BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.

BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.

Cancer Stem Cells Persist Despite Cellular Damage, Emergence of the Refractory Cell Population.

PURPOSE: Cancer stem cells (CSCs) are responsible for chemotherapy resistance and have unique properties that protect them from chemotherapy. Investigating CSCs may help to identify the population that is more resistant to treatments, leading to recurrence. We evaluated persisting CSCs, emerging after chemotherapy that cause tumor recurrence. METHODS: Using human colorectal cancer organoids prepared from surgical specimens, we looked at changes in CSCs, the emergence and changes in the original population, which single-cell analysis identified. RESULTS: With regards to changes in cancer stem cell markers, CD44 showed low levels after 5-fluorouracil administration. Once the CD44-ve population was sorted and cultured, the CD44+ve population gradually emerged, and the CD44-ve population decreased. Compared with the CD44-ve population of an organoid parent, the CD44-ve population proliferated after chemotherapeutic agent stimulation. The CD44-ve population was derived from the CD44+ve population before chemotherapeutic agents. In addition, when the CD44 variants were evaluated, the CD44v9 population remained. In single-cell analysis, we found that POU5F1 was highly expressed in the CD44low population. Velocity analysis showed that the CD44-ve population was induced after chemotherapy and expressed POU5F1. POU5F1-EGFP-Casp9 transfected organoids resulted in the appearance of a CD44-ve population after administration of a chemotherapeutic reagent. Both in vivo and in vitro, the dimerizer administration inhibited tumor growth significantly. CONCLUSIONS: POU5F1 is involved in chemotherapy resistance in relation to stemness. For the treatment against refractory tumors, such as the recurrence after chemotherapy, the treatment should target the emerging specific population such as CD44 (or CD44v9) and proliferative cancer cells.

Development of an ultralow-latency communication system using shared internet access: promoting the implementation of telemedicine.

Telemedicine is becoming increasingly important to address the shortage of gastrointestinal surgeons and disparities in domestic and international treatment outcomes for patients with colorectal cancer. The development of a low-latency communication system using existing communication infrastructure (shared internet access: SIA) is necessary to promote the use of telemedicine. The aim of this study was to develop a low-latency communication system using SIA. We conducted an experiment between Sapporo and Tokyo using an ultralow-latency communication system for remote medical education (TELEPRO®). The latency was measured using 2000 annotations from a monitor in Sapporo, which confirmed a median latency of 27.5 ms. A low-latency communication system based on SIA with latency lower than the maximum allowable latency for telemedicine was developed successfully.

Impact of aspirin discontinuation on thrombotic complications in laparoscopic colorectal cancer surgery.

BACKGROUND: The number of patients taking antiplatelet therapy is increasing. However, there is no definitive guideline for the perioperative management of antiplatelet therapy. Conventionally, the discontinuation of antiplatelet drugs has been the basic treatment as perioperative management. Therefore, we investigated the risk of discontinuing aspirin concerning thrombotic complications in laparoscopic colorectal cancer surgery. METHODS: Between January 2015 and December 2019, a total of 729 patients underwent laparoscopic colorectal cancer surgery in Toyonaka Municipal Hospital. Sixty-four patients taking antithrombotic drugs aside from aspirin were excluded from this study; the remaining 665 patients were considered eligible and divided into three groups. The patients not taking aspirin were classified as the "Control group" (n = 588). Among the patients taking aspirin, those who continued preoperative aspirin were classified as the "Aspirin group" (n = 30), and those who discontinued preoperative aspirin were classified as the "No-aspirin group" (n = 47). The Aspirin, No-aspirin, and Control groups were compared retrospectively. RESULT: Among the 3 groups, there were no significant difference in operative time (p = 0.14), bleeding volume (p = 0.63), or postoperative hospital stay (p = 0.06). Assessing the postoperative complication, bleeding complications were significantly more frequent in the Aspirin group (p < 0.01), although those complications were all Clavien-Dindo grade II. In contrast, thrombotic complications were significantly more frequent in the No-aspirin group (p < 0.01). Note that those complications were all Clavien-Dindo Grade III/IV. This result suggested that discontinuing aspirin increased the risk of severe thrombotic complication. CONCLUSION: Discontinuation of aspirin as perioperative management in laparoscopic colorectal cancer surgery increased the risk of severe thrombotic complications.

Clinical Utility and Characteristics of the LARS Score Compared to the CCIS.

PURPOSE: The low anterior resection syndrome (LARS) score (LS) has been widely validated and has become an international tool for evaluating postoperative bowel dysfunction. However, many physicians still use the conventional incontinence scores in LARS treatment. Moreover, interpretation of LS and its relationship with conventional incontinence scores are not yet well understood. Here we compared the LS with the Cleveland Clinic Incontinence Score (CCIS) to clarify the clinical utility and characteristics of the LARS score. METHODS: We performed a multicentre observational study, recruiting 246 rectal cancer patients following sphincter-preserving surgery. Patients completed the LS, CCIS, and SF36 questionnaires. RESULTS: The response rate was 76.4%, and a total of 180 patients were analysed. The LS was strongly correlated with the CCIS (P < 0.001, rs = 0.727). However, among 116 patients determined to not have incontinence (CCIS 0-5), 51 (44%) were diagnosed with LARS (29 with minor LARS and 22 with major LARS). Among 68 patients without LARS, only 3 were diagnosed as having incontinence (CCIS > 6). In comparison with background factors, aging and elapsed time were associated with only LS. High LS and CCIS both showed significant quality-of-life impairment as assessed by the SF-36. CONCLUSION: This is the first study to determine the difference in the numeric values between the CCIS and LS. The LS can be a convenient tool for LARS screening, identifying a wide range of patients with LARS, including those with incontinence evaluated by CCIS. Assessment using the CCIS may often underestimate LARS.

Timing of indocyanine green injection prior to laparoscopic colorectal surgery for tumor localization: a prospective case series.

BACKGROUND: Accurate identification of tumor sites during laparoscopic colorectal surgery helps to optimize oncological clearance. We aimed to assess the timing of the local injection preoperatively and clarify the usefulness and limitation of tumor site marking using indocyanine green (ICG) fluorescence imaging. METHODS: Consecutive patients who underwent primary colorectal cancer surgery from September 2017 to January 2019 were included. Preoperatively, lower endoscopy was used to inject the ICG solution into the submucosal layer near the tumor. During laparoscopic surgery, ICG fluorescence marking as the tumor site marking was detected using a laparoscopic near-infrared camera system. The detection rate and factors associated with successful intraoperative ICG fluorescence visualization including the interval between local injection and surgery were evaluated. RESULTS: One hundred sixty-five patients were enrolled. Using the laparoscopic near-infrared system, the intraoperative detection rates of ICG marking were 100% for ICG injection within 6 days preoperatively, 60% for injection between 7 and 9 days preoperatively, and 0% for injection earlier than 10 days preoperatively. There were no complications associated with ICG marking. Additionally, this method did not disturb the progress of the surgical procedure because injected ICG in the submucosal layer did not cause any tissue inflammation, and if ICG spilled into the serosa, it was invisible by white light. CONCLUSION: Advantages of ICG fluorescence tumor site marking were high visibility of infrared imaging during laparoscopic colorectal surgery and minimal adverse events of surgery. One of the most important findings regarding practical use was a rapid decrease in fluorescence marking visibility if one week passed from the time of ICG local injection.

Perspectives for circulating tumor DNA in clinical management of colorectal cancer.

Growing evidence has demonstrated that circulating tumor DNA (ctDNA) detection in colorectal cancer might be a promising approach to address current important clinical questions. During chemotherapy for metastatic colorectal cancer, tumor cells acquire potential resistance by generating additional somatic mutations related to therapeutic resistance. ctDNA can capture the tumor landscape, including heterogeneity, which might provide the opportunity for additional treatment options. Moreover, ctDNA detection is advantageous, because it can monitor tumor heterogeneity serially, in a non-invasive manner. ctDNA is considered valid for detecting minimal residual disease after a curable resection. By utilizing ctDNA detection, adjuvant chemotherapy for patients with stage II-III colorectal cancer might be omitted for patients at low risk of recurrence; or conversely, adjuvant chemotherapy might be highly recommended for patients at high risk, based on ctDNA findings. During multidisciplinary treatments for locally advanced rectal cancer, it is essential to monitor the responses to sequential treatments to make appropriate decisions. Currently, these decisions are mainly based on radiological or pathological findings. ctDNA can add value by providing the real-time status of locally advanced rectal cancer. In this review, we summarized the current evidence and discussed future strategies for using ctDNA in the treatment of colorectal cancer.

CT reconstruction with thick slices not only underestimates lymph node size but also reduces data reproducibility in colorectal cancer.

BACKGROUND: Reliable size measurement of lymph node (LN) metastases is important for the evaluation of cancer treatment. However, image analyses without proper settings may result in inappropriate diagnoses and staging. PURPOSE: To investigate whether reconstruction slice thickness in computed tomography (CT) affects measurements of LN size and reproducibility. MATERIAL AND METHODS: We analyzed 48 patients with histological diagnoses of sigmoid colon and rectal cancer who underwent contrast-enhanced CT colonography as part of a surgical treatment preparation. A board-certified radiologist selected 106 LNs whose short-axis diameter was ≥5 mm on 1-mm-thick images; the short-axis diameters were measured on 1- and 5-mm-thick images by the radiologist and residents and compared using Wilcoxon matched-pairs signed rank test. Data variation and reproducibility were evaluated using the F test and Bland-Altman analysis. P<0.05 was considered significant. RESULTS: Short-axis diameters measured on 5-mm-thick images were significantly lower than those measured on 1-mm-thick images (P<0.01), even in the LNs whose short-axis diameters were over twice the slice thickness (P<0.05). Of the 106 LNs, 57 showed short-axis diameter <5 mm on 5-mm-thick images; the maximum short-axis diameter was 6.7 mm on a 1-mm thick image. Data variation was significantly larger on 5-mm thick images than 1-mm-thick images in small LNs (P<0.05) and reproducibility on 5-mm-thick images was inferior to that on 1-mm-thick images. CONCLUSION: Thick reconstruction slices in CT can result in an underestimation of LN size and reduce data reproducibility. When measuring LN size, a thin reconstruction slice would be recommended based on targeted LN size.

MRI-detected extramural vascular invasion potentiates the risk for pathological metastasis to the lateral lymph nodes in rectal cancer.

PURPOSE: Multidisciplinary treatment for locally advanced rectal cancer requires an accurate assessment of the risk of metastasis to the lateral lymph nodes (LNs). We herein aimed to stratify the risk of pathological metastasis to lateral LNs based on the preoperatively detected malignant features. METHODS: All patients with rectal cancer who underwent surgery from January 2016 to July 2020 were identified. We recorded the TNM factors; perirectal and lateral LN sizes; and MRI findings, including mesorectal fascia involvement, extramural vascular invasion (EMVI), tumor site, and tumor distance from the anal verge. RESULTS: 101 patients underwent rectal resection with lateral lymph node dissection, of whom 16 (15.8%) exhibited pathological metastases to the lateral LNs. Univariate analyses demonstrated that lateral LN metastasis was significantly correlated with mrEMVI positivity (p = 0.0023) and a baseline lateral LN short-axis length of ≥ 5 mm (p < 0.0001). These significant associations were confirmed by a multivariate analysis (p = 0.0254 and 0.0027, respectively). The lateral LN metastasis rate was as high as 44% in cases bearing both risk factors, compared to 0% in cases lacking both risk factors. CONCLUSION: The results elucidated in this study may contribute to risk stratification, which can be used when determining the indications for lateral lymph node dissection.

Efficacy of indocyanine green fluorescence angiography in preventing anastomotic leakage after laparoscopic colorectal cancer surgery.

PURPOSE: Some recent studies have suggested that fluorescence angiography with indocyanine green (ICG) might be useful for preventing anastomotic leakage (AL) after laparoscopic colorectal surgery. However, its efficacy has not been proven. We evaluated whether intraoperative ICG fluorescence angiography could decrease the AL rate with laparoscopic colorectal cancer surgery. METHODS: This retrospective study included patients with colorectal cancer who underwent laparoscopic surgery at our institution between March 2014 and December 2018. Patients were divided into two groups: with or without ICG fluorescence angiography. The primary outcome was the rate of AL. RESULTS: A total of 488 patients were included: 223 patients in the ICG group and 265 patients in the no-ICG group. In the ICG group, the transection line was changed to a more proximal location in seven patients (3.1%), including one patient with transverse colon surgery and six with rectal surgery. None of these seven patients developed AL. There were 18 ALs (3.7%) overall. The AL rate was 1.8% in the ICG group and 5.3% in the no-ICG group. For colon cancer, there were no significant differences in the AL rate between the groups (p = 0.278). In rectal cancer, the AL rate was significantly lower in the ICG group than in the no-ICG group (3.5% vs. 10.5%, p = 0.041). After propensity score matching, the AL rate was also significantly lower in the ICG group for rectal cancer (p = 0.044). CONCLUSION: ICG fluorescence angiography can potentially reduce the AL rate with laparoscopic rectal cancer surgery.

Prospective multicenter study of reduced port surgery combined with transvaginal specimen extraction for colorectal cancer resection.

PURPOSE: The relevance of transvaginal specimen extraction (TVSE) combined with reduced port surgery (RPS) remains unknown. This study investigated the feasibility of TVSE with RPS according to short-term outcomes and cosmesis. METHODS: This prospective multicenter study enrolled ten patients at three institutions. For the semi-quantification of each parameter, we administered questionnaires to assess pain (visual analogue scale), subjective/objective wound healing esthetics [photo series questionnaires (PSQ)], and quality of life (QOL). RESULTS: No operative complications occurred, except one case of urinary tract infection, which was promptly cured with antibiotics. On day 0, pain was rated at 2.3 ± 0.67 at rest and 4.9 ± 0.82 during sneezing; these ratings gradually declined over time. The PSQ showed that the patient ratings of wound esthetics after TVSE were not inferior to ratings from patients after conventional laparoscopy or single incision laparoscopic surgery, and they were significantly higher than the patient ratings of wounds after laparotomy (P < 0.05). The QOL scores showed that, in comparison to before surgery, after surgery, patients reported significant deterioration of their physical function (96.67 ± 1.49 vs. 87.33 ± 2.71), emotional function (93.33 ± 2.72 vs. 86.67 ± 2.22), fatigue (7.78 ± 3.72 vs. 26.67 ± 8.31), and pain (6.67 ± 3.69 vs. 18.33 ± 4.61). CONCLUSION: TVSE with RPS for colorectal cancer was feasible and was associated with a low degree of postoperative pain.

Evaluation of negative-pressure wound therapy for surgical site infections after ileostomy closure in colorectal cancer patients: a prospective multicenter study.

PURPOSE: Surgical site infection (SSI) occurs at a high rate after ileostomy closure. The effect of preventive negative-pressure wound therapy (NPWT) on SSI development in closed wounds remains controversial. We conducted a prospective multicenter study to evaluate the usefulness of preventive NPWT for SSI after ileostomy closure. METHODS: From January 2018 to November 2018, 50 patients who underwent closure of ileostomy created after surgery for colorectal cancer participated in this study. An NPWT device was applied to each wound immediately after surgery and then treatment was continued for 3 days. The primary endpoint was 30-day SSI, and the secondary endpoints were the incidence of seroma, hematoma, and adverse events related to NPWT. RESULTS: No patients developed SSI, seroma, or hematoma. Adverse events that may have been causally linked with NPWT were contact dermatitis in two patients and wound pain in one patient, and there were no cases of discontinuation or decompression of NPWT. CONCLUSION: The use of NPWT following ileostomy closure may be useful for reducing the development of SSI in colorectal cancer patients. This is a prospective multicenter pilot study and we are planning a comparative study based on these successful results. TRAIL REGISTRATION: Registration number: UMIN000032053 ( https://www.umin.ac.jp/ ).

Analysis of anatomical variations of intrapelvic vessels for advanced pelvic surgery.

BACKGROUND: In pelvic surgery, it is important to anticipate potential anatomic variations, which may be unknown, and inter-relationships among intrapelvic vessels. Here, we comprehensively analyzed intrapelvic vessel patterns. METHOD: This retrospective analysis included 81 patients that underwent colorectal surgery in our institution in 2016. A total of 162 half-pelvises were imaged with contrast-enhanced computed tomography. We scrutinized thin-slice images. RESULTS: We found variations in the number of internal iliac veins. In 47.5% of cases, one internal iliac vein drained into the ipsilateral common iliac vein in both halves of the pelvis. In the other cases, several internal iliac veins were observed in one or both halves of the pelvis. We analyzed the inter-relationships between the superior gluteal artery and the sacral nerve plexus in pelvic halves. Superior gluteal arteries ran between the 5th lumbar nerve and 1st sacral nerves, in 82% of halves, and lateral to the 5th lumbar nerve, in 17% of halves. Dorsally, the superior gluteal artery ran on the medial side of the internal iliac vein in 15% of halves. In 28% of half-pelvises, two superior gluteal veins were observed. Superior gluteal veins passed through the sacral nerve plexus lateral to 5th lumbar, between 5th lumbar and 1st sacral, and between 1st and 2nd sacral nerve, in 42.0, 47.5, and 37.7% of halves, respectively. We evaluated the rate of symmetric pelvic anatomies, and found that all anatomic variations formed symmetrically, except the number of internal iliac veins. CONCLUSION: This study clarified the anatomical variations of intrapelvic vessels and their inter-relationships. These findings will benefit our understanding of pelvic anatomy and enhance the safety of radical surgery for treating pelvic diseases.

Indocyanine green fluorescence-guided laparoscopic surgery, with omental appendices as fluorescent markers for colorectal cancer resection: a pilot study.

BACKGROUND: Currently, we lack tools that can reliably guide laparoscopic surgeons to a target anatomical destination for dissection. We aimed to develop and evaluate a fluorescent destination marker (FDM), composed of a resected omental appendix injected with indocyanine green (ICG), for real-time navigation in laparoscopic surgery for colorectal cancer in this pilot study. METHODS: This study included ten patients diagnosed with colorectal cancer. To prepare FDMs, we laparoscopically harvested omental appendices attached to the colon we planned to resect. The harvested appendices were injected with diluted ICG, and a gauze tag was attached. The FDMs were placed at target intra-abdominal sites with a ligation clip. RESULTS: Patient diagnoses included 1 cecal, 2 ascending colon, 3 transverse colon, 2 sigmoid colon, and 2 rectal cancers. No conversion to open surgery was required and no intraoperative complications occurred. We created 12 sets of FDMs, which were placed at a total of 13 sites in abdominal cavities. FDM fluorescence was successfully detected in all cases. Furthermore, FDMs could be detected earlier than the gauze tags at 12 points, and they were detected at the same time at 1 point. CONCLUSIONS: All FDMs facilitated laparoscopic surgery by allowing the surgeon to find the tissue to be dissected, particularly in procedures that required the dissection of lymph nodes around middle colic vessels and mobilization of the splenic flexure. FDMs showed potential for guiding the laparoscopic surgeon to a target anatomical destination. This marker represents a contribution to the evolution of real-time navigation surgery.

Analysis of the Vascular Interrelationships Among the First Jejunal Vein, the Superior Mesenteric Artery, and the Middle Colic Artery.

BACKGROUND: The technical difficulty of laparoscopic surgery for transverse colon cancer is partly due to the vascular variability around the middle colic vessels. Although individual variations in the arteries or veins in this area were previously investigated, the vascular interrelationships between these vessels remain unknown. This study was designed to investigate the vascular interrelationships between the arteries and veins around the middle colic vessels and to provide practically useful classifications. METHODS: This study included 105 consecutive patients who underwent colorectal surgery for colorectal tumors in our institution in 2016. Patients with a history of colectomy were excluded. Vascular anatomical classifications were analyzed by evaluating thin-slice images of preoperative contrast-enhanced computed tomography. RESULTS: Vascular anatomical patterns were classified according to whether the first jejunal vein ran behind (type A) or in front (type B) of the superior mesenteric artery. Type B was subclassified into two subtypes, depending on whether the middle colic artery originated cephalad (type B1) or caudad (type B2) to the first jejunal vein. We identified 83 (79.0%) cases of type A, 11 (10.5%) of type B1, and 11 (10.5%) of type B2. In 17 cases, the middle colic vein drained into the inferior mesenteric vein, and all of these were type A (P = 0.0202). Furthermore, in eight cases, the middle colic vein drained into the first jejunal vein, and all of these were type B (P < 0.0001). CONCLUSIONS: This study elucidated the vascular interrelationships around the middle colic vessels. Our findings provided important knowledge for laparoscopic surgery in treating transverse colon cancer.

[A Case of Locally Advanced Gastric Cancer Treated with Chemoradiotherapy before Surgical Resection].

A 70-year-old woman presented to our hospital because of stomach pain. She was diagnosed as having clinical Stage ⅢC gastric cancer with invasion into the pancreas and treated with S-1+oxaliplatin(SOX)as neoadjuvant therapy, after palliative radiotherapy for tumor bleeding. After 4 courses of SOX therapy and 7 courses of S-1 therapy, the tumor size reduce and the invasion into the pancreas disappeared. Subsequently, she underwent distal gastrectomy. The pathological diagnosis was ypStage ⅢB, with no findings of tumor invasion into the pancreas. As of 1 year 9 months after the surgery, no metastasis or recurrence was observed.

[A Case of Successful Control of Advanced Duodenal Cancer with Liver Metastasis Receiving Paclitaxel Chemotherapy and Potential Radical Resection].

We report a case of successful control of advanced duodenal cancer with paclitaxel chemotherapy. A woman in her 70s with epigastralgia was diagnosed with hemorrhagic duodenal ulcer upon upper gastrointestinal endoscopy. A type 3 tumor was found in the duodenal bulb upon upper gastrointestinal endoscopy and biopsy at our hospital. By contrast CT, we found wall hypertrophy of the duodenal bulb, lymph node metastasis, and liver metastasis and started chemotherapy. Four courses of SOX therapy were first administered. The wall hypertrophy of the duodenal bulb worsened, and new lesions appeared in the liver, so we diagnosed progressive disease. Next, 4 courses of wPTX therapy were administered. The wall hypertrophy of the duodenal bulb improved, and all liver metastatic lesions shrunk and became obscure. The reduction rate was 75%, so we diagnosed partial response. Accumulation in the primary tumor was observed on PET-CT, and the lymph node and liver metastases disappeared, so we considered radical curative resection. The patient underwent subtotal stomach preserving pancreatoduodenectomy, D2 lymph node dissection, reconstruction of the digestive tract by the modified CHILD method, partial hepatectomy, and Brawn's anastomosis. No cancer cells were found in the hepatectomized area. Paclitaxel chemotherapy may be useful for advanced duodenal cancer.

[A Case Report of SOX Treatment for Primary Duodenal Carcinoma with Liver Metastasis].

We report a case of effective S-1 plus oxaliplatin (SOX) treatment for duodenal cancer with liver metastases. The patient was a 70-year-old female diagnosed with duodenal carcinoma that was unresectable because of liver metastasis(cT4N1M1, cStage IV in UICC 7th). She received SOX treatment(100mg/m / 2 of oxaliplatin on day 1 combined with 40 mg/day of S-1 twice daily on days 1-14, was repeated every 3 weeks). After 4 courses, a partial response was confirmed by computed tomography and no severe adverse events were observed. However, during the 5th courses, several new liver metastases were observed, so we changed to weekly paclitaxel treatment. This case suggests that SOX treatment may be an effective chemotherapy for advanced primary duodenal carcinoma.

[A Case of Unresectable Advanced Gastric Neuroendocrine Cell Carcinoma Treated with Nivolumab].

A 69-year-old man was administered S-1/oxaliplatin/trastuzumab as induction chemotherapy for advanced gastric cancer (cT4b[liver, pancreas], N2M1(H1P0CYX), cStage IV). After 4 courses, because contrast-enhanced computed tomography showed remarkable reduction of the tumor, distal gastrectomy, partial hepatectomy, and radiofrequency ablation for the liver metastasis were performed. The patient was histopathologically diagnosed with gastric neuroendocrine carcinoma(NEC). S- 1/oxaliplatin/trastuzumab was continued after surgery; however, recurrence in the remnant liver was observed after 4 cours- es. For recurrence, cisplatin/irinotecan as first-line and paclitaxel/ramucirumab as second-line treatment were administered, but progression of liver metastasis and ascites due to peritoneal dissemination were observed. As third-line treatment, nivolumab was initiated. Ascites decreased after 3 courses, but after 2 more courses, progression of ascites, liver recurrence, and multiple metastasis in the lumbar vertebra were observed.

Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition.

Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-ß-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-ß signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.