Clinical significance of the post/preoperative anti-p53 antibody ratio in predicting the prognosis of patients with colorectal cancer after curative surgery and its usefulness in combination with carcinoembryonic antigen.

[Introduction] Anti-p53 antibody (p53Ab) is useful for monitoring colorectal cancer (CRC) recurrence. We retrospectively analyzed the clinical impact of p53Ab ratio (p53R) before and after surgery to predict recurrence in patients with CRC. [Methods] In total, 1,223 patients with stage I-III CRC who underwent curative surgery between January 2005 and December 2019 were enrolled in this retrospective study. In patients with elevated p53Ab levels, p53R was calculated by measuring p53Ab levels within one month preoperatively and three months postoperatively. The optimal p53R level was determined, and its relationship with clinicopathological factors and prognosis was examined. We also evaluated the efficacy of the combination of p53R and preoperative carcinoembryonic antigen (CEA) values. [Results] Overall, 341 patients (27.9%) showed elevated p53Ab levels. Preoperative p53Ab levels were significantly associated with tumor location, lymphatic invasion, and venous invasion. The p53R level was significantly higher in patients with recurrent disease. Patients with high p53R levels had significantly shorter relapse-free survival (RFS) than those with low p53R levels (p < 0.001). When p53R was combined with preoperative CEA values, specificity improved to 0.97, with an accuracy of 0.88. [Conclusion] In patients with CRC and elevated preoperative p53Ab levels, p53R expression may be prognostically useful after radical resection. Furthermore, the combination of p53R and preoperative CEA levels may be useful for postoperative follow-ups.

Prospective observational study comparing the perioperative outcomes of laparoscopic colectomy with or without epidural anesthesia: the Kanagawa Yokohama Colorectal Cancer Study Group (KYCC) 1806.

PURPOSE: There have been no adequate comparisons of the efficacy, safety, and efficiency of analgesia after laparoscopic colorectal resection (LAC), with and without epidural anesthesia (EDA). METHODS: This was a multicenter prospective observational study of patients undergoing LAC. The primary end point was the mean visual analog scale (VAS) score on postoperative days (PODs) 1-7. The secondary end points were the highest VAS, complication rate, days to first ambulation and fatigue, length of hospital stay, and time to commencement of surgery. RESULTS: We compared an EDA group (Group E, n = 48) and a no-EDA group (Group O, n = 48) after matching. The mean VAS was not significantly different between the groups (28.7 vs. 30.1, p = 0.288). On assessing the secondary end points, the highest VAS was not significantly different between the groups. In fact, the VAS was lower in Group E only on POD 2. There was no difference in the incidence of complications, the time to first postoperative evacuation was shorter in Group E, and postoperative hospitalization was similar. The time to surgery was shorter in Group O. CONCLUSION: These results suggest that LAC without EDA is a feasible option, but with the early and regular use of adjunctive measures to provide more stable analgesia.

Short- and long-term outcomes of transanal decompression tube and self-expandable metallic stent for obstructive colorectal cancer based on a multicenter database (KYCC2110).

AIM: There are well-known methods for decompressing the colorectal tract before surgery, including transanal decompression tubes (TDT) and self-expanding metallic stents (SEMS). This study aimed to compare the short and long-term results in patients with malignant large bowel obstruction in whom TDT or SEMS were placed before surgery. METHODS: This retrospective observational study enrolled 225 patients with malignant large bowel obstruction in whom TDT or SEMS were placed preoperatively and underwent R0 resection between 2008 and 2020. One-to-two propensity score matching was performed according to patient characteristics. Short- and long-term outcomes were compared. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were the overall survival (OS) and postoperative complication rate. RESULTS: Fifty-seven patients in the TDT group and 114 in the SEMS group were matched. The 3-year RFS rates were 66.7% in the TDT group and 69.9% in the SEMS group (p = 0.54), and the 3-year OS rates were 90.5% in the TDT group and 87.1% in the SEMS group (p = 0.52). No significant differences in the long-term results were observed between the two groups. Regarding short-term results, the SEMS group had significantly fewer stoma construction (p = 0.007) and shorter postoperative hospitalization (p < 0.001). The incidence of postoperative complications (grade ≥ 2) was significantly lower in the SEMS group (p = 0.04). CONCLUSION: No significant differences in the long-term results were observed between the TDT and SEMS group. The SEMS showed significant usefulness in terms of improving short-term outcomes.

Analysis of surgical outcomes of laparoscopic versus open surgery for locally advanced mid-transverse colon cancer.

PURPOSE: This study compared the surgical outcomes between laparoscopic colectomy (LC) and open colectomy (OC) for mid-transverse colon cancer (MTC). METHODS: This multicenter retrospective study compared the short- and long-term surgical outcomes for patients with advanced MTC (T3 and T4 with or without nodal involvement) who underwent LC or OC between January 2008 and December 2019 using a propensity score-matched analysis. RESULTS: A total of 177 patients with advanced MTC were enrolled. After matching, 58 cases for the OC and LC groups were selected. No significant differences in age, sex, tumor progression, or procedure type (extended resection or segmental resection) existed between groups. The LC group had significantly less blood loss (20 mL vs. 50 mL, p=0.048) and a shorter postoperative hospital stay (8 days vs. 12 days, p<0.001) than the OC group. Postoperative complications (Clavien-Dindo grade ≥ 2) occurred in 27.6% and 25.9% of the OC and LC groups respectively (p=1). Three patients (5.2%) and one patient (1.7%) of the OC and LC groups respectively developed anastomotic leakage (p=0.62). Re-operation was required in five patients (8.6%) in the OC group and one patient (1.7%) in the LC group (p=0.21). No surgery-related deaths occurred in either group. The 3-year overall survival rates (stage II: LC 100% vs. OC 92.8%, p=0.15; stage III: 88.9% vs. 84.3%, p=0.88, respectively) were similar between the two groups. CONCLUSION: LC is a minimally invasive technique with lesser blood loss, shorter postoperative hospital stays, and oncologic equivalence to OC. Hence, LC is useful for MTC treatment. TRIAL REGISTRATION: UMIN000042676.

Laparoscopic extended right hemicolectomy versus laparoscopic transverse colectomy for mid-transverse colon cancer: a multicenter retrospective study from Kanagawa Yokohama Colorectal Cancer (KYCC) study group.

PURPOSE: The laparoscopic surgery approach for mid-transverse colon cancer (MTC) varies depending on tumor characteristics and the guidelines implemented by each surgeon; the optimal surgical procedure for MTC has not been established. This study aimed to compare the surgical outcomes of laparoscopic extended right hemicolectomy (Lap-ERHC) and laparoscopic transverse colectomy (Lap-TC) for MTC. METHODS: This was a multicenter, retrospective study. We surveyed eight hospitals, by questionnaire, on MTC surgery policies and retrospectively compared the short- and long-term surgical outcomes for patients with MTC who underwent Lap-ERHC or Lap-TC between January 2008 and December 2019. RESULTS: A total of 129 patients were enrolled, of whom 35 underwent Lap-ERHC and 94 underwent Lap-TC. There were no significant differences in tumor progression between the two groups. Operation time was significantly longer (202 min vs. 185 min, p = 0.026). We observed a higher complication rate (≥ grade 3) in the Lap-ERHC group than in the Lap-TC group (11.4% vs. 3.2%, p = 0.086). Three patients (8.6%) who underwent Lap-ERHC developed anastomotic leakage; none of the patients who underwent Lap-TC had this complication (p = 0.018). The 3-year overall survival rates (stage I: 100% vs. 91.9%, p = 0.64; stage II: 100% vs. 95.5%, p = 0.46; stage III: 100% vs. 88.2%, p = 0.91, respectively) were similar between the two groups. CONCLUSION: Lap-ERHC for MTC has the same long-term outcomes as Lap-TC. However, Lap-ERHC for MTC has a higher complication rate. Therefore, Lap-TC may be recommended for patients with MTC. TRIAL REGISTRATION: UMIN000042674.

[Resected Metachronous Pancreatic Metastasis from Rectal Cancer-A Case Report].

A 68-year-old woman had undergone laparoscopic high anterior resection for rectal cancer. Two years postoperatively, metachronal pulmonary metastases and cerebellar metastasis were surgically resected. Three and a half years after the primary surgery, computed tomography(CT)demonstrated a nodule at the pancreatic tail. Under suspected primary pancreatic cancer or metastasis from rectal cancer, we performed distal pancreatectomy. Histological examination of the pancreatic tumor suggested a metastasis from the rectal cancer since tumor cells were negative for CK7 and positive for CK20 and CDX2 immunohistochemically. Three months after the pancreatic resection, CT demonstrated hepatic and cerebellar metastases. After subsequent chemotherapy, liver metastasis disappeared. The cerebellar metastasis shrank with radiotherapy.

[The Strategy for the Treatment of Perforated Gastric Cancer].

Perforated gastric cancer reported to be relatively rare and to have a poor prognosis. This study examined 9 patients with perforated gastric cancer. Two-thirds of the patients were male and the median age was 69 years. The timing of the diagnosis of gastric cancer was preoperative clinical findings in 4 cases, intraoperative surgical findings in 3 cases, and postoperative examination in 2 cases. The depths of tumor invasion were T3 in 3 cases, T4a in 4 cases, and T4b in 2 cases and 5 patients were Stage Ⅳ. Four patients underwent palliative gastrectomy and only 1 patient underwent curative(R0)gastrectomy. Four patients underwent repair surgery, 2 of which underwent omental patch repair during the initial surgery. One of patients with omental patch repair received 2-stage curative gastrectomy; the other patient received chemotherapy after recovering from acute peritonitis. The median overall survival was 17.9 months and the prognosis was favorable in cases with curative resection or chemotherapy. For patients with perforated gastric cancer, if curative resection cannot be expected, the initial surgery should be directed toward the treatment of peritonitis and radical oncological surgery or systemic chemotherapy should be planned following patient recovery.

[Clinical Outcomes of Palliative Radiation Therapy for Gastric Cancer Bleeding].

Only a few studies have been conducted regarding the palliative radiation therapy(RT)for gastric cancer(GC)bleeding. Data of 9 patients with gastric cancer requiring blood transfusions due to gastric bleeding who were treated with RT were reviewed. All patients were men with a median age of 83(range, 70-91)years. The clinical stage was ⅡB in 2 patients, Ⅲin 1, ⅣA in 1, and ⅣB in 5. Performing gastrectomy was difficult in 4 patients with distant metastasis or tumor invasion to adjacent organ, 3 with poor performance status, and 2 with advanced age. The median hemoglobin levels before RT was 6.0 (range, 3.3-7.7)g/dL, and all patients received blood transfusions before RT. Seven patients received 30 Gy RT and 2 patients received 50 Gy. Two patients received concurrent chemotherapy. A total of 2 hematological and 4 non-hematological treatment-related adverse events occurred. All patients improved conservatively. Hemorrhage occurred in 8 patients, except for 1. Of the 8 patients who responded to RT, 1 had rebleeding on day 81. The median rebleeding-free survival time from the beginning of RT was 125(range, 21-421)days. Palliative radiation therapy was useful for bleeding control in nonresectable gastric cancer.

[Short-Term Outcomes of Laparoscopic-Assisted Total Gastrectomy Using the Endoscopic Purse-String Suture Instrument ENDO-PSI].

Laparoscopic-assisted total gastrectomy(LATG)has several complications early during the introduction of the procedure, so a careful approach is necessary. In this study, we evaluated short-term outcomes after LATG at our hospital. From 2014 to 2017, 21 patients underwent LATG using ENDO-PSI. A 6-cm midline incision was made at the epigastrium, and the abdominal esophagus was transected using ENDO-PSI. The anvil head was fixed with extracorporeal ligation, and an end loop was added to the proximal side of the first suture. Reconstruction was performed with the Roux-en-Y method. The jejunojejunal anastomosis was performed extracorporeally, and esophagojejunostomy was performed using a circular stapler through the small incision. There were 15 men and 6 women, with a mean age of 74 years. The mean operation time was 296 min, and volume of blood loss was 75 mL. The median fasting period was 3(3-10)days, and the postoperative hospitalization period was 12(8-28)days. The postoperative complications were Grade Ⅱ in 4 patients and Grade Ⅲ in 1 patient. The complication due to esophagojejunostomy was anastomotic leakage in 1 patient, while no anastomotic stenosis was found. LATG using ENDO-PSI can be safely performed.

[Short-Term Comparison between Trans-Anal Ileus Tube and Self-Expandable Metallic Stent for Obstructive Colorectal Cancer].

The aim of this study was to compare the outcome of using trans-anal ileus tube and self-expandable metallic stent(SEMS) for obstructive colorectal cancer. METHODS: Between 2014 and 2018, 14 patients received trans-anal ileus tube placement (group I)and 34 received SEMS insertion as bridge to surgery(BTS)and underwent primary resection. RESULTS: The technical success rate was 100%in both groups, and the clinical success rate was 85.7%(12/14 cases)in group I and 91.2%(31/34 cases)in group S. In group S, the CROSS score significantly improved, the rates of stoma construction and postoperative complications were significantly lower, and the period until oral intake and hospital discharge was significantly short. CONCLUSION: SEMS insertion is more effective than trans-anal ileus tube placement in terms of short-term outcome.

[Clinical Assessment of 33 Patients with Perforated Colorectal Cancer Who Underwent Surgery].

The aim of this study was to clarify the risk factors of severe postoperative complications and prognostic factors in patients who underwent emergent surgery for colorectal cancer perforation. ASA-PSB3 and Mannheim Prognostic Index(MPI)B27 were selected as the independent risk factors for postoperative severe complications on multivariate analysis. Moreover, severe postoperative complications and non-curative surgery were selected as the independent factors of poor prognosis.

[Appropriate Range of Lymph Node Dissection in Elderly Patients with Colorectal Cancer].

In elderly patients, surgical procesure is decided considering the general condition and surgical invasion. The aim of this study was to clarify the appropriate rage of lymph node dissection for elderly colorectal cancer patients. One hundred forty one colorectal cancer patients aged 75 years or more, who underwent R0 colorectal resection with D2 or D3 lymph node dissection in clinical T3/T4 or clinical N+, were enrolled in this study. The patients whose tumor located in the rectum below the peritoneal reflection(Rb)were excluded. Five-year overall survival(OS)rate and disease specific survival(DSS)rate were 79.1% and 89.4%, respectively. More than 2 preoperative co-morbidities and macroscopic type 3-5 were independent prognostic factors in OS, whereas the rage of lymph node dissection was not risk factor. When comparing the outcomes of D2 and D3 dissections by age, D3 dissection was better tendency in DSS in patients aged under 80, however, D2 dissection was better tendency in patients aged 80 or more. In elderly colorectal cancer patients, there was no difference in prognosis between D2 and D3 dissection, and especially in patients aged 80 years or more, D2 might be sufficient if R0 resection was possible.

ES cell differentiation system recapitulates the establishment of imprinted gene expression in a cell-type-specific manner.

Genomic imprinting is a phenomenon whereby monoallelic gene expression occurs in a parent-of-origin-specific manner. A subset of imprinted genes acquires a tissue-specific imprinted status during the course of tissue development, and this process can be analyzed by means of an in vitro differentiation system utilizing embryonic stem (ES) cells. In neurons, the gene Ube3a is expressed from the maternal allele only, and a paternally expressed non-coding, antisense RNA has been implicated in the imprinting process in mice and humans. Here, to study the genomic imprinting mechanism, we established F1 hybrid ES cells derived from two sub-species of Mus musculus and established an in vitro neuronal differentiation system in which neuron-specific imprinting of Ube3a was recapitulated. With this system, we revealed that the switch from biallelic expression to maternal, monoallelic expression of Ube3a occurs late in neuronal development, during the neurite outgrowth period, and that the expression of endogenous antisense transcript from the Ube3a locus is up-regulated several hundred-fold during the same period. Our results suggest that evaluation of the quality of ES cells by studying their differentiation in vitro should include evaluation of epigenetic aspects, such as a comparison with the genomic imprinting status found in tissues in vivo, in addition to the evaluation of differentiation gene markers and morphology. Our F1 hybrid ES cells and in vitro differentiation system will allow researchers to investigate complex end-points such as neuron-specific genomic imprinting, and our F1 hybrid ES cells are a useful resource for other tissue-specific genomic imprinting and epigenetic analyses.

Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment.

PURPOSE: In metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance. METHODS: This was a retrospective, single-center study that included 82 patients with tissue RAS-mutant (RAS-MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013-April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (aRAS-ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed. RESULTS: aRAS-ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to aRAS-ML; no new conversions were detected at the third assay. The aRAS-ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (aRAS-ML: 84.8% vs. RAS-MT: 59.2%, p = 0.02). Of the 33 patients with aRAS-ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1-6.3, p = 0.02). CONCLUSION: The rate of ctDNA mutation loss in patients with RAS-MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.

Highly parallel SNP genotyping reveals high-resolution landscape of mono-allelic Ube3a expression associated with locus-wide antisense transcription.

We investigated the allele- and strand-specific transcriptional landscape of a megabase-wide genomic region of mouse Ube3a (ubiquitin protein ligase E3A) by means of a highly parallel SNP genotyping platform. We have successfully identified maternal-specific expression of Ube3a and its antisense counterpart (Ube3a-ATS) in brain, but not in liver. Because of the use of inter-subspecies hybrid mice, this megabase-wide analysis provided high-resolution picture of the transcriptional patterns of this region. First, we showed that brain-specific maternal expression of Ube3a is restricted to the second half part of the locus, but is absent from the first half part. Balance of allelic expression is altered in the middle of the locus. Second, we showed that expression of the brain-specific Ube3a-ATS appeared to be terminated in the region upstream to the Ube3a transcription start site. The present study highlights the importance of locus-wide competition between sense and antisense transcripts.

Gallbladder herniation into the lesser sac through the foramen of Winslow: report of a case.

We report a case of gallbladder hernia into the lesser sac through the foramen of Winslow. The patient was a 90-year-old woman, admitted to hospital with obstructive jaundice. Computed tomography (CT) showed a left-deviated and remarkably enlarged gallbladder dragging the liver, and a dilated intrahepatic bile duct. The deviated gallbladder was thought to compress the common bile duct, causing the obstruction. Laparoscopic examination revealed gallbladder herniation into the lesser sac without a floating gallbladder; thus, we performed laparoscopic cholecystectomy. Herniation of the gallbladder is the rarest of all internal hernias and most reported cases have involved a floating gallbladder. The case we report here is therefore considered especially unusual.

A Case of Colon Cancer with Extramural Tumor Deposits in the Main Lymph Node Area: A Case Report.

A 72-year-old man with type 2 sub-circumferential tumors in the descending colon and two nodules around the pedicle of the inferior mesenteric artery (main lymph node area) underwent laparoscopic left hemicolectomy with D3 lymphadenectomy. Two lymph nodes around the inferior mesenteric artery pedicle were completely excised. Pathological examination revealed a moderately differentiated tubular adenocarcinoma. Nodules were only found in the main lymph node area, and no lymph node structures were observed in these nodules. These tumor deposits (TDs) may be extramural TDs without lymph node structure or lymph node skip metastasis. The presence of TDs in colorectal cancer is associated with an adverse prognosis, and the requirement of chemotherapy in such cases should be examined. Therefore, it is important to correctly recognize TDs and categorize the disease into a high- or low-risk group within stage III. We report this case because it is necessary to review the definition of TDs, and the assessment of extramural TDs remains controversial.

[Feasibility of bevacizumab for elderly patients with metastatic colorectal cancer].

The feasibility of treatment containing bevacizumab (BV) for elderly patients is not well established. We investigated the safety of treatment containing BV for advanced or metastatic colorectal cancer in elderly patients. From June 2008 to December 2010, 22 patients were treated with BV in our hospital. We classified them into three groups: less than 65 years (group A: 8 patients), 66-75 years (group B: 9 patients), and more than 76 years (group C: 5 patients). Then, we compared the adverse events involving BV. The patient median age was 71. 5 (range 45-84)years old; 10 patients were treated in first-line therapy and 12 patients in second-line therapy or beyond. The number of patients with hypertension was one (12. 5%) in group A, 3 (33. 3%)in group B, and 3 (60%) in group C. Treatment was continued in 4 patients, and discontinued in 18. The reasons for discontinuing BV treatment were tumor progression in 14 patients, toxicities in 3 patients, and degradation of performance state in one patient. BV-associated adverse events had a tendency to become severe with aging, and patients for whom BV treatment was discontinued because of toxicities were all in group C. Severe adverse events of rectal bleeding, cerebral hemorrhage and cerebral infarction were observed in three patients. These patients had risk factors for BV-associated adverse events such as hypertension or a history of radiation therapy, besides the risk factor of age. It is suggested that BV-associated adverse events are highly frequent and severe in elderly patients. Especially in patients over 76 years old, risk factors such as hypertension and severe adverse events were observed. The administration of BV for elderly patients should be considered very carefully.

[A case of rectal hemorrhage during chemotherapy with bevacizumab for local recurrence of rectal cancer].

Chemotherapy with bevacizumab(BV)has been one of the standard treatments for patients with metastatic colorectal cancer. However, emergent treatments are sometimes required because of severe adverse events associated with it. We experienced a case of massive rectal hemorrhage during BV treatment, and interventional radiology(IVR)successfully controlled it. An 81-year-old male visited our hospital, suffering from local recurrence of rectal cancer. He underwent colostomy for fecal diversion, and chemoradiation therapy was performed. Systemic chemotherapy with XELOX+BV was performed for the residual tumor. On the 27th day after the first administration of BV, the patient was hospitalized because of anal bleeding and a state of shock. The colonoscopic examination showed a dimple caused by tumor shrinkage, which was closed by clipping. However, a state of shock was caused by intermittent hemorrhages again afterwards. The hemorrhagic point was identified as the oral side of the dimple by angiography, and coil embolization led to immediate hemostasis. The colonoscopic examination revealed nothing abnormal besides the dimple. It is therefore suspected that the cause of rectal hemorrhage might be induced by BV. During combination chemotherapy with BV, bleeding is one of the severe adverse events requiring an emergent treatment regardless of BV dose. IVR may be an effective treatment when bleeding can not be controlled by endoscopic hemostasis. Therefore, we should construct a system for emergency hemostasis including IVR.

Solitary Cardiac Metastasis from Colorectal Cancer: A Case Report.

A 73-year-old woman with silent cardiac metastasis underwent high anterior resection for rectal cancer 3 years ago. Follow-up computed tomography showed a tumor in the right atrium. Partial vascular resection of the superior vena cava and right atrium was performed. Early postoperative recurrence occurred, and chemotherapy was unsuccessful. The patient died 7 months after surgery.