Cytoreductive surgery for synchronous and metachronous colorectal peritoneal dissemination: Japanese P classification and peritoneal cancer index.

Aim: The outcomes of cytoreductive surgery (CRS) for synchronous and metachronous colorectal peritoneal dissemination were investigated using the Japanese P classification and peritoneal cancer index (PCI). Methods: CRS was performed in 111 cases of synchronous peritoneal dissemination and 115 cases of metachronous peritoneal dissemination. The P classification and PCI were determined at the time of laparotomy. Results: In the synchronous dissemination group, the 5-year overall survival rates after CRS in P1/P2 and P3 cases were 51% and 13%, respectively. Even for P3, 51% of the patients achieved macroscopic cytoreductive complete resection (CC-0), with a 5-year survival rate of 40%. When P3 cases were classified into PCI 0-9, 10-19, 20-29, and 30-39, CC-0 was achieved in 93%, 70%, 6%, and 0% of the cases, respectively, and the 5-year survival rate of PCI 0-9 was 41%. In the metachronous dissemination group, the 5-year survival rates were 62% for PCI 0-9 and 22% for PCI 10-19; 5-year survival was not observed in patients with a PCI ≥ 20. CC-0 was significantly associated with the postoperative prognosis in both synchronous and metachronous peritoneal dissemination. Conclusion: In cases of synchronous dissemination, CRS must be performed for P1 and P2 cases or those with a PCI < 10, while detailed examination using PCI is required for P3 cases. In cases of metachronous dissemination, CRS should be considered when the PCI score is <20.

A rare case of pseudomyxoma peritonei with Morgagni hernia.

Both pseudomyxoma peritonei and Morgagni hernias in adults are rare clinical conditions. A 70-year-old woman who was diagnosed with pseudomyxoma peritonei with Morgagni hernia underwent cytoreductive surgery and primary repair. Pseudomyxoma peritonei causes increased intra-abdominal pressure that may lead to acquired congenital diaphragmatic hernia when there is a local fragility in the diaphragmatic musculature. Parietal peritonectomy of the right diaphragmatic peritoneum can safely remove the hernia sac. The high rate of infections associated with cytoreductive surgery causes hesitation for concurrent mesh repair for Morgagni hernia. This is the first report of pseudomyxoma peritonei with Morgagni hernia. Cytoreductive surgery including parietal peritonectomy of the right diaphragmatic peritoneum plus primary repair of hernial defect was performed safely and successfully, which achieved positive short-term results for patients with pseudomyxoma peritonei-associated Morgagni hernia.

Successful laparoscopy-assisted repair of a rectovaginal fistula after low anterior resection for rectal cancer: a report of two cases.

BACKGROUND: Rectovaginal fistula (RVF) after low anterior resection for rectal cancer is troublesome and refractory. Although various surgical procedures have been previously described, no definitive procedure has shown a satisfactory outcome. We present two consecutive Japanese patients who underwent successful surgery for an RVF after low anterior resection. CASE PRESENTATION: The patients were two women (61-year-old and a 64-year-old). They were admitted to our hospital with a chief complaint of fecal discharge from the vagina after low anterior resection using the double-stapling technique for rectal cancer. They were diagnosed with RVF. Local surgical procedures, including diverting ileostomy, were unsuccessful in previous hospitals. Therefore, we performed laparoscopy-assisted repair of the RVF. In both patients, laparoscopically robust pelvic adhesions were dissected, and the sigmoid colon was transected at just oral side to the RVF. Thereafter, in combination with a perineal approach, the rectum, along with a previous anastomosis and fistula, were completely removed. Surgeries were completed after vaginal repair, redo coloanal anastomosis, and interposition of the dissected connective tissue. In both patients, the postoperative courses were uneventful. They complained of neither recurrence of any RVF nor fecal incontinence 1 year and 10 months after diverting stoma closure. CONCLUSIONS: A laparoscopy-assisted procedure with reanastomosis and interposition of the perineal connective tissue can be an effective treatment for RVF after low anterior resection for rectal cancer.

Gastric volvulus and giant Bochdalek hernia in an adult patient that were safely repaired by endoscopic reduction and elective laparoscopic surgery.

A Bochdalek hernia (BH) is a congenital abnormality with incomplete closure of the diaphragm. It is usually manifested in infants but rarely in adults. Here, we report an adult patient with gastric volvulus and giant BH that were safely repaired by endoscopic reduction and elective laparoscopic surgery, respectively. A 79-year-old woman presented with left upper abdominal pain but no history of trauma. CT revealed a giant BH with gastric volvulus. After emergency endoscopic reduction of the volvulus, elective laparoscopic repair of the BH was performed. The 8 × 8-cm defect was repaired with interrupted nonabsorbable sutures and a mesh. The patient's postoperative course was uneventful, and no complications or recurrence were observed in the 6 months that followed.

Ileal conduit necrosis after total pelvic exenteration for recurrence of gastrointestinal stromal tumor.

We report a case of ileal conduit necrosis after total pelvic exenteration for recurrence of gastrointestinal stromal tumor. A 47-year-old man was diagnosed with recurrence of gastrointestinal stromal tumor adjacent to the prostate after abdominoperineal resection 10 years prior. With imatinib administration for 18 months, the local recurrence decreased in size but did not separate from the prostate. We performed urinary diversion with conventional total pelvic exenteration. Ileal conduit necrosis was suspected the following day and emergency surgery was performed. The serosa of the ileal conduit showed segmental necrosis extending about 10 cm from the orifice. The ureterointestinal anastomotic site was opposite the orifice and was not necrotic. We resected the necrotic ileum and reconstructed an ileal conduit. The patient was discharged without any symptoms 46 days after surgery for further adjustment to use of a urostomy.

Prognostic predictions based on pathological findings of peritoneal dissemination in patients with stage IV colorectal cancer without residual disease (R0 status).

PURPOSE: This study aimed to clarify the prognosis of patients after resection of stage IV colorectal cancer and synchronous peritoneal metastasis (no residual disease: R0 status) based on histopathologic findings. METHODS: The subjects of this study were 26 patients who underwent radical resection of synchronous peritoneal metastases of stage IV colorectal cancer. Only patients with one synchronous peritoneal metastasis were included in this study. The peritoneal lesions were initially classified into two categories based on the presence or absence of adenocarcinoma on their surface: RM-negative or RM-positive. The lesions were subsequently classified as being of massive or diffuse type and of small (< 6 mm) or large (≥ 6 mm) type according to the maximum metastatic tumor dimension. RESULTS: Multivariate analysis revealed that massive type metastatic tumors were associated with a better disease-free survival (DFS; p = 0.047) and overall survival (OS; p = 0.033), than diffuse type tumors. CONCLUSION: A detailed stratification of pathological findings could contribute remarkably to prognostic predictions for patients with synchronous peritoneal metastases.

The Impact of Circular Stapler Size on the Incidence of Cervical Anastomotic Stricture After Esophagectomy.

BACKGROUND: Cervical anastomotic stricture after esophagectomy is a serious complication that adversely affects postoperative recovery, nutritional status and quality of life. Cervical anastomosis by a circular stapler (CS) has been widely accepted as a simple and convenient method, but anastomotic strictures are likely to occur. The aim of this study was to investigate an association between CS size and the incidence of anastomotic stricture after cervical esophagogastric anastomosis performed by a CS. METHODS: Between April 2011 and March 2016, 236 consecutive patients underwent cervical esophagogastric anastomosis by a CS via a retrosternal route after esophagectomy for esophageal cancer. These patients were divided into according to CS size for the procedure as follows: small-sized (25 mm) CS group (SG, n = 116) and large-sized (28 or 29 mm) CS group (LG, n = 120). The clinical data of patients were analyzed retrospectively to compare the two groups. RESULTS: Overall, anastomotic strictures were observed in 90 patients (38%). The incidence of anastomotic stricture was significantly lower in the LG than the SG (23% vs. 53%, p < 0.001) (Table 3). Chronic obstructive pulmonary disease (COPD: FEV1.0% <70%) (OR 2.35, 95% CI = 1.09-5.14; p = 0.029), anastomotic leakage (OR 8.97, 95% CI = 2.69-41.30; p < 0.001), and a small-sized CS (OR 3.42, 95% CI = 1.82-6.62; p < 0.001) were independent risk factors for anastomotic stricture in the multivariate analysis. CONCLUSIONS: If possible, a large-sized CS should be used to prevent cervical anastomotic strictures when performing cervical anastomoses by CS.

Perioperative enteral supplementation with glutamine, fiber, and oligosaccharide reduces early postoperative surgical stress following esophagectomy for esophageal cancer.

BACKGROUND: We clarified the effects of perioperative enteral supplementation with glutamine, fiber, and oligosaccharide (GFO) after an esophagectomy on preventing surgical stress. METHODS: Of 326 patients with esophageal cancer, 189 received GFO administration (GFO group) and 137 did not (control group). The propensity score matching method was used to identify 89 well-balanced pairs of patients to compare postoperative laboratory parameters and clinical and postoperative outcomes. RESULTS: The duration of the systemic inflammatory response syndrome (SIRS) was significantly shorter in the GFO group compared to the control group (p = 0.002). Moreover, the lymphocyte/neutrophil ratio (L/N ratio) had significantly recovered in the GFO group on postoperative day-3, and the CRP value was significantly lower in the GFO group than that in the control group on postoperative day-2. CONCLUSIONS: Perioperative use of enteral supplementation with glutamine, fiber, and oligosaccharide likely contributes to a reduction in early surgical stress after an esophagectomy. These beneficial effects can bring about early recovery from postoperative immunosuppressive conditions after radical esophagectomy.

Simultaneous resections of left lung cancer and esophageal schwannoma using video-assisted thoracoscopic surgery: A case report.

Esophageal schwannomas are extremely rare esophageal submucosal tumors. Herein, we report a case of simultaneous resection of left lung cancer and an esophageal schwannoma with video-assisted thoracoscopic surgery. An asymptomatic 74-year-old woman received a diagnosis of an esophageal submucosal tumor during the preoperative assessment of a left lung cancer. The esophageal submucosal tumor arose in the left wall of the lower esophagus, and the patient was diagnosed as having a schwannoma by endoscopic ultrasound-guided fine needle aspiration. She underwent video-assisted thoracoscopic surgery for the simultaneous removal of both tumors. Her postoperative course was uneventful. Thoracoscopic surgery is less invasive than thoracotomy, and this allowed the patient to undergo simultaneous operations for two tumors.

Boerhaave syndrome due to hypopharyngeal stenosis associated with chemoradiotherapy for hypopharyngeal cancer: a case report.

BACKGROUND: Spontaneous esophageal rupture, also known as Boerhaave syndrome, is a very serious life-threatening benign disease of the gastrointestinal tract. It is typically caused by vomiting after heavy eating and drinking. However, in our patient, because of a combination of hypopharyngeal cancer with stenosis and chemoradiotherapy (CRT), which caused chemotherapy-induced vomiting, radiotherapy-induced edema, relaxation failure, and delayed reflexes; resistance to the release of increased pressure due to vomiting was exacerbated, thus leading to Boerhaave syndrome. To the best of our knowledge, this is the first report of a patient with esophageal rupture occurring during CRT for hypopharyngeal cancer with stenosis. CASE PRESENTATION: A 66-year-old man with a sore throat was referred to our hospital. He was found to have stage IVA hypopharyngeal cancer, cT2N2bM0, and underwent radical concurrent CRT consisting of weekly cisplatin (30 mg/m2) and radiation (70 Gy/35fr), for larynx preservation. On day 27 of treatment, he vomited, which was followed by severe left chest pain radiating to the back and the upper abdomen. Enhanced computed tomography (CT) revealed extensive mediastinal emphysema and a small amount of left pleural effusion. Esophagography revealed extravasation into the left thoracic cavity, and the patient was diagnosed with an intrathoracic rupture type of Boerhaave syndrome. He underwent emergency left thoracotomy 21 h after the onset. The ruptured esophageal wall was primarily repaired by closure with two-layer suturing and covered by a pedicled omentum. A jejunostomy tube was placed for postoperative enteral nutrition. On postoperative day (POD) 16, the patient was transferred to head and neck surgery to finish CRT and was discharged on POD 56. He has survived without relapse for 11 months after surgery. CONCLUSION: Patients with head and neck cancer are at risk for developing Boerhaave syndrome during CRT. In addition, since such patients often are in poor overall condition because of immunosuppression and protracted wound healing, Boerhaave syndrome can rapidly lead to severe life-threatening infections such as empyema and mediastinitis. Therefore, awareness of this condition is important so that appropriate treatment can rapidly be implemented to increase the likelihood of a good outcome.

Combined resection of re-recurrent lateral lymph nodes and external iliac vein:Case Report and Literature.

Herein, we describe the operative procedure for combined resection of re-recurrent lateral lymph nodes and the external iliac vein. There is no consensus on the clinical implications of resection of locally re-recurrent colorectal tumors, as the operative procedure is extremely difficult. We present the case of a 52-year-old woman who underwent abdominoperineal resection. About one year later, we excised a recurrent lymph node in the left lateral obturator area through an extraperitoneal approach. About 18 months later, lymph node re-recurrence in the left external iliac area was observed. Re-recurrent lymph nodes directly invade the left external iliac vein. We removed the re-recurrent lymph node with combined, radical segmental resection of the left external iliac vein, left obturator artery and vein, and left obturator nerve. J. Med. Invest. 65:136-138, February, 2018.

Peritoneal cecal cancer metastasis to a mesh-plug prosthesis:A case report.

We report the case of a 77-year-old man who presented to our hospital with cecal cancer, lung metastasis, and liver metastasis in January 2013. After four courses of modified infusional intravenous fluorouracil and levofolinate with oxaliplatin (mFOLFOX 6) + bevacizumab, there was no new metastatic lesion and lung metastasis reduction was observed. Ileocecal resection was performed in May, left lower lung lobectomy in August, and extended right posterior segmentectomy + S8 partial liver resection was performed in December. The tumor marker declined initially;thereafter, it gradually increased. Computed tomography (CT) performed in April 2014 revealed right inguinal mass around the mesh-plug prosthesis. A positron emission tomography-CT (PET-CT) also revealed a high 2-fluoro-2-deoxy-D-glucose (FDG) uptake at the same site. Right inguinal tumor resection was performed in July. Cancer tissues were confirmed by performing intraoperative rapid pathological diagnosis, and R0 resection could be achieved. Previous studies have reported malignant tumor metastases to the mesh-plug prosthesis, and this was believed to one of the sites that cancer cells can easily engraft. In particular, in patients with a history of advanced malignant tumors, if mass formation around the artifact insertion site is observed, the possibility of peritoneal metastasis should be considered. J. Med. Invest. 65:142-146, February, 2018.

A case of local recurrence of T1 rectal cancer 10 years after transanal excision.

We report a case of a patient with T1 rectal cancer, which recurred locally after 10 years from the primary operation. A 78-year-old woman was diagnosed with rectal cancer. Transanal excision (TAE) was performed in December 2006. The pathological findings revealed stage I rectal cancer [tub2>muc, pSM (2,510 µm), ly0, v0, pHM0, pVM0]. Because she did not opt for additional treatment, she received follow-up examination. After approximately 10 years from the primary operation, she presented to her physician, complaining of melena, and she was referred to our hospital again in November 2016. She was diagnosed with recurrent rectal cancer. Laparoscopic abdominoperineal resection was performed in December 2016. Pathological findings revealed stage IIIB rectal cancer (tub2>muc, pA, pN1). The reported postoperative local recurrence rate for T1 rectal cancer after TAE is high, but local recurrence after years from the primary operation is rare. In high-risk cases, local recurrence may be observed even after 10 years from the primary operation. Long-term and close postoperative follow-up is important to detect local recurrence early.

Thoracoscopic resection of esophageal cancer with a tracheal diverticulum.

Tracheal diverticulum, a benign entity characterized by single or multiple invaginations of the tracheal wall, is commonly asymptomatic and detected incidentally. We report the case of a 76-year-old man with a tracheal diverticulum who underwent thoracoscopic esophagectomy with a three-field lymphadenectomy for middle thoracic esophageal cancer. The tracheal diverticulum was located at the right posterolateral region of the trachea, which overlapped the region of dissection of the right recurrent laryngeal nerve lymph nodes. Paratracheal lymph node dissection is an important surgical procedure for thoracic esophageal cancer. In such cases, there is a risk of misidentifying a tracheal diverticulum as an enlarged lymph node and injuring it. Injury of a tracheal diverticulum causes serious complications such as mediastinal emphysema, mediastinitis, and pulmonary fistula. It is important to recognize its existence preoperatively and perform accurate lymph node dissection by taking full advantage of the magnified visual effect provided by thoracoscopic surgery.

Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer.

Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer.

Fusobacterium in colonic flora and molecular features of colorectal carcinoma.

Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified overrepresentation of Fusobacterium in colorectal cancer tissues, but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fusobacterium status and molecular features in colorectal cancers through quantitative real-time PCR in 149 colorectal cancer tissues, 89 adjacent normal appearing mucosae and 72 colonic mucosae from cancer-free individuals. Results were correlated with CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI), and mutations in BRAF, KRAS, TP53, CHD7, and CHD8. Whole-exome capture sequencing data were also available in 11 cases. Fusobacterium was detectable in 111 of 149 (74%) colorectal cancer tissues and heavily enriched in 9% (14/149) of the cases. As expected, Fusobacterium was also detected in normal appearing mucosae from both cancer and cancer-free individuals, but the amount of bacteria was much lower compared with colorectal cancer tissues (a mean of 250-fold lower for Pan-fusobacterium). We found the Fusobacterium-high colorectal cancer group (FB-high) to be associated with CIMP positivity (P = 0.001), TP53 wild-type (P = 0.015), hMLH1 methylation positivity (P = 0.0028), MSI (P = 0.018), and CHD7/8 mutation positivity (P = 0.002). Among the 11 cases where whole-exome sequencing data were available, two that were FB-high cases also had the highest number of somatic mutations (a mean of 736 per case in FB-high vs. 225 per case in all others). Taken together, our findings show that Fusobacterium enrichment is associated with specific molecular subsets of colorectal cancers, offering support for a pathogenic role in colorectal cancer for this gut microbiome component.

Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma.

DNA methylation affects the aggressiveness of human malignancies. Cancers with CpG island methylator phenotype (CIMP), a distinct group with extensive DNA methylation, show characteristic features in several types of tumors. In this study, we initially defined the existence of CIMP in 41 lung adenocarcinomas (AdCas) through genome-wide DNA methylation microarray analysis. DNA methylation status of six CIMP markers newly identified by microarray analysis was further estimated in a total of 128 AdCas by bisulfite pyrosequencing analysis, which revealed that 10 (7.8%), 40 (31.3%) and 78 (60.9%) cases were classified as CIMP-high (CIMP-H), CIMP-low and CIMP-negative (CIMP-N), respectively. Notably, CIMP-H AdCas were strongly associated with wild-type epidermal growth factor receptor (EGFR), males and heavy smokers (P = 0.0089, P = 0.0047 and P = 0.0036, respectively). In addition, CIMP-H was significantly associated with worse prognosis; especially among male smokers, CIMP-H was an independent prognostic factor (hazard ratio 1.7617, 95% confidence interval 1.0030-2.9550, P = 0.0489). Compellingly, the existence of CIMP in AdCas was supported by the available public datasets, such as data from the Cancer Genome Atlas. Intriguingly, analysis of AdCa cell lines revealed that CIMP-positive AdCa cell lines were more sensitive to a DNA methylation inhibitor than CIMP-N ones regardless of EGFR mutation status. Our data demonstrate that CIMP in AdCas appears to be a unique subgroup that has distinct clinical traits from other AdCas. CIMP classification using our six-marker panel has implications for personalized medical strategies for lung cancer patients; in particular, DNA methylation inhibitor might be of therapeutic benefit to patients with CIMP-positive tumors.

Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses.

Meningiomas are among the most common intracranial tumors and are mostly curable by surgical resection. However, some populations of meningiomas with benign histological profiles show malignant behavior. The reasons for this inconsistency are yet to be ascertained, and novel diagnostic criteria other than the histological one are urgently needed. The aim of the present study is to subclassify meningiomas from the viewpoint of gene methylation and to determine the subgroup with malignant characteristics. Thirty meningiomas were analyzed using microarrays for 6157 genes and were classified into three clusters on the basis of their methylation status; these were found to be independent of the histological grading. One of the clusters showed a high frequency of recurrence, with a marked accumulation of methylation in a subset of genes. We hypothesized that the aggressive meningiomas universally share characteristic methylation in certain genes; therefore, we chose the genes that strongly contributed to cluster formation. The quantified methylation values of five chosen genes (HOXA6, HOXA9, PENK, UPK3A and IGF2BP1) agreed well with microarray findings, and a scoring system consisting of the five genes significantly correlated with a high frequency of recurrence in an additional validation set of 32 patients. Of particular note is that three cases with malignant transformation already showed hypermethylation at histologically benign stage. In conclusion, a subgroup of meningiomas is characterized by aberrant hypermethylation of the subset of genes in the early stage of tumorigenesis, and our findings highlight the possibility of speculating potential malignancy of meningiomas by assessing methylation status.

Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour.

BACKGROUND AND AIMS: The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs. METHODS: Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75). RESULTS: Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034). CONCLUSION: Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.

Distinct profiles of epigenetic evolution between colorectal cancers with and without metastasis.

Liver metastasis is a fatal step in the progression of colorectal cancer (CRC); however, the epigenetic evolution of this process is largely unknown. To decipher the epigenetic alterations during the development of liver metastasis, the DNA methylation status of 12 genes, including 5 classical CpG island methylator phenotype (CIMP) markers, was analyzed in 62 liver metastases and in 78 primary CRCs (53 stage I-III; 25 stage IV). Genome-wide methylation analysis was also performed in stage I-III CRCs and in paired primary and liver metastatic cancers. Methylation frequencies of MGMT and TIMP3 increased progressively from stage I-III CRCs to liver metastasis (P = 0.043 and P = 0.028, respectively). The CIMP-positive cases showed significantly earlier recurrence of disease than did CIMP-negative cases with liver metastasis (P = 0.030), whereas no such difference was found in stage I-III CRCs. Genome-wide analysis revealed that more genes were methylated in stage I-III CRCs than in paired stage IV samples (P = 0.008). Hierarchical cluster analysis showed that stage I-III CRCs and stage IV CRCs were clustered into two distinct subgroups, whereas most paired primary and metastatic cancers showed similar methylation profiles. This analysis revealed distinct methylation profiles between stage I-III CRCs and stage IV CRCs, which may reflect differences in epigenetic evolution during progression of the disease. In addition, most methylation status in stage IV CRCs seems to be established before metastasis.