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Abstract Background Systemic therapy is the standard treatment for unresectable colorectal cancer with liver metastasis (CRCLM). Transarterial chemoembolization with drug-eluting beads (DEB-TACE) is considered an effective treatment option for CRCLM. Few studies have investigated the combination of DEB-TACE, chemotherapy, and targeted therapy for CRCLM. In the present study, we evaluated the disease control rate (DCR), adverse events, and survival among patients with CRCLM who underwent the combination of DEB-TACE and chemotherapy/targeted therapy. Materials We retrospectively reviewed 35 patients with CRCLM who were treated between January 2015 and January 2021. Standard systemic chemotherapy, targeted therapy, and 66 DEB-TACE procedures were administered. Data were collected on each DEB-TACE procedure, including chemotherapy agents, tumor burden of liver metastasis, number of DEB-TACE courses, and adverse events. Patients who received DEB-TACE after failure of first-line systemic therapy were categorized into the first-line failure group. Patients who received DEB-TACE after the failure of second-line, third-line, or fourth-line therapy were categorized into the other group. Subgroup analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between the two groups. Results In total, 35 patients with CRCLM (34 patients with adenocarcinoma and 1 patient with neuroendocrine carcinoma) were enrolled. In total, 13 patients (37.1%) had extrahepatic metastases at initial diagnosis. In this study, 66 DEB-TACE procedures were performed. The DCR was 54.3%. The median OS period was 47.4 months, and the estimated 3-year OS rate was 59.5%. The median PFS period was 6.3 months, and the estimated 1-year PFS rate was 20.6%. The PFS period was longer in the first-line failure group than in the other group (7.2 vs. 6.3 months). No significant difference was observed in OS between the two groups. Four episodes (6.1%) of grade 3 intra-abdominal infection were observed. Conclusion The combination of chemotherapy, targeted therapy, and DEB-TACE can lead to a favorable DCR and survival outcomes in patients with CRCLM. Early intervention with DEB-TACE (i.e., after the failure of first-line therapy) has the potential to extend the PFS period in patients with CRCLM. Severe adverse events were rare and manageable. Further prospective, randomized controlled studies are warranted to obtain more conclusive findings.

Abstract Background PEGylated nanoparticles (PEG-NPs) are not effective for hematologic malignancies as they lack the enhanced permeability and retention effect (EPR effect). Tumor-targeted PEG-NPs can systemically track lymphoma and actively internalize into cancer cells to enhance therapeutic efficacy. We generated an anti-PEG bispecific antibody (BsAb; mPEG × CD20) which was able to simultaneously bind to methoxy PEG on liposomes and CD20 to form multivalent αCD20-armed liposomes. This αCD20-armed liposome was able to crosslink CD20 on lymphoma cells to enhance cellular internalization and the anti-cancer efficacy of the liposomes to lymphoma. We generated mPEG × CD20 and used this bispecific antibody to modify PEGylated liposomal doxorubicin (PLD) through a one-step formulation. Results αCD20-armed PLD (αCD20/PLD) specifically targeted CD20+ Raji cells and enhanced PLD internalization 56-fold after 24 h. αCD20/PLD also increased cytotoxicity to Raji cells by 15.2-fold in comparison with PLD and control mPEG × DNS-modified PLD (αDNS/PLD). mPEG × CD20 significantly enhanced the tumor accumulation 2.8-fold in comparison with mPEG × DNS-conjugated PEGylated liposomal DiD in Raji tumors. Moreover, αCD20/PLD had significantly greater therapeutic efficacy as compared to αDNS/PLD (P

Patients with cancer use low-molecular-weight fucoidan (LMF) as a supplement to therapy. However, most studies of LMF are in vitro or conducted using animals. Concurrent chemoradiotherapy (CCRT) is the gold standard for locally advanced rectal cancer (LARC). This study investigated the quality of life (QoL) and clinical outcomes of patients with LARC taking LMF as a supplement to neoadjuvant CCRT. This was a double-blind, randomized, placebo-controlled study. The sample comprised 87 patients, of whom 44 were included in a fucoidan group and 43 were included in a placebo group. We compared their QoL scores and clinical outcomes before treatment, and at 1 month, 2 months, and 3 months posttreatment. Pretreatment and posttreatment gut microbiota differences were also compared. Although enhanced physical well-being (PWB) at 2 months and 3 months posttreatment in the fucoidan group were observed (both P .0125). Skin rash and itching and fatigue were less common in the fucoidan group (both P

Abstract Neuroendocrine neoplasm (NEN) is a common gastrointestinal (GI) tract tumor divided into the neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) according to mitosis and Ki-67 index. However, the objective discordance between interobserver may cause unsuitable diagnosis and misleading treatment. Nowadays, aberrant glycosylation of glycoconjugates inducing further populations of elongated complex oligosaccharide covalent attached to glycoconjugates anchored in the cell membrane by neo-synthesis of cancer-associated alteration of carbohydrate determinants were observed during cancer development. This study aimed to demonstrate the wax physisorption kinetics coupled with Fourier transform infrared (WPK-FTIR) imaging between NET and NEC in the rectum, colon, and stomach by utilizing two wax reagents (beeswax and paraplast) as glycan adsorbents for physical binding glycans of glycoconjugates based on dipole-induced dipole interaction. Results showed greater physisorption with beeswax than that of paraplast, suggesting highly populated elongated glycans of glycoconjugates adhering onto the tumor surfaces of NETs than that of adjacent benign mucosa in the rectum and colon. Besides, the WPK results of gastric NEN tissue sections showed a higher infrared absorbance ratio of beeswax-remnant to paraplast-remnant remains onto the tissue sections referring to a higher population of elongated glycans in gastric NET as compared with that of gastric NEC. Based on our findings, different anatomical locations could share similar phenomena with minor variance. In conclusion, WPK-FTIR imaging may have the potential to be employed as an alternative diagnostic method in GI NENs in the future.

Abstract Background Owing to the heterogeneity of microbiota among individuals and populations, only Fusobacterium nucleatum and Bacteroides fragilis have been reported to be enriched in colorectal cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin. Methods Microbiota composition was determined through 16S rRNA V3–V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as “tri-part samples”) in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria. Results Prevotella intermedia was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of P. intermedia and F. nucleatum was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from P. intermedia promoted the migration and invasion of CRC cells. Conclusion This report is the first to demonstrate that P. intermedia is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover, P. intermedia and F. nucleatum exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.

Background and Objectives: Approximately 5–10% of all patients with metastatic colorectal cancer (mCRC) harbor a BRAFV600E mutation. These patients exhibit distinct metastatic patterns, poor prognosis, and heterogenous survival outcomes. The findings from the TRIBE study indicated that the administration of FOLFOXIRI plus bevacizumab as first-line treatment extended the median duration of overall survival (OS). In this study, we explored the effects of UGT1A1 polymorphism on the outcomes of irinotecan dose escalation versus FOLFOXIRI plus bevacizumab in patients with BRAFV600E-mutant mCRC. Materials and Methods: We retrospectively reviewed the medical records of 25 patients who had received a diagnosis of BRAFV600E-mutant mCRC between October 2015 and August 2022. All patients underwent UGT1A1 genotyping before receiving bevacizumab plus FOLFIRI. The primary end point was progression-free survival (PFS), and secondary endpoints were OS and adverse events (AEs). The two treatment arms were compared in terms of 6-month PFS and 12-month OS. Results: Over a median follow-up duration of 15.0 (interquartile range, 10.0–30.5) months, no significant differences were noted between the treatment arms in severe AEs (SAEs), 6-month PFS, or 12-month OS (all p < 0.05). Regarding AEs, the FOLFIRI plus bevacizumab regimen was associated with a lower incidence of anorexia than was the FOLFOXIRI plus bevacizumab regimen (p = 0.042). Conclusions: Our findings indicate that FOLFIRI plus bevacizumab with irinotecan dose escalation is an effective first-line treatment regimen for patients with BRAFV600E-mutant mCRC. This regimen leads to acceptable clinical outcomes with manageable AEs. However, the effects on survival and safety outcomes could only be speculated, and further studies are needed because of the sample size, the follow-up for the OS evaluation, and the non-uniformity in all the variables considered in the two groups.

Personalized treatments based on the genetic profiles of tumors can simultaneously optimize efficacy and minimize toxicity, which is beneficial for improving patient outcomes. This study aimed to integrate gene alterations associated with predictive and prognostic outcomes in patients with metastatic colorectal cancer (mCRC) with polymerase chain reaction (PCR) and in-house next-generation sequencing (NGS) to detect KRAS, NRAS, and BRAF mutations. In the present study, 41 patients with mCRC were assessed between August 2017 and June 2019 at a single institution. The overall concordance between NGS and PCR results for detecting KRAS, NRAS, and BRAF mutations was considerably high (87.8–92.7%), with only 15 discrepant results between PCR and NGS. Our companion diagnostic test analyzes KRAS, NRAS, and BRAF as a panel of CRC molecular targets; therefore, it has the advantages of requiring fewer specimens and being more time and cost efficient than conventional testing for separate analyses, allowing for the simultaneous analysis of multiple genes.

BackgroundNeoadjuvant chemoradiotherapy followed by total mesorectal excision is the standard treatment for patients with nonmetastatic locally advanced rectal cancer (LARC). However, for patients with LARC and synchronous metastasis, the optimal treatment strategy and sequence remain inconclusive. In the present study, we evaluated the efficacy and safety of concurrent radiotherapy in patients with de novo metastatic rectal cancer who received chemotherapy and targeted therapy.MethodsWe retrospectively reviewed the data of 63 patients with LARC and synchronous metastasis who received intensive therapy at the study hospital between April 2015 and November 2018. The included patients were divided into two groups: RT-CT, those who received systemic chemotherapy with targeted therapy and concurrent radiotherapy (for primary rectal cancer), and CT, those who received only systemic chemotherapy with targeted therapy.ResultsTreatment response was better in the RT-CT group than in the CT group. The rate of primary tumor resection (PTR) was higher in the RT-CT group than in the CT group (71.4% and 42.9%, respectively; P = .0286). The RT-CT group exhibited considerably longer local recurrence-free survival (P = .0453) and progression-free survival (PFS; from 13.3 to 22.5 months) than did the CT group (P = .0091); however, the groups did not differ in terms of overall survival (OS; P = .49). Adverse events were almost similar between the groups, except frequent diarrhea, the prevalence of which was higher in the RT-CT group than in the CT group (59.5% and 23.8%, respectively; P = .0075).ConclusionsIn the era of biologics, radiotherapy may increase the resectability of primary rectal tumors, reducing the risk of locoregional failure and prolonging PFS. Concurrent pelvic radiotherapy may not substantially improve OS, which is indicated by metastasis. Hence, the resection of the distant metastases may be essential for improving long-term OS. To further determine the efficacy of concurrent radiotherapy, additional prospective, randomized studies must combine preoperative pelvic radiotherapy with PTR and metastectomy to treat patients with stage IV LARC.

Abstract Background Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed. Methods We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1–C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4β1 integrin HP1/2L mAbs. Results The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10−10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4β1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively). Conclusions Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use. Graphical Abstract

Background/Purpose: This analysis reports safety and effectiveness data from the Taiwanese cohort of the CORRELATE study. Methods: CORRELATE was a prospective, observational study to assess the safety and effectiveness of regorafenib for the treatment of metastatic colorectal cancer (CRC) in real-world clinical practice that was conducted in 13 different countries in Asia, Europe and Latin America. The primary endpoint of the study was incidence of all treatment-emergent AEs (TEAEs), and secondary endpoints included overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: The global study population (N = 1037) included 128 Taiwanese patients with a median age of 64 years, median weight of 62.02 kg and 66.41% were male. Reduced initiating doses of regorafenib and dose interruptions were common in Taiwanese patients (71.87% and 50.00%, respectively). The safety profile of regorafenib was consistent with that seen in Asian patients in the clinical development trials, including the CORRECT and CONCUR studies, with hand–foot–skin reactions (HFSR) of any grade occurring in 33.59% of patients. Median OS was 11.64 months in the Taiwanese patients (95% confidence interval [CI], 8.36–13.82) and median PFS was 2.17 months (95% CI, 1.97–2.89). Conclusion: The safety and effectiveness of regorafenib in this real-world study was generally consistent with the known efficacy and safety profile in Asian patients in clinical trials. Trial registration: NCT02042144.

Aims: This study analyzed the oncological outcomes of robotic-assisted total mesorectal excision (TME) in patients with rectal cancer after neoadjuvant concurrent chemoradiotherapy (CCRT). Methods: We enrolled 109 consecutive patients with stage II–III rectal cancer who underwent robotic-assisted TME after neoadjuvant CCRT at one hospital between July 2013 and June 2018. Results: All 109 patients underwent preoperative CCRT. Of them, 37 (33.9%) achieved a pathologic complete response, and 29 (26.6%) experienced relapse, with local recurrence in 9 (8.3%) and distant metastasis in 20 (18.3%). R0 resection was performed in 104 (95.7%) patients; however, 7 (6.7%) of them developed local recurrence and 17 (16.3%) developed distant metastasis. Over a median follow-up of 42 months, the 3-year disease-free survival and overall survival rates were 73.4% and 87.2%, respectively. Conclusions: Robotic-assisted TME after neoadjuvant CCRT is safe and effective for treating patients with stage II–III rectal cancer in one institution with acceptable short-term oncological outcomes. It may be a therapeutic alternative to salvage surgery for T4 tumors invading adjacent organs, such as the bladder, prostate, and uterus.

Studies have reported the effects of the gut microbiota on colorectal cancer (CRC) chemotherapy, but few studies have investigated the association between gut microbiota and targeted therapy. This study investigated the role of the gut microbiota in the treatment outcomes of patients with metastatic CRC (mCRC). We enrolled 110 patients with mCRC and treated them with standard cancer therapy. Stool samples were collected before administering a combination of chemotherapy and targeted therapy. Patients who had a progressive disease (PD) or partial response (PR) for at least 12 cycles of therapy were included in the study. We further divided these patients into anti-epidermal growth factor receptor (cetuximab) and anti-vascular endothelial growth factor (bevacizumab) subgroups. The gut microbiota of the PR group and bevacizumab-PR subgroup exhibited significantly higher α-diversity. The β-diversity of bacterial species significantly differed between the bevacizumab-PR and bevacizumab-PD groups (P = 0.029). Klebsiella quasipneumoniae exhibited the greatest fold change in abundance in the PD group than in the PR group. Lactobacillus and Bifidobacterium species exhibited higher abundance in the PD group. The abundance of Fusobacterium nucleatum was approximately 32 times higher in the PD group than in the PR group. A higher gut microbiota diversity was associated with more favorable treatment outcomes in the patients with mCRC. Bacterial species analysis of stool samples yielded heterogenous results. K. quasipneumoniae exhibited the greatest fold change in abundance among all bacterial species in the PD group. This result warrants further investigation especially in a Taiwanese population.

Colorectal cancer (CRC) is a global public health concern because of its high prevalence and mortality. Although radiotherapy is a key method for treating CRC, radioresistance is an obstacle to radiotherapy use. The molecular mechanisms underlying the radioresistance of CRC remain unclear. Increasing evidence has revealed the multiple regulatory functions of non-coding RNAs (ncRNAs) in numerous malignancies, including CRC. Several ncRNAs have been reported to be involved in the determination of radiosensitivity of CRC cells, and some have excellent potential to be prognostic biomarkers or therapeutic targets in CRC treatment. The present review discusses the biological functions and underlying mechanisms of ncRNAs (primarily lncRNA, miRNA, and circRNA) in the regulation of the radiosensitivity of CRC. We also evaluate studies that examined ncRNAs as biomarkers of response to radiation and as therapeutic targets for enhancing radiosensitivity.

Objective The UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity, which may increase the risk of severe toxicity in patients who receive standard-dose irinotecan, such as severe neutropenia and diarrhea. This real-world study assessed the optimal irinotecan dose in terms of efficacy and toxicity in metastatic colorectal cancer (mCRC) patients homozygous for the UGT1A1*28 polymorphism and receiving FOLFIRI plus bevacizumab or cetuximab as first-line therapy. Methods We analyzed toxicity and treatment outcomes in seven mCRC patients who were homozygous for UGT1A1*28 and received FOLFIRI plus bevacizumab or cetuximab, with an initial irinotecan dose of 120 mg/m 2 . Results Six of the seven patients tolerated 120 mg/m 2 irinotecan without requiring dose reductions in subsequent cycles. The overall response and disease control rates were 43.0% (3/7) and 71.4% (5/7), respectively. The median progression-free survival and overall survival were 11.0 and 33.0 months, respectively. Only one severe adverse event, grade III neutropenia (2.5%), was observed. Conclusions mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m 2 with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.

Malnutrition is a common problem in patients with metastatic colorectal cancer (mCRC) receiving targeted therapy plus chemotherapy, resulting in severe toxicity and decreased survival rates. This retrospective study employing propensity score matching (PSM) examined the efficacy and safety of a supplemental home parenteral nutrition (HPN) program for patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy. This retrospective nationwide registry study included data from 14 medical centers/hospitals across Taiwan, and the data period ranged from November 2016 to December 2020. Patients with RAS wild-type mCRC receiving cetuximab plus chemotherapy as their first-line therapy were included and divided into HPN and non-HPN program groups. HPN was initiated based on patient-specific factors, such as baseline nutritional status, treatment-related toxicities, and comorbidities. Clinical outcomes were evaluated using response to therapy, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). This study recruited 758 patients, of whom 110 and 648 were included in the HPN and non-HPN program groups, respectively. After 1:3 PSM, the data of 109 and 327 patients from the HPN and non-HPN program groups were analyzed, respectively. The HPN program group had a higher metastasectomy rate (33.9% vs. 20.2%, p = 0.005), and longer duration of treatment and DoR than the non-HPN program group (13.6 vs. 10.3 and 13.6 vs. 9.9 months, p = 0.001 and < 0.001, respectively). The HPN program group tended to have a longer median PFS (18.2 vs. 13.9 months, p = 0.102). Moreover, we noted a significant improvement in the median OS in the same group (53.4 vs. 34.6 months, p = 0.002). Supplemental HPN programs may be recommended for select patients with mCRC receiving targeted therapy plus chemotherapy to improve oncological outcomes.

Background: The incidence of early-onset colorectal cancer (CRC) is increasing. Many guidelines recommend initiating screening at 45 years. This study investigated the detection rate of advanced colorectal neoplasm (ACRN) by using fecal immunochemical tests (FITs) in individuals aged 40–49 years. Methods: PubMed, Embase, and Cochrane Library databases were searched from inception to May 2022. The primary outcomes were the detection rates and positive predictive values of FITs for ACRN and CRC in people aged 40–49 (younger age group) and ≥50 years (average risk group). Results: Ten studies with 664,159 FITs were included. The FIT positivity rate was 4.9% and 7.3% for the younger age and average risk groups, respectively. Younger individuals with positive FIT results had significantly higher risks of ACRN (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.79–3.73) or CRC (OR 2.86, 95% CI 1.59–5.13) than did individuals in the average-risk group, regardless of FIT results. Individuals aged 45–49 years with positive FIT results had a similar risk of ACRN (OR 0.80, 95% CI 0.49–1.29) to that of people aged 50–59 years with positive FIT results, although significant heterogeneity was observed. The positive predictive values of the FIT were 10–28.1% for ACRN and 2.7–6.8% for CRC in the younger age group. Conclusion: The detection rate of ACRN and CRC based on FITs in individuals aged 40–49 years is acceptable, and the yield of ACRN might be similar between individuals aged 45–49 and 50–59 years. Further prospective cohort and cost-effective analysis are warranted.

Background: Although surgical resection is the main treatment for rectal cancer, the optimal surgical protocol for elderly patients with rectal cancer remains controversial. This study evaluated the feasibility of robot-assisted surgery in elderly patients with rectal cancer. Patients and Methods: This retrospective study enrolled 156 patients aged 28–93 years diagnosed with Stage I–III rectal cancer, who underwent robot-assisted surgery between May 2013 and December 2018 at a single institution. Results: In total, 156 patients with rectal cancer, including 126 non-elderly (aged < 70 years) and 30 elderly (aged ≥70 years) patients, who underwent robot-assisted surgery were recruited. Between the patient groups, the post-operative length of hospital stay did not differ statistically significantly (P = 0.084). The incidence of overall post-operative complications was statistically significantly lower in the elderly group (P = 0.002). The disease-free and overall survival did not differ statistically significantly between the two groups (P = 0.719 and 0.390, respectively). Conclusions: Robot-assisted surgery for rectal cancer was well tolerated by elderly patients, with similar results to the non-elderly patients. Oncological outcomes and survival did not depend on patient age, suggesting that robot-assisted surgery is a feasible surgical modality for treating operable rectal cancer and leads to age-independent post-operative outcomes in elderly patients.

Colorectal cancer (CRC) is one of the most common malignancies and is associated with high mortality rates worldwide. The underlying mechanism of tumorigenesis in CRC is complex, involving genetic, lifestyle-related, and environmental factors. Although radical resection with adjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy and neoadjuvant chemoradiotherapy have remained mainstays of treatment for patients with stage III CRC and locally advanced rectal cancer, respectively, the oncological outcomes of these treatments are often unsatisfactory. To improve patients’ chances of survival, researchers are actively searching for new biomarkers to facilitate the development of more effective treatment strategies for CRC and metastatic CRC (mCRC). MicroRNAs (miRs), small, single-stranded, noncoding RNAs, can post-transcriptionally regulate mRNA translation and trigger mRNA degradation. Recent studies have documented aberrant miR levels in patients with CRC or mCRC, and some miRs are reportedly associated with chemoresistance or radioresistance in CRC. Herein, we present a narrative review of the literature on the roles of oncogenic miRs (oncomiRs) and tumor suppressor miRs (anti-oncomiRs), some of which can be used to predict the responses of patients with CRC to chemotherapy or chemoradiotherapy. Moreover, miRs may serve as potential therapeutic targets because their functions can be manipulated using synthetic antagonists and miR mimics.

Mammalian STE20‐like kinase 1 (MST1/STK4/KRS2) encodes a serine/threonine kinase that is the mammalian homolog of Drosophila Hippo. STK4 plays an important role in controlling cell growth, apoptosis, and organ size. STK4 has been studied in many cancers with previous studies indicating an involvement in colon cancer lymph node metastasis and highlighting its potential as a diagnostic marker for colon cancer. However, the role of STK4 defect in promoting colon cancer progression is still understudied. Here, we found that STK4 was significantly downregulated in colon cancer and was associated with distal metastasis and poor survival. Furthermore, STK4 knockdown enhanced sphere formation and metastasis in vitro and promoted tumor development in vivo. We found that STK4 colocalized with β‐catenin and directly phosphorylated β‐catenin resulting in its degradation via the ubiquitin‐mediated pathway. This may suggest that STK4 knockdown causes β‐catenin phosphorylation failure and subsequently β‐catenin accumulation, consequently leading to anchorage‐independent growth and metastasis in colon cancer. Our results support that STK4 may act as a potential candidate for the assessment of β‐catenin‐mediated colon cancer prognosis.

The bidirectional interaction between carcinogens and gut microbiota that contributes to colorectal cancer is complicated. Reactivation of carcinogen metabolites by microbial β-glucuronidase (βG) in the gut potentially plays an important role in colorectal carcinogenesis. We assessed the chemoprotective effects and associated changes in gut microbiota induced by pre-administration of bacterial-specific βG inhibitor TCH-3511 in carcinogen azoxymethane (AOM)-treated APCMin/+ mice. AOM induced intestinal βG activity, which was reflected in increases in the incidence, formation, and number of tumors in the intestine. Notably, inhibition of gut microbial βG by TCH-3511 significantly reduced AOM-induced intestinal βG activity, decreased the number of polyps in both the small and large intestine to a frequency that was similar in mice without AOM exposure. AOM also led to lower diversity and altered composition in the gut microbiota with a significant increase in mucin-degrading Akkermansia genus. Conversely, mice treated with TCH-3511 and AOM exhibited a more similar gut microbiota structure as mice without AOM administration. Importantly, TCH-3511 treatment significant decreased Akkermansia genus and produced a concomitant increase in short-chain fatty acid butyrate-producing gut commensal microbes Lachnoospiraceae NK4A136 group genus in AOM-treated mice. Taken together, our results reveal a key role of gut microbial βG in promoting AOM-induced gut microbial dysbiosis and intestinal tumorigenesis, indicating the chemoprotective benefit of gut microbial βG inhibition against carcinogens via maintaining the gut microbiota balance and preventing cancer-associated gut microbial dysbiosis. Thus, the bacterial-specific βG inhibitor TCH-3511 is a potential chemoprevention agent for colorectal cancer.

ObjectivePatients with metastatic colorectal cancer (mCRC) had oncological benefits with irinotecan dose escalation of FOLFIRI regimen combined with bevacizumab according to UGT1A1 genotypes in our previous study. In the current study, we performed a quality of life (QOL) outcome evaluation and cost-utility analysis of different irinotecan dose regimens in patients with mCRC.Materials and MethodsWith inverse probability-of-treatment weighting (IPTW) matching on all covariates, 75 patients with dose escalation of irinotecan (study group) and 121 patients with the recommended dose of irinotecan (control group) were recruited between October 2015 and December 2019. The QOL outcome measures were Functional Assessment of Cancer Therapy-Colorectal, Beck Anxiety Inventory, Beck Depression Inventory, and SF-36; cost-utility outcome measures were medical direct costs, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs).ResultsAll mCRC patients exhibited a significant decrease in both emotional wellbeing and depression from pretherapeutic period to posttherapeutic 6th month (P < 0.05); however, from the posttherapeutic 1st year to the 2nd year, improvement in most QOL measures was significantly better in the study group than in the control group (P < 0.05). Over a 2-year time period, the study group had higher total medical direct costs than the control group (US$ 54,742 ± 14,013 vs. US$ 54,608 ± 9,673) and higher average QALYs gained (1.88 vs. 1.65), with an ICUR of US$ 583 per QALY gained.ConclusionFor patients with mCRC, irinotecan dose escalation appeared cost-effective with considerable QOL improvements during the study period. Further randomized, multi-institutional controlled trials are warranted to corroborate these results.

Background: We aimed to study the safety of cold snare polypectomy (CSP) for colorectal polyps in patients administered periprocedural antithrombotic agents. Methods: We searched the PubMed, Embase, and Cochrane Library databases through June 2021. The primary outcomes were the rates of delayed and immediate bleeding (requiring endoscopic hemostasis). Secondary outcomes included thromboembolic events. Meta-analysis using odds ratios (ORs) and corresponding 95% confidence intervals (CIs) was performed to compare the outcomes. Results: Seventeen studies, including five randomized trials, were included. Over 96% of polyps were ⩽1 cm. The pooled rates of delayed and immediate bleeding for patients receiving CSP and periprocedural antithrombotic agents were 1.6% and 10.5%, respectively. Both the delayed (OR = 4.02, 95% CI = 1.98–8.17) and immediate bleeding (OR = 5.85, 95% CI = 3.84–8.89) rates were significantly higher in patients using periprocedural antithrombotic agents than in non-users. Although both antiplatelet agents and anticoagulants increased the risk of delayed bleeding, the risks associated with the use of direct oral anticoagulants (DOACs; 2.5%) or multiple agents (3.9%) were particularly high. Compared to their counterparts, diminutive polyps and uncomplicated lesions not requiring hemoclipping were associated with lower risks of delayed bleeding (pooled estimates of 0.4% and 0.18%, respectively). Thromboembolic risk was similar among patients using and not using periprocedural antithrombotic agents. Conclusions: CSP with periprocedural antiplatelet agents and warfarin may be feasible, especially for diminutive polyps. However, drug discontinuation should be considered with the use of DOACs or multiple agents which entail higher bleeding risk even with hemoclipping.

Malnutrition and systemic inflammatory response (SIR) frequently occur in patients with colorectal cancer (CRC) and are associated with poor prognosis. Anti-inflammatory nutritional intervention is not only a way to restore the malnourished status but also modulate SIR. Nine experts, including colorectal surgeons, physicians and dieticians from 5 hospitals geographically distributed in Taiwan, attended the consensus meeting in Taiwan Society of Colon and Rectum Surgeons for a 3-round discussion and achieved the consensus based on a systematic literature review of clinical studies and published guidelines. The consensus recommends that assessment of nutritional risk and SIR should be performed before and after CRC treatment and appropriate nutritional and/or anti-inflammatory intervention should be adapted and provided accordingly.

Abstract Introduction Post-operative pain control remains unsatisfactory in patients after laparotomy. This study aimed to evaluate the efficacy, safety, and quality of life with a single dose of extended-release dinalbuphine sebacate (ERDS) pre-operatively to intravenous patient-controlled analgesia (PCA) with fentanyl in patients undergoing laparotomy. Methods This was a prospective, open-label, randomized controlled study. Of 110 randomized patients, 107 completed all assessments. The area under the curve (AUC) of visual analogue scale (VAS) from baseline to 48 h after surgery, VAS throughout 7 days after surgery, post-operative analgesics use, quality of life, satisfaction, and safety were evaluated. Results The AUC of VAS from baseline to 48 h after surgery were 118.6 [97.5% confidence interval (CI) 95.6–141.6] in ERDS group and 176.13 (97.5% CI 150.8–201.4) in PCA group, which showed the non-inferiority because the upper limit of the 97.5% CIs of ERDS group was lower than the lower limit of PCA group (P

Abstract Colorectal cancer is a major public health problem worldwide, and locally advanced rectal cancer (LARC) is known for its poor prognosis. A multimodal treatment approach is the only method to achieve satisfactory local recurrence and survival rates in LARC. Determining which therapeutic modality for LARC has the most satisfactory influence on quality of life and disease outcome is still controversial. LARC treatment is subject to continuous advancement due to the development of new and better diagnostic tools, radiotherapy techniques, and chemotherapeutic agents. Herein, we review various therapeutic modalities for LARC from several aspects. In addition to radiotherapy techniques such as neoadjuvant chemoradiotherapy (NCRT), we discuss the progress of chemotherapy, appropriate time interval between NCRT and surgery, relationship between tumor location and NCRT efficacy/safety, wait‐and‐watch policy, and predictors of treatment response following NCRT. Because of the controversies and unanswered questions regarding NCRT treatments for LARC, additional investigations are required to determine which therapeutic approach is the most feasible for LARC patients.

Abstract Background Total mesorectal excision (TME) with or without neoadjuvant concurrent chemoradiotherapy (CCRT) is the treatment for rectal cancer (RC). Recently, the use of conventional laparoscopic surgery (LS) or robotic-assisted surgery (RS) has been on a steady increase cases. However, various oncological outcomes from different surgical approaches are still under investigation. Methods This is a retrospective observational study comprising 300 consecutive RC patients who underwent various techniques of TME (RS, n = 88; LS, n = 37; Open surgery, n = 175) at a single center of real world data to compare the pathological and oncological outcomes, with a median follow-up of 48 months. Results Upon multivariate analysis, histologic grade (P = 0.016), and stage (P

Abstract Background Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, disease control rate, time to progression, and duration of treatment. Safety assessments will also be recorded. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidence regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC. Trial registration ClinicalTrials.gov, NCT03880877. Prospectively registered on 19 March 2019.

BackgroundWhether high or low ligation of the inferior mesenteric artery (IMA) is superior in surgery for rectal and sigmoid colon cancers remains controversial. Although several meta-analyses have been conducted, the level of lymph node clearance was poorly defined. We performed a meta-analysis comparing high and low ligation of the IMA for sigmoid colon and rectal cancers, with emphasis on high dissection of the lymph node at the IMA root in all the included studies.MethodsPubMed, MEDLINE, and EMBASE databases were searched to identify relevant articles published until 2020. The patient’s perioperative and oncologic outcomes were analyzed. Statistical analysis was performed using the statistical software RevMan version 5.4.ResultsA total of 17 studies, including four randomized controlled trials, published between 2011 and 2020 were selected. In total, 1,846 patients received low ligation of the IMA plus high dissection of lymph nodes (LL+HD), and 2,648 patients received high ligation of the IMA (HL). LL+HD was associated with low incidence of anastomotic leakage (p < 0.001), borderline long operative time (p = 0.06), and less yields of total lymph nodes (p = 0.03) but equivalent IMA root lymph nodes (p = 0.07); moreover, LL+HD exhibited non-inferior long-term oncological outcomes.ConclusionIn comparison with HL, LL+HD was an effective and safe oncological procedure for sigmoid colon and rectal cancers. Therefore, to ligate the IMA below the level of the left colic artery with D3 high dissection for sigmoid colon and rectal cancers might be suggested once the surgeons are familiar with this technique.Systematic Review RegistrationINPLASY.com, identifier 202190029.

Therapeutic options for metastatic CRC (mCRC) have changed significantly in recent years, greatly increasing the complexity of therapeutic decision-making. Although oncology guidelines have helped improve the care process, guidelines may also limit the flexibility to individualize in-clinic decision-making. This consensus paper addresses specific gaps in the current international guidelines to assist Taiwanese colon and rectal experts make specific therapeutic choices. Over 3 years and three meetings with selected experts on “real-world” Taiwanese practice patterns for mCRC, consensus was achieved. The experts also discussed specific questions during in-depth one-on-one consultation. Outcomes of the discussion were then correlated with published evidence by an independent medical writer. The final consensus includes clinically implementable recommendations to provide guidance in treating Taiwanese mCRC patients. The consensus includes criteria for defining fit and unfit intensive treatment patients, treatment goals, treatment considerations of molecular profiles, treatment consideration, and optimal treatment choices between different patient archetypes, including optimal treatment options based on RAS, BRAF, and microsatellite instability (MSI) status. This consensus paper is the second in the Taiwan Society of Colon and Rectal Surgeons (TSCRS) Consensus series to address unmet gaps in guideline recommendations in lieu of Taiwanese mCRC management. Meticulous discussions with experts, the multidisciplinary nature of the working group, and the final drafting of the consensus by independent medical professionals have contributed to the strong scientific value of this consensus.

Despite the implementation of global screening programs, colorectal cancer (CRC) remains the second leading cause of cancer-related deaths worldwide. More than 10% of patients with colon cancer are diagnosed as having locally advanced disease with a relatively poor five-year survival rate. Locally advanced colon cancer (LACC) presents surgical challenges to R0 resection. The advantages and disadvantages of preoperative radiotherapy for LACC remain undetermined. Although several reliable novel biomarkers have been proposed for the prediction and prognosis of CRC, few studies have focused solely on the treatment of LACC. This comprehensive review highlights the role of predictive biomarkers for treatment and postoperative oncological outcomes for patients with LACC. Moreover, this review discusses emerging needs and approaches for the discovery of biomarkers that can facilitate the development of new therapeutic targets and surveillance of patients with LACC.

Perivascular epithelioid cell tumour (PEComa) is an extremely rare neoplasm with distinctive morphology and specific expression of immunohistochemical markers. The lesion is typically diagnosed in middle-aged women, with few reports of paediatric cases, and there is no standardized treatment for the tumour type. Here, the case of a 17-year-old female, who presented with painless haematochezia for 2 days and was diagnosed with gastrointestinal PEComa of the sigmoid colon with regional lymph node metastasis after serial examination, is presented. She was treated by surgical resection of the tumour and cytotoxic chemotherapy comprising 900 mg/m 2 gemcitabine and 100 mg/m 2 docetaxel every 3 weeks for six cycles. Haematochezia did not recur, and complete response was achieved, with progression-free survival at the 24-month follow-up examination. Surgical resection with adjuvant conventional cytotoxic chemotherapy may be considered as an option for treating gastrointestinal PEComa.

Diabetes mellitus (DM) and hyperglycemia have been shown to have significant effects on the incidence, chemoresistance, and prognosis of colorectal cancer (CRC), as well as the outcomes of localized and metastatic CRC. Inflammation and endocrine effects may act as central mechanisms of DM and cancer and stimulate the insulin‐like growth factor 1–phosphoinositide 3-kinase–Akt–mammalian target of rapamycin (IGF-1–PI3K–AKT–mTOR) pathway. Dysregulation of the AMP-activated protein kinase (AMPK) pathway leads to metabolic imbalance and indicates cancer risk. The use of metformin for chemoprevention has been shown to reduce CRC and adenoma incidence through the upregulation of AMPK, which causes cell cycle arrest in the Gap 1–S (G1–S) phase and inhibits the mTOR pathway, even potentially reversing the epithelial–mesenchymal transition. However, evidence of the effects of metformin remain controversial in cancer prognosis. Several genes, such as transcription factor 7-like 2(TCF7L2), tumor protein P53 inducible nuclear protein 1(TP53INP1), gremlin 1 (GREM1), and potassium voltage-gated channel subfamily Q member 1(KCNQ1), are pleiotropically related to DM as well as cancer risk and prognosis. Epigenetic modification of members of the Let-7 family such as miR-497, miR-486, and miR-223 is strongly associated with impaired glucose tolerance and CRC risk. Herein we review the pathophysiological and epidemiological evidence as well as potential underlying molecular mechanisms by which DM and hyperglycemia affect CRC risk. We also suggest potential roles of glucose modulation in CRC therapy and propose an agenda for future research and clinical practice.

Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients.

The perioperative and short-term oncological outcomes of robotic-assisted rectal surgery (RRS) are unclear. This retrospective observational study enrolled patients with rectal adenocarcinoma undergoing RRS from three high-volume institutions in Taiwan. Of the 605 enrolled patients, 301 (49.75%), 176 (29.09%), and 116 (19.17%) had lower, middle, and upper rectal cancers, respectively. Low anterior resection (377, 62.31%) was the most frequent surgical procedure. Intraoperative blood transfusion was performed in 10 patients (2%). The surgery was converted to an open one for one patient (0.2%), and ten (1.7%) patients underwent reoperation. The overall complication rate was 14.5%, including 3% from anastomosis leakage. No deaths occurred during surgery and within 30 days postoperatively. The positive rates of distal resection margin and circumferential resection margin were observed in 21 (3.5%) and 30 (5.0%) patients, respectively. The 5-year overall and disease-free survival rates for patients with stage I–III rectal cancer were 91.1% and 86.3%, respectively. This is the first multi-institutional study in Taiwan with 605 patients from three high-volume hospitals. The overall surgical and oncological outcomes were equivalent or superior to those estimated in other studies. Hence, RRS is an effective and safe technique for rectal resection in high-volume hospitals.

Anorectal malignant melanoma is a very rare but aggressive cancer which carries poor prognosis. Surgical intervention is the main management but whether wide local excision or abdominoperineal resection has better survival benefit remains controversial. However, robotic-assisted restorative proctectomy with coloanal anastomosis with intersphincteric resection (ISR) has not been reported yet. Hence, we presented a case with anorectal malignant melanoma treated with robotic-assisted ISR with coloanal anastomosis. The patient has satisfied post-operative life quality, and no local recurrence was noted after 3-year follow-up.

Gastric ectopic pancreas presenting as a submucosal tumour accounts for approximately 11% of all endoscopic ultrasonography (EUS) examinations. Definitive diagnosis through endoscopy is difficult, even with EUS-guided fine-needle aspiration biopsy for histological examination. For symptomatic patients or those with uncertain diagnosis, complete surgical resection is the primary strategy for treatment and diagnosis. Herein, we report a case of gastric ectopic pancreas treated using robotic surgery.

Abstract Current studies have proven the strong association between gut microbiota dysbiosis and the pathogenesis of gastrointestinal diseases. Fecal microbiota transplantation (FMT) from a healthy donor is a promising therapeutic strategy to change and restore composition of the recipient's gut microbiota. Rapidly increasing clinical literatures confirmed the truth of the benefits of FMT on recurrent Clostridium difficile infection (rCDI) and inflammatory bowel disease. This article retrospectively reviewed nine cases (four cases had ulcerative colitis [UC], five cases had rCDI) who received FMT in Kaohsiung Medical University Hospital from April 2016 to November 2018. We summarized the procedure including donor selection, fecal materials preparation, transplantation delivery methods, and clinical outcomes. All of the four UC cases got clinical improvement and four rCDI cases achieved clinical remission after FMT. The other one rCDI case remained positive stool Toxin A+B result after FMT, and got remission after salvage treatment with fidaxomicin. FMT is considered to be a well‐tolerated adjuvant treatment for UC and effective salvage treatment for rCDI in our initial experience. Multiple infusions of FMT in UC and rCDI might have exceptional clinical efficiency, and enteral tube insertion could be a useful method to reach this goal and make multiple sessions of FMT easier.

Abstract Fecal microbiota transplantation (FMT) had been an ancient remedy for severe illness several centuries ago. Under modern medical analysis and evidence‐based research, it has been proved as an alternative treatment for recurrent Clostridium difficile infection and recent randomized control study also showed that FMT could be an adjuvant treatment for inflammatory bowel disease. As we get a better understanding of the relationship between gut microbiota and systemic disease, FMT became a potential treatment to explore. This article summarized procedures such as donor selection, fecal material preparation, transplantation delivery methods, and adverse events. We also review the present evidence about FMT in clinical practice.

Abstract Background In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy. Methods A total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed. Discussion Liquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC. Trial registration The date of trial registration (NCT03401957) in this study was January 17, 2018.

BACKGROUND: To evaluate the efficacy and toxicities of regorafenib plus irinotecan, dose-escalated on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping, in previously heavily treated metastatic colorectal cancer (mCRC) and the prognostic values of EGFR expression, KRAS mutations, and tumor sidedness. METHODS: Forty-one patients with mCRC with disease progression after treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR MoAbs were subjected to UGT1A1 genotyping and received regorafenib combined with FOLFIRI with dose-escalated irinotecan. RESULTS: The median follow-up period was 10.0 months (1.3-23.5 months). The overall disease control rate was 58.5%, whereas the median progression-free survival (PFS) and overall survival (OS) were 6.0 months and 12.0 months, respectively. KRAS mutations were significantly associated with positive EGFR expression (P = .026). KRAS mutations significantly correlated with a shorter OS than KRAS wild-type (6.0 vs. 14.4 months, P = .014) but had no significant association with PFS. Positive EGFR expression had an inverse correlation with PFS (2.5 vs. 14.0 months, P = .039) and OS (9.6 vs. 19.7 months, P = .044). Moreover, left-sided tumors associated with superior PFS (2.0 vs. 7.0 months, P

Abstract Background A long-acting prodrug of nalbuphine, nalbuphine sebacate, has been developed for meeting the unmet medical need of long-acting analgesics. Naldebain® (nalbuphine sebacate) has been developed as a new premedication for postoperative pain management. The primary objective of this study is to determine the efficacy and safety of a single dose of intramuscular Naldebain® in patients scheduled to undergo elective laparotomy. Methods/design A total of 110 patients will be recruited and randomized into two treatment groups. Group 1 receives a single dose of Naldebain® intramuscularly 24 ± 12 h prior to surgery. Group 2 receives intravenous patient-controlled analgesia (PCA) with fentanyl through 48 h postsurgery. Both groups will have follow-up observations until the final visit (day of discharge, day 6–30). The primary efficacy endpoint is to assess time-specific pain intensity calculated as the area under the curve (AUC) of a visual analog scale at individual time points and by using total AUC. Safety endpoints—including incidence of treatment, emergent adverse events, and percentage of abnormality from baseline to final visit—in vital signs, laboratory tests, and injection site evaluations will also be analyzed. Statistical analyses will be performed on the data to compare the two groups. Discussion Post-laparotomy pain can have a harmful effect on patient recovery; therefore, a slow-release formulation that can cover at least 7 days of analgesic effect is required. This study will demonstrate whether a single use of Naldebain® is not less efficacious than PCA with fentanyl for pain management as a non-inferior trial. Trial registration NCT03296488.

Summary: Background: In colorectal cancer (CRC) patients, pulmonary nodules are usually considered lung metastases (LM). However, approximately 10% of LM is presented as a solitary pulmonary nodule which mimics primary lung cancer (PLC). This study aims to determine the distinguishing characteristics of the two pulmonary nodule types during postoperative surveillance of CRC patients. Methods: Between March 2009 and February 2018, 47 CRC patients with pulmonary nodules from a single institution were retrospectively analyzed. They were divided into two groups, namely CRC with second PLC (CSPLC) and CRC with LM (CRCLM), and their demographic data and clinicopathological features were analyzed. Results: When pulmonary nodules are presented, multiple lesions and serum carcinoembryonic antigen (CEA) level >5 ng/mL indicated a higher probability of CRCLM (p 5 ng/mL when an isolated pulmonary nodule detected, and initial TNM stage IV CRC are more likely related to LM rather than SPLC. Image-guided needle biopsy and IHC stain can reduce the probability of misdiagnosis and rule out LM. CSPLC may have a favorable prognosis owing to early detection and receiving appropriate treatment. Keywords: Colorectal cancer, Lung metastasis, Lung nodules, Postoperative surveillance, Second primary lung cancer

Locally advanced gastric cancer (LAGC) has a poor prognosis with surgical resection alone, and neoadjuvant treatment has been recommended to improve surgical and oncological outcomes. Although neoadjuvant chemotherapy has been established to be effective for LAGC, the role of neoadjuvant chemoradiotherapy (NCRT) remains under investigation. Clinical experience and research evidence on esophagogastric junction adenocarcinoma (e.g., cardia gastric cancers) indicate that the likelihood of achieving sustainable local control is higher through NCRT than through resection alone. Furthermore, NCRT also has an acceptable treatment-related toxicity and adverse event profile. In particular, it increases the likelihood of achieving an R0 resection and a pathological complete response (pCR). Moreover, NCRT results in higher overall and recurrence-free survival rates than surgery alone; however, evidence on the survival benefits of NCRT versus neoadjuvant chemotherapy (NCT) remains conflicting. For noncardia gastric cancer, the efficacy of NCRT has mostly been reported in retrospective studies, and several large clinical trials are ongoing. Consequently, NCRT might play a more essential role in unresectable LAGC, for which NCT alone may not be adequate to attain disease control. The continual improvements in systemic treatments, radiotherapy techniques, and emerging biomarkers can also lead to improved personalized therapy for NCRT. To elucidate the contributions of NCRT to gastric cancer treatment in the future, the efficacy, potential toxicity, predictive biomarkers, and clinical considerations for implementing NCRT in different types of LAGC were reviewed.

Studies have demonstrated that metformin has antitumor effects in addition to therapeutic effects on hyperglycemia; however, few studies have explored the effects of metformin in chemotherapy. Therefore, we hypothesized that the administration of metformin would enhance the therapeutic effects of 5-fluorouracil and oxaliplatin (FuOx) to inhibit the growth of colorectal cancer (CRC) cells in vitro and in vivo. The results of our in vitro experiments demonstrated that metformin significantly increased the effects of FuOx with respect to cell proliferation (p < 0.05), colony formation (p < 0.05), and migration (p < 0.01) and induced cell cycle arrest in the G0/G1 phase in HT29 cells and the S phase in SW480 and SW620 cells (p < 0.05). Flow cytometry analysis revealed that metformin combined with FuOx induced late apoptosis (p < 0.05) by mediating mitochondria-related Mcl-1 and Bim protein expression. Furthermore, in vivo, metformin combined with FuOx more notably reduced tumor volume than FuOx or metformin alone did in BALB/c mice (p < 0.05). These findings demonstrate that metformin may act as an adjunctive agent to enhance the chemosensitivity of CRC cells to FuOx. However, further clinical trials are warranted to validate the clinical implications of the findings.