A pathological complete response after nivolumab plus ipilimumab therapy for DNA mismatch repair-deficient/microsatellite instability-high metastatic colon cancer: A case report.

The standard treatment for colorectal cancer has always been surgery and chemotherapy, which may be used in combination to treat patients. Immune checkpoint inhibitors have been a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair. However, little information is available about their use in neoadjuvant and conversion settings with only a few case reports and only one phase 2 trial. The present study reports the case of a large, locally advanced right-sided metastatic deficient mismatch repair/microsatellite instability-high colon cancer, which showed a pathological complete response after combination treatment with nivolumab and ipilimumab. To the best of our knowledge, resected metastatic colon cancer with a pathological complete response after treatment using dual immune checkpoint inhibitors has not been previously reported. Overall, this case report suggests the use of immune checkpoint inhibitors before colorectal surgery.

An anatomical review of various superior mesenteric artery-first approaches during pancreatoduodenectomy for pancreatic cancer.

When pancreatic head cancer invades the superior mesenteric artery (SMA), attempts at curative resection are aborted. Preoperative imaging diagnostics to determine the surgical curability have yet to surpass the intraoperative information acquired via inspection, palpation, and trial dissection. Pancreatoduodenectomy (PD) is a standard measure for treating periampullary cancers. In conventional PD, SMA invasion is usually identified by dissecting the retroportal lamina, which connects the uncinate process and SMA nerve plexus after dividing the neck of the pancreas. During PD for pancreatic head cancer, this retroperitoneal margin frequently vitiates surgical curability. SMA-first approaches during PD are methods where the SMA is dissected first by severing the posterior pancreatic capsule to assess the SMA involvement of pancreatic cancer early in the operation. The first report of such an approach prompted subsequent reports of various maneuvers that are now known collectively as "artery-first" approaches. We herein review those approaches by classifying them according to (1) the side of the mesocolon from where the SMA approach occurs (supracolic or infracolic) and (2) the direction of access (right or left and anterior or posterior). The steps of the reported PD procedures are numbered according to a timeline and summarized using anatomical division of the SMA.

Assessment of the Changes in Mitochondrial Gene Polymorphism in Ulcerative Colitis and the Etiology of Ulcerative Colitis-associated Colorectal Cancer.

BACKGROUND: Mitochondria are energy-producing organelles, and dysfunction in these organelles causes various types of disease. Although several studies have identified mutations in nuclear DNA that are associated with the etiology of ulcerative colitis (UC), information regarding mitochondrial DNA (mtDNA) in UC is limited. This study aimed to investigate the mitochondrial DNA polymorphism underlying the etiology of UC and UC-associated colorectal cancer. MATERIALS AND METHODS: Next-generation sequencing was performed to assess mitochondrial DNA mutations in 12 patients with UC-associated cancer. The mtDNA mutations in the non-neoplastic mucosa, tumor tissues, and healthy controls were compared. RESULTS: The incidence of mutations of nicotinamide adenine dinucleotide phosphate ubiquinone oxidase subunit, ATP synthetase, and tRNA was higher in non-neoplastic mucosa in those with UC compared with the healthy controls. However, no statistically significant differences were observed in mutations between the tumor tissues and non-neoplastic mucosa in UC. CONCLUSION: Significant mutations in mtDNA were observed in the non-neoplastic mucosa of patients with UC-associated cancer.

The influence of pulmonary comorbidities on treatment choice and short-term surgical outcomes among elderly patients with colorectal cancer.

PURPOSE: Most elderly patients with colorectal cancer have comorbidities and reduced functional reserve, which may increase their risks of postoperative morbidity and mortality, and subsequently influence the treatment choice. Therefore, this study aimed to investigate the treatment choice and compare laparoscopic and open surgery in this setting. METHODS: This retrospective study evaluated 118 patients with colorectal cancer (≥ 85 years old between January 2007 and February 2018) to determine the influence of comorbidities on treatment choice, as well as the safety and feasibility of laparoscopic surgery for these patients. RESULTS: The patients included 42 men (35.6%) and 106 patients (89.8%) with comorbidities. The treatments were curative resection for 90 patients and palliative surgery for 16 patients, including 5 cases of colostomy/ileostomy because of the difficulty of primary cancer resection, pneumonia, or pulmonary hypertension. Twelve patients received non-surgical treatment, including 7 patients with decreased respiratory function because of chronic obstructive pulmonary disease or pneumonia. Forty-three patients underwent open curative resection and 47 patients underwent laparoscopic curative resection, which was associated with a significantly shorter hospital stay (14 days vs. 19days, P < 0.01), a lower morbidity rate (17.0% vs. 37.2%, P = 0.035), and less blood loss (10 mL vs. 140 mL, P < 0.01). One patient in each group died during the postoperative period because of worsened pre-existing pneumonia. CONCLUSION: Laparoscopic surgery was safer and less invasive than open surgery for colorectal cancer among ≥ 85-year-old patients. Pulmonary comorbidities affected the choice of non-curative surgery and may be related to the risk of postoperative mortality.

Cecal cancer with essential thrombocythemia treated by laparoscopic ileocecal resection: a case report.

BACKGROUND: Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Here, we report a case of colorectal cancer in an ET patient treated using laparoscopic ileocecal resection. CASE PRESENTATION: A 40-year-old woman was admitted to our hospital after presenting with liver dysfunction. She had been previously diagnosed with ET; aspirin and anagrelide had been prescribed. Subsequent examination at our hospital revealed cecal cancer. Distant metastasis was absent; laparoscopic ileocecal resection was performed. Anagrelide was discontinued only on the surgery day. She was discharged on the seventh postoperative day without thrombosis or hemorrhage. However, when capecitabine and oxaliplatin were administered as adjuvant chemotherapy with continued anagrelide administration, she experienced hepatic dysfunction and thrombocytopenia; thus, anagrelide was discontinued. Five days later, her platelet count recovered. Subsequently, anagrelide and aspirin administration was resumed, without any adjuvant chemotherapy. Her liver function normalized gradually in 4 months. One-year post operation, she is well without tumor recurrence or new metastasis. CONCLUSIONS: To our knowledge, this is the first report of laparoscopic colectomy performed on an ET patient receiving anagrelide. Our report shows that complications such as bleeding or thrombosis can be avoided by anagrelide administration. Contrastingly, thrombocytopenia due to anagrelide intake should be considered when chemotherapy that could cause bone marrow suppression is administered.

The component changes of lysophospholipid mediators in colorectal cancer.

Although lysophospholipids are known to play an important role in the development and progression of several kinds of cancers, their role in human colorectal cancer is as yet unclear. In this study, we aim to investigate lysophospholipid levels in colorectal cancer tissues to identify lysophospholipids, the levels of which change specifically in colorectal cancers. We used liquid chromatography-tandem mass spectrometry to measure lysophospholipid levels in cancerous and normal tissues from 11 surgical specimens of sigmoid colon cancers, since recent advances in this field have improved detection sensitivities for lysophospholipids. Our results indicate that, in colon cancer tissues, levels of lysophosphatidylinositol and lysophosphatidylserine were significantly higher ( p = 0.025 and p = 0.01, respectively), whereas levels of lysophosphatidic acid were significantly lower ( p = 0.0019) than in normal tissues. Although levels of lysophosphatidylglycerol were higher in colon cancer tissues than in normal tissues, this difference was not found to be significant ( p = 0.11). Fatty acid analysis further showed that 18:0 lysophosphatidylinositol and 18:0 lysophosphatidylserine were the predominant species of lysophospholipids in colon cancer tissues. These components may be potentially involved in colorectal carcinogenesis.

Molecular Subtypes Are Frequently Discordant Between Lesions in Patients With Synchronous Colorectal Cancer: Molecular Analysis of 59 Patients.

BACKGROUND: We aimed to investigate the molecular features of synchronous colorectal cancer (CRC). MATERIALS AND METHODS: Out of 1,262 patients with CRC, 130 lesions in 59 patients with synchronous CRC were retrospectively analyzed. Microsatellite, v-Ki-Ras2 Kristen rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), tumor protein 53 (TP53) and ß-catenin status were evaluated and compared between synchronous CRC lesions in each patient. RESULTS: The subtypes of instability, BRAF and ß-catenin subtypes was significant but low. Patients with discordant KRAS and TP53 were not concordant between lesions in the same patient, and concordance of microsatellite KRAS/BRAF subtypes comprised 50.8% of those with synchronous CRC. The rate of patients with lesions containing both mutL homolog 1 (MLH1) methylation and microsatellite stable status was 66.7% in those with synchronous CRC, with at least one lesion with high microsatellite instability. CONCLUSION: The present study on synchronous CRC demonstrated a low concordance of molecular subtypes between lesions in the same patient. A molecular analysis of metastatic lesions is warranted for molecular targeted therapy of metastatic synchronous CRC.

Venous thromboembolism in colorectal surgery: Incidence, risk factors, and prophylaxis.

Colorectal surgery is associated with a high risk of perioperative venous thromboembolism (VTE), and this risk is especially high following colorectal cancer resection and surgery for inflammatory bowel disease. Previous analyses of large databases have reported the incidence of postoperative VTE in this population to be approximately 1.1%-2.5%. Therefore, to minimize this risk, patients should be offered appropriate prophylaxis, which may involve a combination of mechanical and pharmacologic prophylaxis with low-dose unfractionated heparin or low molecular weight heparin as recommended by several guidelines. Prior to initiation of treatment, appropriate risk stratification should be performed according to the patients' basic and disease-related as well as procedure-related risk factors, and post-operative factors. Furthermore, a risk-benefit calculation that takes into account patients' VTE and bleeding risk should be performed prior to starting pharmacologic prophylaxis and to help determine the duration of treatment.

Safety of intraperitoneal paclitaxel combined with conventional chemotherapy for colorectal cancer with peritoneal carcinomatosis: a phase I trial.

PURPOSE: Peritoneal carcinomatosis of colorectal cancer origin is associated with poor prognosis. With regard to ovarian, gastric, and pancreatic cancer, the safety and efficacy of intraperitoneal administration of paclitaxel (ip PTX) has been demonstrated. This drug can be administered easily and repeatedly through a catheter into the peritoneal cavity. In this phase I study, we evaluated the safety of ip PTX combined with 5-fluorouracil, folinic acid, oxaliplatin, and bevacizumab (mFOLFOX6-bevacizumab) or capecitabine, oxaliplatin, and bevacizumab (CapeOX-bevacizumab) for colorectal cancer with peritoneal metastasis. METHODS: Colorectal cancer patients with histologically confirmed peritoneal carcinomatosis were enrolled. After the implantation of a peritoneal access port, 20 mg/m2 of ip PTX was administered weekly, in combination with mFOLFOX6-bevacizumab or CapeOX-bevacizumab. Primary endpoint was the safety of the combination chemotherapy. RESULTS: Among the six patients enrolled, three received the mFOLFOX6-bevacizumab plus ip PTX regimen and three received the CapeOX-bevacizumab plus ip PTX regimen. Dose-limiting toxicity was not observed. Overall, grade 3 adverse events, such as leukopenia and neutropenia, were observed in two of three patients (66.7%) for each chemotherapeutic regimen, but no grade 4 adverse events were observed. Moreover, adverse events associated with the peritoneal access port, such as infection or occlusion of the catheter, were not observed. CONCLUSIONS: The adverse events of mFOLFOX6-bevacizumab or CapeOX-bevacizumab in combination with ip PTX were considered similar to those described in previous studies of oxaliplatin-based treatment alone. 1 year after the start of chemotherapy, the efficacy of ip PTX will be evaluated as a secondary outcome.

Neoadjuvant imatinib therapy in rectal gastrointestinal stromal tumors.

Rectal gastrointestinal stromal tumor (GIST) is a rare entity. Thus, its clinical features have not been well documented, and optimal treatment strategies have not been established. Surgery for rectal GISTs may be difficult because they are often large in size. In addition, rectal GISTs were found to be associated with high rates of local recurrence, regardless of the surgical procedure, before imatinib was introduced in the early 2000s. Since the introduction of imatinib therapy, accumulating evidence suggests that neoadjuvant imatinib therapy may improve the outcomes of rectal GIST treatment. Neoadjuvant imatinib therapy for rectal GISTs offers a number of potential benefits, including tumor downsizing, reduction in mitotic activity, reduced morbidity, and a reduced risk of recurrence. Less radical procedures may allow for the preservation of the anal sphincter and avoidance of a permanent colostomy. This review summarizes the current status and future perspectives of neoadjuvant imatinib therapy for the treatment of rectal GISTs.

Prognostic Significance and Clinicopathological Features of Synchronous Colorectal Cancer.

AIM: This study aimed to clarify the difference in the clinicopathological and prognostic features between synchronous colorectal cancer (CRC) and solitary CRC. MATERIALS AND METHODS: A retrospective analysis was conducted in patients with synchronous and solitary CRC. RESULTS: A total of 92 (7.1%) out of 1,295 consecutive patients had synchronous CRC. Mucinous adenocarcinoma was more frequent in patients with synchronous CRC than in those with solitary CRC (13.0% vs. 3.7%; p<0.001). The 5-year relapse-free survival (RFS) rate was poorer in patients with synchronous CRC than in those with solitary CRC (65.3% vs. 75.1%; p=0.035), which was contrived by the multivariate analysis (hazard ratio=1.52(HR); p=0.039). CONCLUSION: Patients with synchronous CRC had a poorer RFS than those with solitary CRC; thus, patients with synchronous CRC might require more intensive care than those with solitary CRC in follow-up.

Predictors for High Microsatellite Instability in Patients with Colorectal Cancer Fulfilling the Revised Bethesda Guidelines.

BACKGROUND: The revised Bethesda guidelines (rBG) are generally used for screening of Lynch syndrome, and few researchers have investigated the associations between microsatellite instability (MSI) status and each item of the rBG. PATIENTS AND METHODS: This retrospective study included patients with colorectal cancer who were classified into those fulfilling the rBG (Bethesda group) and those not (control group). The breakdown of each item in the rBG and predictors of high MSI (MSI-H) were determined in the Bethesda group. RESULTS: Of 809 consecutive patients, 161 (19.9%) were found to fulfil the rBG criteria. As a predictor of MSI-H, items 2 or 5 of the rBG showed a sensitivity of 93.3%. Item 5 and right-sided tumour location were independent predictors of MSI-H in patients fulfilling the rBG (odds ratio(OR)=4.49 and 25.1; p=0.0260 and <0.0001, respectively). CONCLUSION: Item 5 of the rBG and right-sided tumour location are significant predictors of MSI-H.

MYU, a Target lncRNA for Wnt/c-Myc Signaling, Mediates Induction of CDK6 to Promote Cell Cycle Progression.

Aberrant activation of Wnt/ß-catenin signaling is a major driving force in colon cancer. Wnt/ß-catenin signaling induces the expression of the transcription factor c-Myc, leading to cell proliferation and tumorigenesis. c-Myc regulates multiple biological processes through its ability to directly modulate gene expression. Here, we identify a direct target of c-Myc, termed MYU, and show that MYU is upregulated in most colon cancers and required for the tumorigenicity of colon cancer cells. Furthermore, we demonstrate that MYU associates with the RNA binding protein hnRNP-K to stabilize CDK6 expression and thereby promotes the G1-S transition of the cell cycle. These results suggest that the MYU/hnRNP-K/CDK6 pathway functions downstream of Wnt/c-Myc signaling and plays a critical role in the proliferation and tumorigenicity of colon cancer cells.

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1.

Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its ß-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.

REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.

The transcription factor GATA6 is a critical regulator of cell proliferation and development in the gastrointestinal tract. We have recently reported that GATA6 induces the expression of the intestinal stem cell marker LGR5 and enhances the clonogenicity and tumorigenicity of colon cancer cells, but not the growth of these cells cultured under adherent conditions. Here we show that REG4, a member of the regenerating islet-derived (REG) family, is also a target of GATA6. We further demonstrate that REG4 is downregulated by overexpression of miR-363, which suppresses GATA6 expression. Moreover, we show that GATA6-mediated activation of REG4 enhances the growth of colon cancer cells under adherent conditions and is required for their tumorigenicity. Taken together, our findings demonstrate that GATA6 simultaneously induces the expression of genes essential for the growth of colon cancer cells under adherent conditions (REG4) and genes required for their clonogenicity (LGR5), and that the miR-363-GATA6-REG4/LGR5 signaling cascade promotes the tumorigenicity of colon cancer cells.

Phospholipase A2 Group III and Group X Have Opposing Associations with Prognosis in Colorectal Cancer.

BACKGROUND: Although secretory phospholipase A2 (sPLA2) has been shown to be involved in various biological processes, its specific roles in sub-types of cancer development remain to be elucidated. MATERIALS AND METHODS: We examined the expression of sPLA2 group III (GIII) in 142 patients with colorectal cancer using immunohistochemistry, and its correlation with clinicopathological features and outcomes. In addition, we examined the co-expression of sPLA2GIII and sPLA2GX using serial tissue sections to clarify the roles of both proteins in colorectal carcinogenesis. RESULTS: In 66 cases, diffuse staining of sPLA2GIII was seen; this was defined as the group with high expression. High expression was associated with a significantly higher rate of lymph node metastasis (p=0.02) and poorer survival (p=0.03) compared with low expression. Patients with low sPLA2GIII and high sPLA2GX expression had a significantly higher survival rate than those with high sPLA2GIII and low sPLA2GX expression (p=0.038). CONCLUSION: sPLA2GIII expression may be used as a risk factor for lymph node metastasis and a prognostic marker in colorectal cancer. In addition, sPLA2GIII and sPLA2GX may play opposing roles in colorectal carcinogenesis.

Tracheobronchitis with dyspnea in a patient with ulcerative colitis.

We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patient's respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement.

Phosphatidylserine-specific phospholipase A1 (PS-PLA1) expression in colorectal cancer correlates with tumor invasion and hematogenous metastasis.

BACKGROUND: The function of phosphatidylserine-specific phospholipase A1 (PS-PLA1), a phospholipase that acts specifically on phosphatidylserine and produces lysophosphatidylserine, a lysophospholipid mediator, has not been fully elucidated. We evaluated the role of PS-PLA1 in oncogenesis and metastasis of colorectal cancer (CRC). MATERIALS AND METHODS: Specimens from 85 patients with CRC were immunostained with a monoclonal antibody against PS-PLA1. The correlation between PS-PLA1 expression and the clinicopathological variables was analyzed. RESULTS: Tumor depth and hematogenous metastasis independently positively correlated with PS-PLA1 expression. High PS-PLA1 expression was associated with shorter disease-free survival, although it was not an independent predictive factor. CONCLUSION: PS-PLA1 expression in CRC is associated with tumor invasion and metastasis.

Successful treatment of rectovaginal fistula complicating ulcerative colitis with infliximab: a case report and review of the literature.

Rectovaginal fistula is a rare complication of ulcerative colitis (UC) regardless of surgical history of rectum. Various surgical treatment modalities for the closure of rectovaginal fistula have been developed, but a radically curative therapy remains to be developed. Recently, infliximab, the chimeric anti-human tumor necrosis factor alpha (TNF-α) antibody, has been largely applied for the treatment of inflammatory bowel disease (IBD), and a few reports have shown its partial effectiveness in the management of rectovaginal fistulas associated with UC. In the present report, we describe the successful management of a rectovaginal fistula, following the stapled ileo-anal canal anastomosis in a UC patient, by administration of infliximab. The patient was a 40-year-old female, initially diagnosed as UC (total colitis type) at the age of 15. She received a restorative proctocolectomy at the age of 22, and developed a rectovaginal fistula at the eighth postoperative day. The surgical treatment of the fistula was repeated four times during the 10-year period, but it recurred in intervals ranging between 2 months and 5 years after the operation. The last recurrence occurred at the age of 32, but the surgical repair was considered difficult and a conservative management was indicated. At the age of 40, infusions of infliximab were started. Four weeks after the first infusion, drainage from the fistula was evidently reduced, and 2 weeks later, the fistula was completely closed. Thereafter, no recurrence of the fistula is observed, as confirmed by the abdominal magnetic resonance imaging (MRI) and the barium-enema study. From the present case, we concluded that infliximab may be an effective strategy for the management of fistulas associated with UC.