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This study aimed to identify radiotherapy dosimetric parameters related to local failure (LF)-free survival (LFFS) in patients with lung and liver oligometastases from colorectal cancer treated with stereotactic body radiotherapy (SBRT). We analyzed 75 oligometastatic lesions in 55 patients treated with SBRT between January 2014 and December 2021. There was no constraint or intentional increase in maximum dose. LF was defined as the progression of the treated lesion until the last follow-up or death. The dose distributions were recalculated using Monte Carlo-based algorithms. The significance of the planning target volume (PTV) biologically effective dose (BED) 10s (D2, D95, D98, Dmean) in LFFS was evaluated using Cox regression, considering sex, age, primary cancer, tumor site, oligometastatic status, multiplicity, and either tumor size or one of the volume parameters. LF occurred in 23.4% of the lesions. Lesions showing LF received significantly lower PTV D2 (146 ± 21 vs. 164 ± 23, p = 0.006). Multivariate analysis revealed that PTV D2 (< 159 Gy10 vs. ≥ 159 Gy10) was the sole dosimetric parameter associated with LFFS. Tumors equal to or larger than the median size/volume yet receiving < 159 Gy10 of PTV D2 showed the lowest LFFS following stratification by median PTV D2 combined with tumor size or volume parameters. The maximum dose (PTV D2) was significantly associated with LFFS after SBRT for lung and liver oligometastases from colorectal cancer. Increasing the maximum dose may be beneficial for managing larger tumors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Numerous studies have explored the role of vitamin D in various cancers; however, its impact on advanced biliary tract cancers (BTC) within a prospective cohort remains to be investigated. This preplanned subgroup analysis of the NIFTY trial evaluated the prognostic implications of serum vitamin D levels in patients with advanced BTC undergoing second-line chemotherapy., Methods: From the 174 patients in the NIFTY trial, a total of 173 patients (99.4%) were included in this analysis comparing a liposomal irinotecan plus 5-FU/leucovorin group (n = 87) and a 5-FU/leucovorin alone group (n = 86). Baseline serum 25-hydroxyvitamin D (25(OH)D) levels, an indicator of vitamin D status, were analyzed for their association with baseline characteristics and overall survival (OS) in patients undergoing second-line chemotherapy. Multivariable Cox proportional hazards regression and a restricted cubic spline function were used to assess the association with OS., Results: There were no significant associations between baseline characteristics and serum 25(OH)D levels. Baseline serum 25(OH)D levels were not associated with OS in either the multivariable Cox proportional hazard regression or restricted cubic spline analysis. In the subgroup analysis, however, higher serum 25(OH)D levels were significantly associated with poorer OS in female patients, while no significant association was observed in male patients, indicating a significant interaction by sex. Additionally, a marginally significant interaction was observed between body mass index and serum 25(OH)D levels for OS, with higher levels associated with better OS in patients who were underweight., Conclusions: Our preplanned subgroup analysis of the NIFTY trial indicates that the serum 25(OH)D levels did not have a significant effect on OS in the overall patient population with advanced BTC. However, higher serum 25(OH)D levels were associated with worse OS in female patients, underscoring the need for further investigation into the role of vitamin D in BTC., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Alzheimer's disease (AD) poses a major societal challenge, yet no definitive cure exists. Noninvasive brain stimulation methods, such as transcranial magnetic stimulation and transcranial direct current stimulation, have shown promise in alleviating cognitive symptoms associated with neurodegenerative disorders. This study investigated the effects of 40 Hz vibrotactile stimulation on AD-related cellular responses using SH-SY5Y neuroblastoma cells, primary human brain pericytes, and BV2 microglia. SH-SY5Y cells and brain pericytes treated with oligomeric beta-amyloid (Aβ) underwent 40 Hz vibrational stimulation for varying durations. Cell viability was determined via the CCK-8 assay, while intracellular calcium levels in pericytes were assessed. Protein expression was measured using western blotting, and gene expression was quantified via a real-time quantitative polymerase chain reaction. Detailed vibrational parameters were employed to ensure precise stimulation. Notably, 40 Hz vibrotactile stimulation improved cell viability in Aβ-exposed SH-SY5Y cells, reduced intracellular calcium ion (Ca2+) levels in Aβ-treated pericytes, activated autophagy, and mitigated tau hyperphosphorylation in SH-SY5Y cells. Additionally, it exhibited anti-neuroinflammatory properties in BV2 microglia. These findings highlight the potential of 40 Hz vibrotactile stimulation as a therapeutic strategy for AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jong Gwang Kim reports financial support was provided by Korea Health Industry Development Institute. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Systemic inflammatory response (SIR) is a crucial determinant of disease progression and survival in patients with colorectal cancer. This study investigated the prognostic relevance of changes in the platelet count on survival and the predictive value of changes in the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) on the pathological tumor response to preoperative chemoradiotherapy (CRT) in patients with microsatellite instability-high (MSI-H) rectal cancer. From 2011 to 2022, data of 46 consecutive patients with MSI-H rectal cancer who were treated with preoperative CRT followed by curative surgery at Kyungpook National University Chilgok Hospital (Daegu, South Korea) were retrospectively analyzed. A 235 cut-off value was used to define whether PLR was high or low. Any change in the PLR or NLR was calculated on the basis of subtracting the pre-CRT PLR or NLR from the post-CRT values. Both pre-CRT and post-CRT values of the NLR and PLR were not significantly associated with clinical outcomes. Simple logistic regression analysis showed that a change in the PLR following CRT was not significantly associated with survival outcomes; however, patients who maintained a high change in the PLR following CRT showed significantly better pathologic T-stage. No statistically significant association was noted between changes in the platelet count and clinical outcomes of patients. The results suggested that changes in the PLR following CRT are associated with pathologic T-stage of the group. However, the SIR markers showed no prognostic values on the survival outcomes of the patients with MSI-H/mismatch repair-deficient (dMMR) locally advanced rectal cancer (LARC)., Competing Interests: CONFLICT OF INTEREST STATEMENT: None declared., (© Chonnam Medical Journal, 2024.)

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 )., (Copyright © The ASCRS 2023.)

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., (© 2023. The Author(s).)

Background: Evidence is lacking regarding the earliest timing of initiating adjuvant chemotherapy to maximize its efficacy safely. A trial was designed and conducted to evaluate the safety and oncological efficacy of early adjuvant chemotherapy compared with conventional adjuvant chemotherapy. The short-term outcomes are reported here., Methods: A multicentre, randomized (1 : 1), open-label, phase III trial was conducted comparing early adjuvant chemotherapy with conventional adjuvant chemotherapy in patients with stage III colon cancer. Patients who underwent radical surgery who had stage III colon cancer confirmed by histopathological assessment were screened and randomized into the early adjuvant chemotherapy arm or the conventional adjuvant chemotherapy arm. The primary endpoint was 3-year disease-free survival. The adjuvant chemotherapy with FOLFOX was delivered between postoperative day 10 and 14 in the early adjuvant chemotherapy arm, and between postoperative day 24 and 28 in the conventional adjuvant chemotherapy arm. Toxicity and quality of life were evaluated., Results: Between 9 September 2011 and 6 March 2020, 443 patients consented to randomization at eight sites. The intention-to-treat population included 423 patients (209 in the early adjuvant chemotherapy arm and 214 in the conventional adjuvant chemotherapy arm), and the safety population included 380 patients (192 in the early adjuvant chemotherapy arm and 188 in the conventional adjuvant chemotherapy arm). There was no statistically significant difference in overall toxicity (28.1 per cent in the early adjuvant chemotherapy arm and 28.2 per cent in the conventional adjuvant chemotherapy arm, P = 0.244), surgical complications, and quality of life between the two arms., Conclusion: Adjuvant chemotherapy can be safely initiated 2 weeks after surgery with toxicity and quality of life comparable to conventional adjuvant chemotherapy for stage III colon cancer., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Purpose: Poorly cohesive cells-gastric cancer (PCC-GC) represents distinct features within the GC spectrum. The present study investigated the clinicopathologic characteristics and chemo-sensitivity for a relatively large cohort of PCC-GC patients., Materials and Methods: A total of 268 patients diagnosed with stage II or III PCC-GC were included. GC cell lines were also analyzed for drug sensitivity to 5-fluorouracil (5-FU) and oxaliplatin in vitro., Results: One hundred fifteen (42.9%) patients were stage II and 153 (57.1%) were stage III. Two hundred twenty-three (83.2%) patients received adjuvant therapy. Among these patients, 139 (62.3%) received CAPOX and 84 (37.7%) received S-1. With a median follow-up of 38.9 (1.6-137.8) months, the estimated 5-year disease-free survival (DFS) and overall survival (OS) rates were 52.3% and 61.0%, respectively. In the univariate analysis, survival was significantly better in the adjuvant chemotherapy group than in the surgery only group. In the subgroup analysis, there was no significant difference in DFS or OS between the types of adjuvant chemotherapy for either disease stage. In vitro cell line analysis, different responses to 5-FU and oxaliplatin were observed in SRC and non-SRC, where the treatment in KATOIII cell lines with oxaliplatin had less effect at a higher concentration compared to non-SRC cell lines., Conclusion: The current study found that adjuvant chemotherapy was not significantly associated with survival benefit for patients with resected stage II and III PCC-GC. Plus, S-1 showed numerically longer DFS and OS compared to CAPOX in PCC-GC patients, although no significant in the multivariate analysis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: The NIFTY trial demonstrated the benefit of treatment with second-line liposomal irinotecan (nal-IRI) plus fluorouracil (FU) and leucovorin (LV) for patients with advanced biliary tract cancer (BTC)., Objective: To report the updated efficacy outcomes from the NIFTY trial with extended follow-up of 1.3 years with reperformed masked independent central review (MICR) with 3 newly invited radiologists., Design, Setting, and Participants: The NIFTY trial was a randomized, multicenter, open-label, phase 2b clinical trial conducted between September 5, 2018, and December 31, 2021, at 5 tertiary referral centers in South Korea. Patients with advanced BTC whose disease progressed while receiving first-line gemcitabine plus cisplatin with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors, version 1.1, were eligible. Data analysis was completed on May 9, 2022., Interventions: Patients were randomized 1:1 to receive LV, 400 mg/m2, bolus and FU, 2400 mg/m2, for a 46-hour infusion intravenously every 2 weeks with or without nal-IRI, 70 mg/m2, before LV intravenously. Patients were treated until disease progression or unacceptable toxic effects., Main Outcomes and Measures: Primary end point was progression-free survival (PFS) as assessed by MICR. Secondary end points were PFS as assessed by the investigator, overall survival, and objective response rate., Results: A total of 178 patients (75 women [42.1%]; median [IQR] age, 64 [38-84] years) were randomly assigned, and 174 patients were included in the full analysis set (88 patients [50.6%] in the nal-IRI plus FU/LV group vs 86 patients [49.4%] in the FU/LV alone group). In this updated analysis, the median MICR-assessed PFS was 4.2 months (95% CI, 2.8-5.3) for the nal-IRI plus FU/LV group and 1.7 months (95% CI, 1.4-2.6) for the FU/LV alone group (hazard ratio, 0.61; 95% CI, 0.44-0.86; P = .004), in contrast to the 7.1 and 1.4 months reported in the previous study, respectively. The discordance rate for tumor progression date between the MICR and investigators was 17.8% (vs 30% in the previous study)., Conclusions and Relevance: The NIFTY randomized clinical trial demonstrated significant improvement in PFS with treatment with nal-IRI plus FU/LV compared with FU/LV alone for patients with advanced BTC after progression to gemcitabine plus cisplatin. The combination of nal-IRI plus FU/LV could be considered as a second-line treatment option for patients with previously treated advanced BTC., Trial Registration: clinicaltrials.gov Identifier: NCT03524508.

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., (© 2022 Wiley Periodicals LLC.)

Background: Alzheimer's disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-β (Aβ) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo[3,2-d]pyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties., Methods: To evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG)/cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wnt/β-catenin signaling., Results: Here, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aβ and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aβ through the modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3β (GSK-3β) activity, GR transcriptional activity, and the Wnt/β-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wnt/β-catenin signaling., Conclusions: These findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMP/PKG/CREB pathway, GSK-3β kinase activity, GR signaling, and the Wnt/β-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent., (© 2022. The Author(s).)

Backgruound: The present study evaluated the clinical implications of adjuvant chemotherapy according to the mismatch repair (MMR) status and clinicopathologic features of patients with intermediate- and high-risk stage II colon cancer (CC)., Methods: This study retrospectively reviewed 5,774 patients who were diagnosed with CC and underwent curative surgical resection at Kyungpook National University Chilgok Hospital. The patients were enrolled according to the following criteria: (1) pathologically diagnosed with primary CC; (2) stage II CC classified based on the 7th edition of the American Joint Committee on Cancer staging system; (3) intermediate- and high-risk features; and (4) available test results for MMR status. A total of 286 patients met these criteria and were included in the study., Results: Among the 286 patients, 54 (18.9%) were identified as microsatellite instability-high (MSI-H) or deficient MMR (dMMR). Although all the patients identified as MSI-H/dMMR showed better survival outcomes, T4 tumors and adjuvant chemotherapy were identified as independent prognostic factors for survival. For the intermediate-risk patients identified as MSI-low (MSI-L)/microsatellite stable (MSS) or proficient MMR (pMMR), adjuvant chemotherapy exhibited a significantly better disease-free survival (DFS) but had no impact on overall survival (OS). Oxaliplatin-containing regimens showed no association with DFS or OS. Adjuvant chemotherapy was not associated with DFS in intermediate-risk patients identified as MSI-H/dMMR., Conclusion: The current study found that the use of adjuvant chemotherapy was correlated with better DFS in MSI-L/MSS or pMMR intermediate-risk stage II CC patients.

Aim: This study evaluated the clinical implication of KRAS proto-oncogene, GTPase (KRAS) mutation variants in patients with resected colon cancer (CC)., Patients and Methods: We retrospectively reviewed 482 patients diagnosed with CC who underwent curative surgical resection at Kyungpook National University Chilgok Hospital. The inclusion criteria were: Pathologically diagnosed with primary CC; stage I-III CC according to the 7th edition of American Joint Committee on Cancer staging system; and with available test results for KRAS mutation status. In total, 345 patients met these criteria and were included in this study., Results: Among the 345 patients, 140 (40.6%) exhibited KRAS mutations, with their incidences as follows: 90/140 (64.3%) in exon 2 codon 12, 37/140 (26.4%) in exon 2 codon 13, 1/140 (0.1%) in exon 3 codon 59, 7/140 (5.0%) in exon 3 codon 61, and 5/140 (3.6%) in exon 4 codon 146. KRAS mutation status was not a significant prognostic factor for disease-free survival or overall survival. Although there were no significant differences in survival between patients with exon 2 codon 12 and exon 2 codon 13 mutations, poorer disease-free survival (p=0.085) and overall survival (p=0.005) were seen in those with exon 3 codon 61 mutation than in others., Conclusion: KRAS mutation status was not correlated with survival, but exon 3 codon 61 mutation might be a factor for poor prognosis in patients after resection of CC., Competing Interests: The Authors have no conflicts of interest to declare., (Copyright 2022, International Institute of Anticancer Research.)

Although nivolumab shows survival benefits for patients with advanced gastric cancer (AGC), predictive biomarkers for nivolumab treatment in AGC remain unclear, especially in the case of peritoneal metastases. This study investigated the clinical significance of the prognostic nutrition index (PNI), reflecting the host nutritional status and immunity, in AGC patients undergoing nivolumab monotherapy. This study retrospectively analyzed 53 AGC patients who received nivolumab between October 2017 and February 2021. Among them, 35 patients with peritoneal metastases were reviewed to investigate the relationship between the PNI and oncological outcomes. The PNI was calculated as 10×serum albumin level (g/dl)+0.005×total lymphocyte count (per mm 3 ) at the first administration of nivolumab. With a median follow-up duration of 2.0 (0.3-13.5) months, the median overall survival (OS) was 2.0 months. The overall response and disease-control rates were 0.0% and 20.0%, respectively. Among the 35 patients, 13 patients were identified as a high-PNI group. In the univariate analysis, the high-PNI group showed a significantly longer PFS and OS than the low-PNI group. In the multivariate analysis, the high-PNI was independently associated with a longer PFS (p=0.021) and OS (p=0.022). The PNI can be useful for predicting PFS and OS in AGC patients with peritoneal metastases. However, further studies are required to validate these results in AGC and new strategies are needed to improve the outcome for AGC patients with peritoneal metastases., Competing Interests: CONFLICT OF INTEREST STATEMENT: None declared., (© Chonnam Medical Journal, 2022.)

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/m 2 for 90 min) plus intravenous leucovorin (400 mg/m 2 for 30 min) and intravenous fluorouracil (2400 mg/m 2 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., Competing Interests: Declaration of interests CY received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen, and received research grants from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceuticals, CKD Pharmaceuticals, and HK inno.N. JHJ received honoraria from Boryung Pharmaceutical, Daewoong Pharmaceutical, Eisai, HK inno.N, Lilly, Novartis, Pfizer, and Roche. JC received honoraria from Roche, Bayer, Eisai, Ipsen, and Bristol Myers Squibb, and received research grants from Bayer and Dong-A Pharmaceuticals. GKAA reports research grants from Arcus, Agios, AstraZeneca, BioNtech, Bristol Myers Squibb, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, and Yiviva, and personal consultation fees from Adicet, AstraZeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, Cend, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Vector, and Yiviva. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Despite the recent development of new chemotherapeutic regimens and combination strategies, metastatic pancreatic cancer (mPC) still shows only a modest response to conventional cytotoxic agents. However, several novel therapeutic agents targeting the unique features of mPC are showing promise in clinical trials., Area Covered: This article reviews the current state of development of new agents targeting various systems and molecular pathways. We searched PubMed and clinicaltrials.gov in September 2021 with a special focus on ongoing early phase clinical trials to identify the promising therapeutic strategies for mPC., Expert Opinion: Extensive tumor heterogeneity, complex tumor microenvironment, genetic alterations of the oncogenic signaling pathways, metabolic dysregulation, and a low immunogenicity are hurdles for current treatment approaches. Ongoing research efforts strive to overcome these hurdles and are showing some promising early results.

Epstein-Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the DNMT3A gene, whereas shRNA-targeted removal of DNMT3A mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of DNMT3A mRNA upregulated the ATM gene through DNA demethylation on the ATM promoter. Furthermore, CRISPR/Cas9-targeted removal of the ATM gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC.

Pancreatic cancer (PC) presents extremely aggressive tumours and is associated with poor survival. This is attributed to the unique features of the tumour microenvironment (TME), which is known to create a dense stromal formation and poorly immunogenic condition. In particular, the TME of PC, including the stromal cells and extracellular matrix, plays an essential role in the progression and chemoresistance of PC. Consequently, several promising agents that target key components of the stroma have already been developed and are currently in multiple stages of clinical trials. Therefore, the authors review the latest available evidence on novel stroma-targeting approaches, highlighting the potential impact of the stroma as a key component of the TME in PC., Competing Interests: IC: Advisory Board: Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, Oncologie International, Pierre Fabre, Boehringer Ingelheim. Research funding: Eli-Lilly, Janssen-Cilag, Sanofi Oncology, Merck-Serono. Honorarium: Eli-Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Edwards, Kang and Chau.)

Background/aim: There are no clinically significant cutoff values of serum vitamin D levels and time points to predict the prognosis of colon cancer, particularly in patients who underwent curative surgical resection., Patients and Methods: We retrospectively analyzed serum vitamin D levels in 795 patients with stages I to III colon cancer who underwent curative surgical resection., Results: Patients with vitamin D levels below 12 ng/ml at one year after surgical resection demonstrated a significantly reduced disease-free survival (DFS) than those who did not have vitamin D deficiency (p=0.01). In the multivariate analysis, an age of 70 years or older [hazard ratio (HR)=1.992; p=0.001], pathologic stage (HR=3.739; p<0.001), and vitamin D deficiency (less than 12 ng/ml) at one year after surgery (HR=0.563; p=0.020) were factors unfavorably influencing DFS., Conclusion: In patients with stages I to III of colon cancer, vitamin D deficiency at one year after surgical resection was associated with increased disease relapse., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although testicular germ cell tumors (GCTs) are known to curable disease even in cases with metastatic disease, patients in intermediate or poor-risk group may experience disease progression or refractory to the initial chemotherapy and needed second-line therapy. Long-term disease-free survival was unsatisfactory in relapsed/refractory patients with poor-risk factors and clinical trials for those patients are still insufficient. High-dose chemotherapy (HDCT) with stem-cell rescue may be an effective alternative for conventional chemotherapy-resistant patients who are eligible for transplantation. Herein, we present successful treatment experience with HDCT followed by autologous stem-cell transplantation in a severely ill patient with heavily pretreated metastatic GCT., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

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.

In 2017, Korean Society of Medical Oncology (KSMO) published the Korean management guideline of metastatic prostate cancer. This paper is the 2nd edition of the Korean management guideline of metastatic prostate cancer. We updated recent many changes of management in metastatic prostate cancer in this 2nd edition guideline. The present guideline consists of the three categories: management of metastatic hormone sensitive prostate cancer; management of metastatic castration resistant prostate cancer; and clinical consideration for treating patients with metastatic prostate cancer. In category 1 and 2, levels of evidence (LEs) have been mentioned according to the general principles of evidence-based medicine. And grades of recommendation (GR) was taken into account the quality of evidence, the balance between desirable and undesirable effects, the values and preferences, and the use of resources and GR were divided into strong recommendations (SR) and weak recommendations (WR). A total of 16 key questions are selected. And we proposed recommendations and described key evidence for each recommendation. The treatment landscape of metastatic prostate cancer is changing very rapid and many trials are ongoing. To verify the results of the future trials is necessary and should be applied to the treatment for metastatic prostate cancer patients in the clinical practice. Especially, many prostate cancer patients are old age, have multiple underlying medical comorbidities, clinicians should be aware of the significance of medical management as well as clinical efficacy of systemic treatment.

(1) Background: Lymph node (LN) status is an indubitable prognostic factor for survival among colon cancer patients. MicroRNAs (miRNAs) have been implicated in the development and progression of many cancers and are potential biomarkers for cancer diagnosis and prognosis. Therefore, we validated candidate biomarkers using circulating miRNAs by analyzing the plasma miRNA concentrations from patients with colon cancer to predict LN metastasis. (2) Methods: This study included 79 blood samples from patients diagnosed with colon cancer. The NanoString assay was used for screening, and TaqMan miRNA assays for quantitative real-time polymerase chain reaction (RT-PCR) test was used for validation. In a discovery set, we compared the expression of 800 circulating miRNAs in 24 samples (stage 0/I/IIA versus IIIB/IIIC). For validation, a total 79 samples were tested using quantitative RT-PCR. (3) Results: In the discovery set, 10 candidate circulating miRNAs were detected (4 up-regulated miRNAs: miR-323a-3p, miR-382-5p, miR-29a-3p, and miR-376a-3p; 6 down-regulated miRNAs: miR-26a-5p, let-7g-5p, miR-15b-5p, miR-142-3p, miR-374a-5p, and let-7b-5p). In the validation set, higher expression of three circulating miRNAs (miR-323a-3p, miR-382-5p, and miR-376a-3p) was significantly associated with LN metastasis ( p = 0.0063, 0.0107, and 0.0022). (4) Conclusions: High expression of circulating miR-323a-3p, miR-382-5p, and miR-376a-3p was significantly associated with LN metastasis in colon cancer patients. These miRNAs could be circulating biomarker candidates that predict the presence of LN metastasis.

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/m 2 /day) on days -5 and -4, and melphalan (50 mg/m 2 /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., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

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.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects, and its aberrant activation results in the pathogenesis of cancer. Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes., Competing Interests: Competing interests: IC—Advisory Board: Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, Oncologie International; Pierre FabreResearch funding: Eli-Lilly, Janssen-Cilag, Sanofi Oncology; Merck-SeronoHonorarium: Eli-Lilly., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Immunotherapy is revolutionising cancer treatment and has already emerged as standard treatment for patients with recurrent or metastatic gastric cancer (GC). Recent research has been focused on identifying robust predictive biomarkers for GC treated with immune checkpoint inhibitors (ICIs). The expression of programmed cell death protein-ligand-1 (PD-L1) is considered a manifestation of immune response evasion, and several studies have already reported the potential of PD-L1 expression as a predictive parameter for various human malignancies. Meanwhile, based on comprehensive molecular characterisation of GC, testing for Epstein-Barr virus and microsatellite instability is a potential predictive biomarker. Culminating evidence suggests that novel biomarkers, such as the tumour mutational burden and gene expression signature, could indicate the success of treatment with ICIs. However, the exact roles of these biomarkers in GC treated with ICIs remain unclear. Therefore, this study reviews recent scientific data on current and emerging biomarkers for ICIs in GC, which have potential to improve treatment outcomes., Competing Interests: Competing interests: IC: Advisory Board: Eli-Lilly, Bristol-Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, AstraZeneca, Oncologie International, Pierre Fabre Research funding: Eli-Lilly, Janssen-Cilag, Sanofi Oncology, Merck-Serono honorarium: Eli-Lilly, (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background/aim: The present study compared the prognostic value of the yield pathologic (yp) stage, tumor regression grade (TRG), and neoadjuvant rectal (NAR) score in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (nCRT)., Patients and Methods: For the assessment of tumor regression, the Dworak grading system was used. The NAR score was calculated using the following equation: (5ypN-3[cT-ypT]+12) 2 ÷9.61., Results: In univariate analysis, the NAR score and ypTNM stage were significantly associated with DFS [hazard ratio (HR)=2.514, p<0.001 and HR=3.200, p<0.001] and OS (HR=2.292, p=0.001 and HR=2.859, p<0.001), whereas the TRG was significantly associated with only DFS (HR=2.008, p=0.017). In multivariate analysis, the ypTNM stage was the only independent prognostic factor for DFS (HR=3.796, p<0.001) and OS (HR=3.591, p=0.0034)., Conclusion: Only the ypTNM stage was significantly associated with survival outcomes in multivariate analysis, suggesting that it is the most powerful prognostic factor of nCRT in patients with LARC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: High dietary sodium is a leading contributor to hypertension, and hypertension is the leading underlying cause of death globally. There is a robust body of evidence supporting the health benefits of sodium reduction. Sodium intake in South Korea is high, with about half the population consuming > 4000 mg/day, twice the recommended upper limit., Methods: In 2012, South Korea implemented its National Plan to Reduce Sodium Intake, with a goal of reducing population sodium consumption by 20%, to 3900 mg/day, by 2020. The plan included five key components: (1) a consumer awareness campaign designed to change food consumption behaviours; (2) increased availability of low-sodium foods at schools and worksites; (3) increased availability of low-sodium meals in restaurants; (4) voluntary reformulation of processed foods to lower sodium content; and (5) development of low-sodium recipes for food prepared at home. Monitoring and evaluation included tracking sodium intake and sources of dietary sodium using the Korea National Health and Nutrition Examination Survey., Results: By 2014, South Korea had reduced dietary sodium consumption among adults by 23.7% compared to a survey conducted in 2010 prior to implementation of a nationwide salt reduction campaign that used this comprehensive, multipronged approach. The reductions in sodium intake were accompanied by reductions in population blood pressure and hypertension prevalence. Although causal associations between the sodium reduction programme and reduced sodium intake cannot be made, the declines occurred with the introduction of the programme., Conclusion: Multicomponent interventions have great potential to reduce population sodium intake. Lessons learnt from South Korea could be applied to other countries and are likely very relevant to other Asian countries with similar food sources and consumption profiles., Competing Interests: Competing interests: NRCC is a member of World Action on Salt and Health (WASH)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We aimed to identify biomarkers of response to preoperative CRT in patients with LARC using comprehensive miRNA analysis., Methods: This study included 65 rectal cancer specimens and 89 serum samples from patients diagnosed with LARC and treated with preoperative. All specimens were collected before CRT for evaluation of biologic differences between the good and poor CRT response groups (ypStage 0/I versus II/III/IV). For specific miRNA discovery, 800 miRNAs in 20 rectal cancer specimens were analyzed with a NanoString assay. For validation, a total of 65 tissue and 89 serum samples were tested with reverse transcription-polymerase chain reaction (RT-PCR)., Results: In the discovery set, 16 target miRNAs were detected. In the validation set, higher expression of three miRNAs (miR-199a/b-3p, miR-199a-5p, and miR-199b-5p) was significantly associated with better response to CRT. In the univariate survival analysis, upregulation of these three miRNAs was associated with superior relapse-free survival (RFS) and overall survival (OS). Meanwhile, only a higher level of tissue miR-199a-5p was associated with superior RFS [hazard ratio (HR), 0.0.91; 95% confidence interval (CI) 0.035-0.580; p = 0.002] and OS (HR, 0.272; 95% CI 0.023-0.658; p < 0.001) in the multivariate survival analysis. Also, a higher level of exosomal miR-199b-5p correlated with better response to CRT (p = 0.0397)., Conclusion: High expression of tissue miR-199a/b-3p, miR-199a-5p, and miR-199b-5p was significantly associated with response to CRT, and a high level of tissue miR-199a-5p was associated with superior survival outcomes. Also, upregulated exosomal miR-199b-5p correlated with CRT response, reflecting its promise as a circulating biomarker of CRT response in patients with LARC.

Background/aims: For metastatic renal cell carcinoma (RCC), various prognostic scoring systems have been developed. However, owing to the low prevalence of nonclear cell RCC, the three most commonly used tools were mainly developed based on patients with clear cell histology. Accordingly, this study applied three prognostic models to Korean non-clear cell RCC patients treated with first-line temsirolimus., Methods: This study analyzed data for 74 patients with non-clear cell RCC who were treated with temsirolimus as the first-line therapy at eight medical centers between 2011 and 2016. The receiver-operating characteristic (ROC) curves for the different prognostic models were analyzed., Results: Twenty-seven (36.5%), 24 (32.4%), and 44 patients (59.5%) were assigned to the poor prognosis groups of the Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic RCC Database Consortium (IMDC), and Advanced Renal Cell Carcinoma (ARCC) risk stratification models, respectively. All three prognostic models reliably discriminated the risk groups to predict progression-free survival and overall survival (p < 0.001). The area under the ROC curve (AUC) for progression and survival was highest for the ARCC model (0.777; 0.734), followed by the IMDC (0.756; 0.724) and the MSKCC (0.742; 0.712) models. Furthermore, the sensitivity and specificity for predicting progression were highest with the ARCC model (sensitivity 63.6%, specificity 85.7%), followed by the MSKCC (sensitivity 58.2%, specificity 86.5%) and the IMDC models (sensitivity 56.4%, specificity 85.7%)., Conclusion: All three prognostic models accurately predicted the survival of the non-clear cell RCC patients treated with temsirolimus as the first-line therapy. Furthermore, the ARCC risk model performed better than the other risk models in predicting survival.

Background/aim: Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a promising target in gastric cancer. This study aimed to evaluate the clinical relevance of CLDN18.2 expression in gastric cancer., Patients and Methods: This study included 367 patients diagnosed with gastric cancer, who underwent curative surgical resection. Immunohistochemical staining for CLDN18.2 was carried out, and expression was scored semi-quantitatively, based on staining intensity and the percentage of staining., Results: CLDN18.2 expression was observed in 273 patients (74.4%), and 108 (29.4%) were classified as CLDN18.2-positive by predefined criteria. CLDN18.2 expression was not correlated with age, sex, tumor location, or stage. Expression rates were higher in diffuse-type and HER2-positive tumors. In multivariate survival analysis, CLDN18.2 expression was not associated with survival outcomes., Conclusion: Higher expression of CLDN18.2 was observed in diffuse-type and HER2-positive gastric cancers. Meanwhile, CLDN18.2 expression was not associated with survival in patients with gastric cancer., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study evaluated clinicopathological and molecular features and their prognostic impact on patients with locally advanced rectal cancer (LARC) who received preoperative chemoradiotherapy (CRT)., Patients and Methods: We retrospectively gathered data from 284 patients with LARC who underwent total mesorectal excision (TME) after CRT., Results: In the univariate analysis, lower yield pathologic T (ypT) category, yield pathologic N (ypN) category, yield pathologic TNM (ypTNM) stage, as well as the absence of lymphovascular invasion (LVI) and perineural invasion (PNI), were significantly associated with better disease-free survival (DFS) and overall survival (OS). Meanwhile, the expression of Ki-67, p53, and the mismatch repair (MMR) status showed no association with clinical outcomes. A multivariate survival analysis revealed that ypT category and LVI were independent prognostic factors of a worse DFS (HR=3.081, p-value=0.001; HR=2.818, p-value=0.030) and OS (HR=3.158, p-value=0.006; HR=3.837, p-value=0.014)., Conclusion: The ypT category and the presence of LVI were found to be prognostic factors for patients with LARC after CRT followed by TME., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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.

Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is classified as one of four GC subtypes by comprehensive molecular characterization. Though the mechanism of tumorigenesis by EBV infection has not yet been fully clarified, EBV infection might contribute to the malignant transformation of GC cells by involving various cellular processes and signaling pathways. EBVaGC has shown the following distinct characteristics in contrast to other subtypes: extreme DNA hypermethylation, recurrent phosphatidylinositol 4,5-biphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutations, overexpression of programmed cell death ligand 1/2 (PD-L1/2), and occasional immune cell signaling activation. Therefore, using these molecular features as guides, targeted agents need to be evaluated in clinical trials for EBVaGC. Accordingly, this review uses the best available evidence to focus on novel therapeutic approaches using the distinct pathologic characteristics of EBVaGC patients., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recent studies have shown a marked increase of AT-rich interactive domain 3A (ARID3A) in colon cancer tissue compared to normal colon mucosa. However, the role of ARID3A has not yet been determined in rectal cancer. We, therefore, investigated the clinical relevance of ARID3A expression in patients with residual rectal cancer after neoadjuvant chemoradiotherapy (NACRT)., Materials and Methods: One hundred thirty-four patients who underwent surgical resection for residual rectal cancer after NACRT were analyzed. ARID3A expression was evaluated using immunohistochemistry on whole-tissue sections. KRAS exon 2 (codons 12 and 13) and BRAF V600E mutation status were determined using polymerase chain reaction., Results: ARID3A positivity was found in 91 cases (64.5%), and it correlated with absence of perineural invasion (p=0.031), longer disease-free survival (DFS) (p=0.048) and cancer-specific survival (CSS) (p=0.006). However, ARID3A positivity was not correlated with KRAS (p=0.231) or BRAF mutation status (p=0.577). In multivariate analysis, ARID3A positivity was independently associated with a favorable CSS (p=0.035), but not DFS (p=0.051)., Conclusion: ARID3A positivity can predict favorable prognosis in patients with residual rectal cancer after NACRT., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Epstein-Barr virus (EBV)-associated gastric cancer (GC) is known to harbor a significant enrichment of of phosphatidylinositol 4, 5-biphosphate 3- kinase catalytic subunit alpha isoform (PIK3CA). Therefore, this study investigated the clinical relevance and prognostic role of PIK3CA mutations in patients with EBV-GC., Materials and Methods: After reviewing 1,318 consecutive cases of surgically resected GC, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. PIK3CA mutations were identified in formalin-fixed and paraffin-embedded surgical specimens from 112 patients with EBV-GC with available tumor tissue samples. Real-time polymerase chain reaction was used to evaluate hot-spot mutations of exons 1, 4, 7, 9, and 20 of PIK3CA., Results: Among the 112 patients, the frequency of PIK3CA mutations was 25.0% (n=28), and among the 28 patients harboring a PIK3CA mutation, most mutations were identified in exon 9 (n=21, 18.8%). The presence of PIK3CA mutation was also correlated with a higher T category (p<0.001) and N category (p<0.001), as well as the presence of perinueral invasion (p<0.001) and venous invasion (p<0.001). In a univariate analysis, PIK3CA mutation showed no association with overall survival (OS) (p=0.184) or disease-free survival (DFS) (p=0.150). Patients harboring exon 9 PIK3CA mutations exhibited a significantly shorter OS (p=0.023) and DFS (p=0.013) than the patients lacking an exon 9 PIK3CA mutation, yet without statistical significance in the multivariate analysis. Notably, exon 9 E542K mutation of PIK3CA was associated with the worst DFS (p=0.011)., Conclusion: The current data show that PIK3CA mutations appear to play an important role in carcinogenesis and tumor aggressiveness in EBV-GC, and also support the concept that exon 9 mutation of PIK3CA is a prognostic indicator for predicting patient outcomes and a rationale for therapeutic targeting in EBV-GC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The purpose of this study was to investigate the safety of laparoscopic cytoreductive surgery versus open surgery for patients with limited peritoneal metastases from colorectal cancer., Methods: Laparoscopic surgery for patients with colorectal cancer with peritoneal metastases has been performed at our institution since December 2004. We retrospectively evaluated data from patients with colorectal cancer metastatic to the peritoneum, with a peritoneal cancer index ≤10. We compared short-term operative and survival outcomes in the laparoscopic cytoreductive surgery group and open cytoreductive surgery group., Results: A total of 21 patients underwent open cytoreductive surgery and 42 underwent laparoscopic cytoreductive surgery, of whom 6 (14%) required open conversion. Clinicopathologic characteristics and operative outcomes were comparable between the groups. Complete cytoreduction was achieved in all patients in the laparoscopic cytoreductive surgery group and in 19 patients (91%) in the open cytoreductive surgery group (P = .042). Both the mean hospital stay and use of postoperative narcotics were significantly less in the laparoscopic cytoreductive surgery group than in the open cytoreductive surgery group. The type of operation (open cytoreductive surgery versus laparoscopic cytoreductive surgery) was not related to survival outcomes., Conclusion: With careful selection by experienced laparoscopic surgeons, laparoscopic cytoreductive surgery was technically feasible and safe to treat colorectal cancer patients with limited peritoneal metastases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

Purpose: To investigate the safety and efficacy of 30-min maintenance infusions of trastuzumab in advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2)., Methods: This was a retrospective study conducted across five Korean hospitals in patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with first-line, 3-weekly trastuzumab plus chemotherapy. The first dose of trastuzumab (8 mg/kg) was administered as a 90-min infusion, with all subsequent maintenance infusions (6 mg/kg) given over 30 min. The primary aim was to investigate infusion-related reactions and cardiac events with 30-min infusions of trastuzumab. Objective response rate, progression-free survival, and overall survival were secondary endpoints., Results: The study included 128 patients (efficacy population), of whom 123 received both induction and maintenance infusions and formed the safety population. The median age was 63 years; 80% were presenting for the first time with metastatic disease, and 94% were treated with trastuzumab plus capecitabine/cisplatin. Infusion-related reactions were observed in 32 of 123 patients (26%). There were no cardiac events. The most frequent adverse events were anorexia and nausea, followed by vomiting, fatigue, mucositis, sensory neuropathy, and hand-foot syndrome. Most events were grade 1-2 and were manageable. No patient discontinued study treatment due to adverse events. The objective response rate was 63%, and included 6 complete responses., Conclusions: Trastuzumab 30-min maintenance infusions were well tolerated with a good safety profile, and resulted in sustained efficacy in patients with HER2-positive advanced gastric cancer.

Background/aim: This study evaluated the clinical significance of the mismatch repair (MMR) status and prognostic factors in patients with high-risk stage II colon cancer (CC)., Materials and Methods: This was a retrospective analysis of 237 patients diagnosed with high-risk stage II CC who had test results for MMR status., Results: Among the 237 patients, 76 (32.1%) were identified as having a microsatellite instability-high (MSI-H) status. No significant differences were identified in disease-free or overall survival according to the MMR status. Moreover, no association was found between the use of adjuvant chemotherapy and survival outcomes of the MSI-H group. In a multivariate survival analysis, the primary tumor location (right-sided versus left-sided, hazard ratio(HR)=0.172, p=0.003) and T-stage (HR=4.764, p=0.005) were identified as independent prognostic factors for disease-free survival., Conclusion: The present study found that the MMR status was neither prognostic nor predictive in patients with high-risk stage II CC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The purpose of this study was to evaluate chemotherapy patterns and changes in quality of life (QOL) during first-line palliative chemotherapy for Korean patients with unresectable or metastatic/recurrent gastric cancer (GC)., Materials and Methods: Thiswas a non-interventional, multi-center, prospective, observational study of 527 patients in Korea. QOL assessments were conducted using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ)-C30 and QLQ-STO22 every 3 months over a 12-month period during first-line palliative chemotherapy. The specific chemotherapy regimens were selected by individual clinicians., Results: Most patients (93.2%) received combination chemotherapy (mainly fluoropyrimidine plus platinum) as their first-line palliative chemotherapy. The median progression-free survival and overall survival were 8.2 and 14.8 months, respectively. Overall, "a little" changes (differences of 5-10 points from baseline)were observed in some of the functioning or symptom scales; none of the QOL scales showed either "moderate" or "very much" change (i.e., ≥ 11 point difference from baseline). When examining the best change in each QOL domain from baseline, scales related to some aspects of functioning, global health status/QOL, and most symptoms revealed significant improvements (p < 0.05). Throughout the course of first-line palliative chemotherapy, most patients' QOL was maintained to a similar degree, regardless of their actual response to chemotherapy., Conclusion: This observational study provides important information on the chemotherapy patterns and QOL changes in Korean patientswith advanced GC. Overall, first-line palliative chemotherapy was found to maintain QOL, and most parameters showed an improvement compared with the baseline at some point during the course.

A good pathologic response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is associated with a better prognosis. However, there is no effective method to predict CRT response in LARC patients. Therefore, this study used whole-exome sequencing (WES) to identify novel biomarker predicting CRT benefit in LARC. Two independent tumor tissue sets were used to evaluate the genetic differences between the good CRT response group (15 patients achieved a pathologic complete response (pCR)) and the poor CRT response group (15 patients with pathologic stage III). After applying WES to the discovery set of 30 patients, additional samples (n = 67) were genotyped for candidate variants using TaqMan or Sanger sequencing for validation. Overall, this study included a total of 97 LARC patients. In the discovery and validation set, there was no known genetic mutation to predict response between two groups, while five candidate variants (BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565) were found to be significantly associated with pCR. In the dominant model, the GC/CC genotype of DLC1 rs3816748 (p = 0.032), AC/CC genotype of DNAH14 rs3105571 (p = 0.009), and TT genotype of RAET1 rs912565 (p < 0.0001) were associated with a higher pCR rate. In the recessive model, BCL2L10 rs2231292 (p = 0.036) and ITIH5 rs3824658 (p = 0.003) were significantly associated with pCR. In the co-dominant model, 4 candidate variants (DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565) were significantly correlated with pCR. However, none of the candidate variants was associated with relapse-free or overall survival. The present results suggest that genetic variations of the BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565 genes can be used as biomarkers predicting the CRT response for patients with LARC.