The tRNA pseudouridine synthase TruB1 regulates the maturation of let-7 miRNA.

Let-7 is an evolutionary conserved microRNA that mediates post-transcriptional gene silencing to regulate a wide range of biological processes, including development, differentiation, and tumor suppression. Let-7 biogenesis is tightly regulated by several RNA-binding proteins, including Lin28A/B, which represses let-7 maturation. To identify new regulators of let-7, we devised a cell-based functional screen of RNA-binding proteins using a let-7 sensor luciferase reporter and identified the tRNA pseudouridine synthase, TruB1. TruB1 enhanced maturation specifically of let-7 family members. Rather than inducing pseudouridylation of the miRNAs, high-throughput sequencing crosslinking immunoprecipitation (HITS-CLIP) and biochemical analyses revealed direct binding between endogenous TruB1 and the stem-loop structure of pri-let-7, which also binds Lin28A/B. TruB1 selectively enhanced the interaction between pri-let-7 and the microprocessor DGCR8, which mediates miRNA maturation. Finally, TruB1 suppressed cell proliferation, which was mediated in part by let-7. Altogether, we reveal an unexpected function for TruB1 in promoting let-7 maturation.

[Assessment of Curative Resection in Patients with Multiple Relapses of Colorectal Cancer].

We assessed the therapeutic effect of curative resection in patients with multiple relapses of colorectal cancer using the time to surgical failure(TSF)as an index. We included 24 patients who experienced recurrence after curative resection of primary colorectal cancer at our department between 1993 and 2015. Curative resection for multiple relapses was possible in these patients. The sites of recurrence included the liver, lungs, peritoneum, lymph nodes, localized, and brain in 9, 8, 3, 3, 2, and 1 patients, respectively. The relapse occurred in 2 organs in 2 patients. The TSF after curative resection of recurrent lesions was 25.6 months, with a 5-year TSF-free rate of 40.2%. The clinicopathological factors associated with poor prognosis were age B65 years at the time of recurrence, absence of distal metastasis at primary onset, and only 2 curative resections for relapses. However, there was no difference in prognosis because of the number of twice recurrent lesions. Therefore, curative resection should be proactively performed as long as feasible in colorectal cancer patients with multiple lesions or multiple relapses.

[A Case of Rectal Neuroendocrine Carcinoma That Developed Two Years after Curative Resection for Sigmoid Colon Cancer].

We report a rare case ofrectal neuroendocrine carcinoma(NEC)following sigmoidectomy of sigmoid colon cancer. NEC of the rectum is a rare disease. It has an extremely poor prognosis and a high potential for malignancy with hematogenous and lymph node metastases. A 90-year-old man who had carcinoma ofthe sigmoid colon 2 years ago was found to have rectal NEC based on endoscopy findings. He underwent the Hartmann operation. Histological and immunohistochemical analyses showed NEC. Four months after the surgery, he developed local recurrence with lymph node metastasis. He was not administered chemotherapy because ofhis old age. Although the patient needed strict outpatient care, he remained symptom-free 4 months after the Hartmann operation.

[Endoscopic Submucosal Dissection(ESD)as a "Loco-Regional Cancer Therapy" for Colorectal Tumors].

INTRODUCTION: Endoscopic submucosal dissection(ESD)for colorectal tumors has been covered by the national health insurance system in Japan since April 2012, and is widely used. We analyzed colorectal ESD cases we performed. PATIENTS AND METHODS: We investigated 515 patients with colorectal lesions(580 lesions)for whom ESD was performed between November 2005 and April 2017. Clinicopathological data, technical methods, complications, and outcomes were analyzed. RESULTS: Most tumors were found in the transverse colon(134 lesions). The average diameter was about 26 mm. The largest lesion was 120 mm. The en bloc resection rate was high(96.2%). The average operative time was 51 minutes. Among complications, the number of delayed major bleeding cases was 7(1.2%). Minor perforations occurred in 3 cases(0.5%). The perforation could be closed with endoscopic clips. About 70% of the cases were adenomas, and the remainder were carcinomas. One patient with carcinoma in situ showed a mucosal recurrence 4 months later and received repeat endoscopic treatment. The cure rate was 99.8%. Among 29 deep submucosal invasion cases, additional colectomy was performed in 21; 3 patients had persistent carcinoma in the colonic wall and another patient had lymph node metastasis. CONCLUSIONS: Colorectal ESD can be performed for all sites in the large intestine, and en bloc resection was possible for a large lesion. A good outcome was observed for "Loco-Regional Cancer Therapy" in early colorectal carcinoma.

[Assessment of Less Invasiveness Based on Serum CRP Level on Postoperative Day Three in Laparoscopic Surgery for Colorectal Cancer].

To evaluate the less invasiveness of laparoscopic surgery for colorectal cancer, we compared open and laparoscopic surgery for sigmoid or recto-sigmoid cancer operations undergoing the same procedures. One hundred forty-three patients curatively resected with D3 dissection were enrolled. All cases underwent the following procedure; high ligation of the inferior mesenteric artery(IMA)with median approach and double stapling technique(DST)for anastomosis. The clinicopathological factors were examined in 70 cases of open surgery(OC)and 73 cases of laparoscopic surgery(LAC). The mean age of all cases was 66(38-88)years, including 83 men and 60 women. The mean operation time was 189(82-413)minutes and the mean blood loss was 45(5-1,025)mL. Postoperative complications were reported in 45 cases including 10 cases with surgical site infection(SSI)and 10 cases with remote infection(RI). There was no difference in sex, BMI, PS, and ASA between the 2 groups; however, the patients were significantly older and the tumor maximum diameter significantly larger in the OC group. There was no significant difference in operation time but the blood loss was significantly lower in the LAC group. There were no differences in postoperative complications, first gait, WBC, and body temperature on postoperative day(POD)3, but the first flatus was earlier and the CRP level was significantly lower on POD 3 in the LAC group. There was no difference in the CRP level on POD 3 in the age, tumor diameter, and blood loss which showed a difference in the both group. Laparoscopic surgery was considered less invasive than open surgery because the serum CRP level was lower in the LAC group.

[A Case of Low-Grade Appendiceal Mucinous Neoplasm with Cecum Cancer].

The case was a 76-year-old man. He visited our hospital for a positive fecal occult blood test finding at a medical examination. A colonoscopy revealed a macroscopic, 30 mm, type-1 lesion in the cecum. We performed laparoscope-assisted ileocolic resection and D3 dissection, with a diagnosis of cecum cancer. In postoperative histopathological examination, the tumor in the cecum was diagnosed as a well-differentiated tubular adenocarcinoma. In addition, a low-grade appendiceal mucinous neoplasm(LAMN)was observed on the distal side of the appendix. The patient has survived for 9 months after surgery without recurrence. We report this case with a review of the literature.

[Impact of Postoperative Inflammatory Status on Colorectal Cancer Prognosis].

To clarify the prognostic impact of postoperative inflammatory status, serum CRP levels on POD3 after radical resection (POD3 CRP)were evaluated as an indicator of inflammatory response after surgery in patients with colorectal cancer. Of the colorectal cancer patients who underwent radical resection at our department between 2000 and 2015, 916 patients with Stage Ⅰto Ⅳdisease were included in the analyses. The patients were divided into 2 groups according to high and low POD3 CRP levels. The POD3 CRP levels of the patients were analyzed for the 75th percentile that was 12.16mg/dL(range, 0.06- 33.78). The cancer-specific 5-year survival rate was 80.6%in patients in the high group and 90.5%in those in the low group, indicating poor prognosis in patients with high values. POD3 CRP levels were an independent prognostic factor in the multivariate analysis. It was suggested that the degree of inflammation after surgery influences the postoperative prognosis after radical resection for colorectal cancer.

Different improvement trends in gait function and quadriceps strength early after total knee arthroplasty.

[Purpose] Improved quadriceps strength is a primary target of rehabilitation early after total knee arthroplasty. However, patients demonstrate varying improvement trends in gait function and quadriceps strength. This study evaluated the relationship between improvements in quadriceps strength and gait function. [Participants and Methods] The study included 49 patients who were scheduled to undergo unilateral total knee arthroplasty. Gait function, bilateral quadriceps strength, and pain were assessed in all patients. All assessments were performed preoperatively and at 2 and 3 weeks postoperatively. [Results] A significant correlation between gait function and the quadriceps strength on the operated side was observed preoperatively and 3 weeks postoperatively. The quadriceps strength on the non-operated side was significantly correlated with gait function at all time points. Multiple regression analysis showed that the quadriceps strength on the non-operated side was significantly associated with gait function, except the gait speed at 2 weeks. However, the quadriceps strength on the operated side was not observed to be an independent variable at all time points. [Conclusion] The quadriceps strength on the operated side is not an important determinant of gait function. It may be necessary to reconsider typical rehabilitation programs by focusing on the quadriceps strength on the operated side in patients undergoing total knee arthroplasty.

[The Influence of Immunity, Nutrition, and Physical Function on the Onset of Pneumonia after Colorectal Cancer Resection].

PATIENTS AND METHODS: Four hundred and nineteen patients with colorectal cancer who underwent laparotomy were included in this study. Indicators that reflected immunity, nutrition, and physical function were selected, and risks associated with the presence of postoperative pneumonia were investigated. Cut-off values of factors affecting the occurrence of pneumonia were determined using the receiver-operating characteristic curve approach. RESULTS: Pneumonia was observed in 2.9%of the patients, and PNI(C40.0), CONUT(B2), BMI(<18.5 kg/m2), PS(B1), %VC(<80.0%), and FEV1.0%(<70.0%)were identified as risk factors in multivariate analysis(p<0.05). %VC(<80.0%)was extracted as an independent factor. The cutoff value of %VC was determined to be 80.0%based on the incidence of postoperative pneumonia. CONCLUSION: Low volume in %VC(<80.0%)may be a risk factor for pneumonia after resection of colorectal cancer.

[Prognostic Relevance of Palliative Tumor Resection and Chemotherapy in Stage â £Unresectable Colorectal Cancer].

This study was conducted to evaluate the prognostic factors in patients with unresectable Stage Ⅳ colorectal cancer. One hundred and twenty-five patients who underwent either primary resection or chemotherapy for unresectable Stage Ⅳ colorectal cancer and were treated at our hospital between April 2004 and March 2014 were enrolled this study. In multiple univariate analysis, the overall survival(OS)was significantly longer in the palliative resection and chemotherapy groups. Upon dividing the 125 patients in 3 groups(the intensive chemotherapy group[L-OHP or CPT-11 regimen], extensive chemotherapy group[other regimen], and non-chemotherapy group), the intensive chemotherapy group showed significantly longer OS. Next, upon comparing the patients based on the treatment they received(surgery plus chemotherapy, surgery alone, and chemotherapy alone), the surgery plus chemotherapy group showed longer OS. With both studies combined as 5 groups, only the surgery plus intensive chemotherapy group showed longer OS. This is shown in unresectable Stage Ⅳ cancer patients, wherein resection of the primary lesion in addition to intensive chemotherapy contributes to longer OS.

[A Case of Ascending Colon Cancer with Hepatic Metastases Showing Remarkable Efficacy of CapeOX plus Bevacizumab].

We report a case of ascending colon cancer with hepatic metastases that was treated by CapeOX plus bevacizumab with remarkable efficacy. A 40-year-old female patient presented with a medical history of surgery for resection of right breast cancer4 years ago, left-sided transverse colon 2 years ago, and right ovarian cancer 6 months ago. Follow-up computed tomography(CT)found wall thickening from the ascending colon to cecum. She was diagnosed with an ascending colon cancer by colonoscopy, and underwent right hemicolectomy. One month after the surgery, her serum marker carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9)levels were high. She was diagnosed with unresectable multiple hepatic metastases by CT 2 months after the surgery. Her tumor was epidermal growth factor receptor(EGFR)- positive and wild-type for RAS; she received 4 courses of CapeOX plus bevacizumab. Thereafter, liver metastases were remarkably decreased in size, and she could undergo central bisegmentectomy. Pathology examination revealed no tumor and that the center of the tumor was changed to necrotic tissue and the surrounding area was changed to fibrous tissue and lymphocyte infiltration. The patient is disease-free since the last operation.

[A Case of Surgery after Chemotherapy for Cecal Cancer with Onset of the Stenosis of the Colostomy].

The patient was 55-year-old woman, undergoing Hartmann operation by the sigmoid colon diverticulum perforation, 2 years later visited our hospital with abdominal pain. Although lower endoscopy and histological examination could not be performed due to stoma stenosis, we diagnosed cecal carcinoma, liver metastasis, distant lymph node metastasis from CT and PET-CT, CapeOX plus Bmabtherapy and IRIS plus Bmabtherapy were performed. After that, repeated intestinal obstruction due to exacerbated stoma stenosis, metastatic lesion increased in CT examination, furthermore the patient had hope of stoma closure, we decided to resect the primacy tumor, performed subtotal colonectomy and stoma closure. Pathological diagnosis revealed RAS wild type. After surgery, Pmabplus CPT-11 therapy was performed and the metastatic lesion was temporarily shrunk but re-exacerbated, the patient died 2 years 2 months after the first treatment started, 7 months after the primary tumor resection. In the treatment of colorectal cancer, when metastatic lesion is unresectable, chemotherapy is often carried out except when the primary tumor is symptomatic. In our case, although the primary tumor was asymptomatic, an intestinal obstruction due to stoma stenosis was developed and it was necessary to examine whether to use anti-EGFR antibody drugs, therefore we performed operation.

[Analyses of Relapsed Cases after Oxaliplatin-Based Adjuvant Chemotherapy for Colorectal Cancer with Cur A Resection].

INTRODUCTION: There are few reports on the outcome of relapsed cases after curative resection for colorectal cancer(CRC) with adjuvant oxaliplatin-based chemotherapy. Thus, we analyzed such cases. PATIENTS AND METHOD: In total, 48 patients with CRC who received oxaliplatin-based postoperative adjuvant chemotherapy from 2012 were analyzed. The clinical course was examined in 9 cases ofrecurrence. RESULTS: Stages II, III a, and III b(1, 3, and 5 cases, respectively)were judged as recurrence in 9 cases. Metastatic sites were the lungs, local sites, liver, and peritoneum(3, 3, 3, and 1 case[s], respectively). The median time to relapse was 390 days. There were 2 cases ofwild -type RAS and 7 cases ofmutant RAS. Although R0 resection was performed in 1 case, re-relapse was recognized. Another 8 cases involved induced chemotherapy. An oxaliplatin-based regimen was administered as first-line treatment in 4 of8 cases. At present, 5 patients died, and 3 of8 cases could not progress to second-line treatment. The overall survival(OS)after relapse was 475 days, and survival more than 3 years was not observed. CONCLUSION: Recurrent cases after Cur A resection for CRC with oxaliplatin-based adjuvant chemotherapy were examined. Although the 3-year RFS and 5-year OS were relatively good, the prognosis after relapse was quite poor.

[A Case of Stage IV Rectal Cancer Achieving Long-Term Stable Disease Treated with Chemotherapy and Residual Tumor Resection].

We herein report a Stage IV case ofrectal cancer in a patient who achieved stable disease and was treated monthly with fluorouracil(FU)monotherapy plus bevacizumab(Bmab)against relapse after residual tumor resection and withdrawal because ofref usal to continue chemotherapy, even though a marked response was obtained with standard chemotherapy. A 73-year-old woman visited a former hospital in 2014, and was diagnosed with rectal cancer with liver and lung metastases (diagnosed with Rb, T3, M1b[liver, lung]cStage IV). Chemotherapy(mFOLFOX6 plus Bmab)was initiated with a consideration of conversion. After 5 courses, she moved to our hospital. Since she was not aggressive to chemotherapy from the beginning, an imaging examination was performed after 9 courses. The primary lesion and lung metastases had disappeared, and there was only one liver metastasis. Partial hepatic resection was performed to attempt chemotherapy withdrawal following informed consent. Six months after surgery with no therapy, since relapse in the rectum and lungs was confirmed, laparoscopic rectal amputation was performed to control the primary tumor. Chemotherapy containing FU monotherapy plus Bmab was reinitiated after 15 months of withdrawal because liver and lung metastases increased 5 months after rectal amputation. Two months after resuming chemotherapy, the metastatic lesion decreased in size, and the tumor marker level normalized. The same regimen is continued monthly, and the response has been maintained for 17 months(infusions of 5-FU/LV plus Bmab, 18 courses).

[Treatment Outcomes of Curative Resection for Colorectal Cancer with Synchronous Liver Metastasis].

The aim of this study was to clarify prognosis for curative resection performed for cases of colorectal cancer with synchronous liver metastasis and to use the findings as future treatment indices. Subjects comprised 61 patients who underwent curative resection at our hospital for colorectal cancer accompanied by synchronous liver metastasis between 1996 and 2014. The degree of liver metastasis was H1 for 47 cases and H2 for 14 cases. The Grade of liver metastasis was A for 29 cases, B for 18 cases, and C for 14 cases. Liver resection was performed simultaneously with that of the primary lesion for 33 cases, and after that of the primary lesion for 28 cases. The post-curative resection survival period was 58.0 months, and the 5-year survival rate was 49.9%. In terms of the relationship between prognosis and clinicopathological factors, prognosis was found to be poor when the wall depth of the primary lesion was pT4 and when the liver metastasis Grade was B or C. Meanwhile, prognosis did not differ depending on the timing of liver metastasis resection, whether chemotherapy was performed after liver resection, and whether curative resection was performed for initial occurrence only or recurrence resection was performed. The results indicated that for cases of colorectal cancer with synchronous liver metastasis, primary lesion wall depth and liver metastasis Grade were prognostic factors, and that the treatment strategy did not necessarily have to consider resection timing.

[Investigation of Cases with Curative Resection for Recurrent Colorectal Cancer].

The aim of this study was to clarify the prognosis of cases with recurrent colorectal cancer that underwent curative resection in order to determine index for recurrent colorectal cancer treatment. Of the cases that exhibited recurrence after undergoing curative resection for primary colorectal cancer at our hospital between 1993 and 2013, this study targeted the 109 cases for which curative resection was possible. The sites of recurrence were the liver(58 cases), the lungs(27 cases), the peritoneum (11 cases), local sites(9 cases), lymph nodes(8 cases), and the anastomotic sites(6 cases). Of these, 10 cases exhibited metastasis to 2 organs. The median survival time after metastasectomy was 75.3 months, and the 5-year survival rate was 53.8%. The primary lesion histological type being a poorly differentiated adenocarcinoma/mucinous carcinoma, degree of progression upon initial onset being Stage III b or greater, and disease-free interval being less than 2 years were associated with poorpr ognosis. Specifically, histological type and disease-free interval were found to be independent factors that correlated with prognosis. Meanwhile, no differences were observed for prognosis related to the number of recurrent organs, the number of recurrent nodules, or the number of times curative resection was performed after recurrence. While the histological type and disease-free interval determine prognosis in cases with recurrent colorectal cancer performed curative resection, it appears that if curative resection is possible, aggressive resection should be pursued even for cases of multiple or repeated recurrence.

[Preoperative Prognostic Nutrition Index Is a Predictive Factor of Complications in Laparoscopic Colorectal Surgery].

Paitients and methods: We retrospectively reviewed a database of 188 patients who underwent resection for colorectal cancer with laparoscopic surgery between July 2007 and March 2015. The prognostic nutrition index(PNI), modified Glas- gow prognostic score(mGPS), controlling nutritional status(CONUT), and neutrophil/lymphocyte ratio(N/L)were measured in these patients. We examined the association between postoperative complications and clinicopathological factors. RESULTS: The study included 110 men and 78 women. Median age was 68 years. The site of the primary lesion was colon in 118 and rectum in 70 patients. Postoperative complications higher than Grade II(Clavien-Dindo classification)were reported in 24(12.8%)patients: Surgical site infection(SSI)in 12, remote infection in 7, ileus in 5, and others in 2 patients. Clinicopathological factors related to complications were rectal surgery, large amount of intraoperative bleeding, and long operative time. The related immunologic and nutritional factors were mGPS 2, PNI below 40, and N/L above 3. CONUT was not associated with complications in ourcases. CONCLUSIONS: mGPS, PNI, and N/L are predictive factors for complications in laparoscopic colorectal surgery.

[Anti-EGFR Antibody Combination Chemotherapy Was Effective against Locally Advanced Ascending Colon Cancer as Well as a Recurrent Lesion - A Case Report].

Here we report a case in which a locally advanced ascending colon cancer was successfully treated with anti-EGFR immunotherapy combined with chemotherapy and curative resection, and recurrent cancer was treated with the same chemotherapy. A 71-year-old man was diagnosed with ascending colon cancer in our department. No distant metastasis was observed, but curative resection was considered impossible because of extensive local cancer invasion. Because a genetic analysis revealed the presence of the wild-type KRAS gene, 6 courses of mFOLFOX6 plus cetuximab were administered. A cPR was obtained and curative resection was performed. The final diagnosis was ypT3N1M0, ypStage III a colon cancer, and chemotherapy improved the cancer stage to Grade 1b. Six courses of FOLFOX6 were then administered, followed by observation. After 2 years 6 months, a tumor of approximately 5 cm in size was noted in the right buttock using surveillance CT and was diagnosed as recurrent colon cancer. We considered further curative resection difficult and therefore 6 courses of mFOLFOX6 plus panitumumab were administered, a cPR was obtained, and right hip tumor extirpation surgery was performed. These results suggest that chemotherapy combined with anti-EGFR antibody immunotherapy is effective in treating recurrent colon cancer.

[A Case of Recurrence in the Posterior Wall of the Virginal after Radical Resection for Rectal Cancer Well Responded in a Long Period by Chemo-Radiotherapy].

We report a case of an advanced rectal cancer recurrence that responded completely to chemo-radiotherapy. The patient was an 80-year-old woman. Low anterior resection with D2(prxD3)lymph node dissection was performed. Sixteen months after operation, CEA level elevated but no recurrence foci were found in any image tests. Administration of TS-1 was initiated since recurrence was highly suspected. Twenty seven months after operation, PET-CT detected local recurrence in the posterior wall of the vagina. After construction colostomy, chemo-radiotherapy(60 Gy+oral UFT)was performed and CEA level dropped promptly to the normal value. No relapse was pointed out in CT scans or MRI tests. There were not any signs of recurrence through 112 months after chemo-radiotherapy.

[Standard Chemotherapy with Bevacizumab as First-Line Therapy for Metastatic Colorectal Cancer with RAS Mutation].

AIM: We examined the outcome of treatment with first-line chemotherapy with bevacizumab(Bmab)formetastatic colorectal cancer in our hospital to clarify the outcome for RAS mutant patients. SUBJECTS AND METHODS: From January 2013 to April 2016, 28 patients who initiated standard chemotherapy(2 chemotherapeutic agents)with Bmab as the first-line regimen for metastatic colorectal cancer were enrolled in this retrospective study. Time to treatment failure(TTF)and overall survival(OS)were analyzed. RESULTS: The median age was 66.5(46-81)years old, including 16 men and 12 women, 11 cases with RAS wild type, and 17 cases with mutant type. The response rate was 30.8% in 2 cases of CR, 6 cases of PR, 14 cases of SD, 4 cases of PD, and 4 cases with conversion surgery after chemotherapy. TTF was 6.5 months and OS was 32.1 months. Among those with RAS mutations, 3 cases received conversion surgery. TTF of the mutant and wild type were 6.3 and 5.6 months, respectively, and OS was 35.8 and 32.1 months, respectively, without any significant difference. In addition, excluding conversion cases, the OS of mutant and wild type patients was 22.7 and 29.5 months, respectively. CONCLUSION: The outcome of treatment using first-line chemotherapy with Bmab for metastatic colorectal cancer with RAS mutations was retrospectively analyzed. There was no difference in therapeutic effect between RAS mutated and not, and it seems that an OS of more than 20 months can be expected for those with RAS mutations with this choice of treatment.