

Taxanes in the Treatment of Advanced Gastric Cancer.

Although rapid advances in treatment options have improved the prognosis of advanced gastric cancer (AGC), it remains a major public health problem and the second leading cause of cancer-related deaths in the world. Taxanes (paclitaxel and docetaxel) are microtubule stabilizing agents that inhibit the process of cell division, and have shown antitumor activity in the treatment of AGC as a single or combination chemotherapy. Accordingly, this review focuses on the efficacy and tolerability of taxanes in the first- or second-line chemotherapy setting for AGC.

Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer.

PURPOSE: Recently, enzymes of the serine synthetic pathway (SSP) have been suggested as key player in the metabolic adaptation of oncogenesis. We assessed the expression of enzymes of the SSP in colonic tumor tissue (TT) and paired normal tissue (pNT) and the prognostic implications. METHODS: From 2006 to 2010, we included 486 patients with colon cancer who underwent curative surgery at Kyungpook National University Hospital. Phosphoglycerate dehydrogenase (PHGDH), pyruvate dehydrogenase kinase (PDK) 1, PDK2, pyruvate kinase M2 (PKM2), and phosphoserine aminotransferase (PSAT) expression were investigated by immunohistochemical staining (IHC) in TT and pNT. The IHC values were calculated by multiplying intensity by proportion. The final score was classified as follows: 0-2 as negative and 3-12 as positive. RESULTS: During the median follow-up duration of 55.5 months (37.4-90.6), 78 patients experienced recurrence. The expression of PHGDH, PDK1, and PSAT was significantly higher in TT than pNT (p < 0.001 for each). The univariate analysis for relapse-free survival revealed that TT PDK2 positivity was the only positive prognostic factor (p = 0.023). However, the expression of TT PDK2 did not represent a prognostic value in multivariate analysis. CONCLUSIONS: In conclusion, PHGDH, PDK1, and PSAT were significantly increased in colonic TT compared with pNT. The prognostic implication of these enzymes needs to be further investigated.

Expression of aquaporin-1, aquaporin-3, and aquaporin-5 correlates with nodal metastasis in colon cancer.

OBJECTIVES: The clinical significance of aquaporin-1 (AQP1), aquaporin-3 (AQP3), and aquaporin-5 (AQP5) expression was analyzed in a large number of patients with colon cancer. METHODS: AQP1, AQP3, and AQP5 expression was investigated based on the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery. Scores were given to the staining intensity and percentage of positive cells, and the staining score was defined as the sum of these scores then used to categorize the AQP expression as negative, weakly AQP-positive, or strongly AQP-positive. RESULTS: A total of 298 (61.3%) patients were identified as strongly AQP1-positive (staining score ≥ 6), while 38 (7.8%) were strongly AQP3-positive and 145 (29.8%) were strongly AQP5-positive. The overexpression of AQP1, AQP3, and AQP5 was significantly correlated with lymph node metastasis in a multivariate logistic analysis (AQP1, p = 0.026; AQP3, p = 0.023; AQP5, p = 0.003). While the multivariate survival analysis, which included age, histology, TNM stage, and CEA level showed that the expression of AQP1, AQP3, and AQP5 had no effect on the overall survival and disease-free survival. CONCLUSIONS: The current study found a significant correlation between AQP1, AQP3, and AQP5 expression and lymph node metastasis in patients with surgically resected colon cancer.

Genetic variations in STK11, PRKAA1, and TSC1 associated with prognosis for patients with colorectal cancer.

BACKGROUND: Assuming an association between cancer and metabolism, oncogene-directed metabolic reprogramming in cancer has revealed new target strategies. For example, the LKB1-AMPK-mTOR signaling pathway genes are already known to alter the cell metabolism and to play a critical role in the malignant behavior of cancer. Accordingly, based on the assumption that genetic variations in the LKB1-AMPK-mTOR signaling pathway can change the intracellular signal in terms of metabolic reprogramming, the present study analyzed 18 single nucleotide polymorphisms (SNPs) of the STK11, PRKAA1, TSC1/2, and mTOR genes and their impact on the survival of patients with colorectal cancer. METHODS: Seven hundred seventy-two patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Eighteen SNPs were selected from an in silico analysis based on previous evidence of association. The SNP genotyping was performed using a SEQUENOM MassARRAY. RESULTS: Among the 18 polymorphisms, three SNPs (STK11 rs741765, PRKAA1 rs461404, and TSC1 rs13295634) were significantly associated with disease-free survival (DFS) or overall survival (OS). In a multivariate analysis, the GG genotype of STK11, TT genotype of PRKAA1, and TG or GG genotype of TSC1 were identified as independent prognostic factors for a worse DFS (hazard ratio = 1.398, 1.408, and 1.388; p = 0.030, 0.013, and 0.002, respectively) and OS (hazard ratio = 1.431, 1.680, and 1.394; p = 0.038, 0.001, and 0.009, respectively). CONCLUSIONS: The present results suggest that genetic variants of the STK11, PRKAA1, and TSC1 genes could be used as prognostic biomarkers for patients with surgically resected colorectal cancer.

Laparoscopic cytoreductive surgery and early postoperative intraperitoneal chemotherapy for patients with colorectal cancer peritoneal carcinomatosis: initial results from a single center.

BACKGROUND: In recent decades, a combination of cytoreductive surgery and intraperitoneal chemotherapy has yielded improvements in the survival of patients with peritoneal carcinomatosis. Laparoscopic cytoreductive surgery and intraperitoneal chemotherapy comprise a challenging and rarely reported surgical procedure. METHODS: Between November 2004 and February 2010, 29 patients underwent cytoreductive surgery and early postoperative intraperitoneal chemotherapy for peritoneal carcinomatosis secondary to colorectal cancer. Of the 29 patients, 15 underwent laparoscopic surgery and 14 underwent open surgery. RESULTS: The patient characteristics did not differ significantly between the two groups. Synchronous peritoneal carcinomatosis with a primary tumor was more common in the laparoscopic group, and the Gilly stage of peritoneal carcinomatosis was found more frequently in the open group. Complication rate and hospital stay were less in the laparoscopic group. However, the outcomes for the patients undergoing the combined treatment were similar between the two groups with respect to completeness of cytoreduction, operation morbidity, and overall survival. The laparoscopic group had a cytoreduction completeness of 86.7 % and an operative morbidity of 13.3 %. Operative mortality occurred for one patient after open surgery. CONCLUSIONS: Laparoscopic cytoreductive surgery and early postoperative intraperitoneal chemotherapy can be performed safely for selected patients with peritoneal carcinomatosis from colorectal cancer to a limited extent. Further studies with longer follow-up periods and larger numbers of patients are warranted to confirm the study findings.

Expression of claudin 18.2 in poorly cohesive carcinoma and its association with clinicopathologic parameters in East Asian patients.

BACKGROUND: Poorly cohesive carcinoma (PCC) is a distinct subtype of gastric cancer with limited therapeutic options. This study investigated claudin (CLDN) 18.2 expression status in PCCs using a 43-13 A clone. METHODS: We retrospectively collected 178 consecutive surgically resected stage Ⅱ-Ⅲ gastric cancer samples. Tissue microarray blocks were constructed for CLDN18.2 immunohistochemical staining. We studied CLDN18.2 expression and its association with clinicopathologic parameters. RESULTS: CLDN18.2 positivity (defined by ≥ 75 % of tumor cells showing moderate to strong membranous positivity) was found in 34.8 % of the PCC cases (62/178). Approximately half of the CLDN18.2 positive PCCs demonstrated heterogeneous expression (51.6 %, 32/62). CLDN18.2 positivity was not associated with any clinicopathologic parameters examined. However, CLDN18.2 positivity tended to be more frequent in E-cadherin-positive PCCs (no loss of expression) than in E-cadherin-negative PCCs (loss of expression) (50 % vs. 27.7 %). The CLDN18.2 expression level, represented by the H-score, gradually decreased as the paraffin block storage time increased (P = 0.046). Overall survival and disease-free survival analyses showed no significant difference between CLDN18.2-positive and negative PCCs. CONCLUSIONS: A significant portion of surgically resected PCC specimens showed CLDN18.2 positivity. Additionally, since the expression level of CLDN18.2 gradually decreases with increased paraffin block storage time, reflex testing can be considered at the time of the cancer diagnosis.