Less demand on stem cell marker-positive cancer cells may characterize metastasis of colon cancer.

BACKGROUND: CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. METHODS: Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. RESULTS: (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). CONCLUSION: Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.

Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma.

BACKGROUND: OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer. METHODS: OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC). RESULTS: OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance. CONCLUSION: Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.

WiNTRLINC1/ASCL2/c-Myc Axis Characteristics of Colon Cancer with Differentiated Histology at Young Onset and Essential for Cell Viability.

BACKGROUND: WiNTRLINC1 is a long non-coding RNA (lncRNA) that positively regulates the Wnt pathway via achaete-scute complex homolog 2 (ASCL2) in colorectal cancer. ASCL2 was recently reported to play a critical role in chemoresistance, however clinical relevance of the WiNTRLINC1/ASCL2 axis remains obscure in colon cancer. PATIENTS AND METHODS: WiNTRLINC1/ASCL2 expression was investigated at messenger RNA (mRNA) level in 40 primary colon cancer tissues and the corresponding normal mucosa tissues, together with Wnt-related genes (c-Myc/PRL-3) and other lncRNAs (H19, HOTAIR, and MALAT1). Knock-down experiments of WiNTRLINC1 clarified its role in their expression and chemoresistance. RESULTS: Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed definite overexpression of WiNTRLINC1 mRNA in primary colon cancer compared with the corresponding normal colon mucosa tissues (p = 0.0005), such as ASCL2, c-Myc, and PRL-3 (p < 0.0001). The four gene expression signatures were tightly associated in the center of the ASCL2 gene (r = 0.72, p < 0.0001) in clinical samples. WiNTRLINC1 was not significantly associated with prognostic factors in colon cancer and other lncRNAs, while the WiNTRLINC1/ASCL2/c-Myc signatures were unique to young-onset colon cancer with differentiated histology. On the other hand, undifferentiated histology was significantly associated with H19 expression. Knockdown of the WiNTRLINC1 gene reduced the expression of ASCL2/c-Myc, but rather augmented PRL-3 at mRNA level, and robustly affected cell viability in colon cancer cell lines. CONCLUSION: The enhanced WiNTRLINC1/ASCL2/c-Myc axis involved in Wnt pathway activation is a common pathway essential for differentiated colon tumorigenesis, especially with young onset, and may be essential for a viable phenotype of colon cancer.

[A Case of Sigmoid Colon Cancer with Complete Visceral Inversion].

Complete visceral inversion occurs in 1/5,000 individuals. In 64%of cases, complete visceral inversion is complicated by the malformation of other organs. Careful attention is required when performing surgeries. In recent years, with the development of laparoscopic surgery, some cases of laparoscopic surgery with complete visceral inversion have been reported. Herein, we report a case of safely performed laparoscopic surgery for sigmoid colon cancer with complete visceral inversion along with a relevant discussion.

Differential Prognostic Relevance of Promoter DNA Methylation of CDO1 and HOPX in Primary Breast Cancer.

BACKGROUND/AIM: We previously identified that promoter DNA methylation of cysteine dioxygenase type 1 (CDO1) and homeobox only protein homeobox (HOPX) were both cancer specific, and have a clinical potential as prognostic biomarkers in breast cancer (BC). The present study compared the differential prognostic relevance of methylation status of the CDO1 and HOPX genes in BC. MATERIALS AND METHODS: Methylation levels (TaqMethVs) were quantified in 7 BC cell lines and 133 BC patients by TaqMan methylation-specific PCR and functional traits were explored for CDO1. RESULTS: TaqMethVs were associated between CDO1 and HOPX (r2=0.072, p=0.002). Multivariate Cox proportional hazards model could identify CDO1 hypermethylation as well as Ki-67 as independent prognostic factors related to disease-specific survival (p=0.016, p<0.001). Overexpression of CDO1 decreased the anchorage-independent growth capacity in BC cell lines. CONCLUSION: CDO1 is a definite tumor suppressor gene, while its prognostic relevance was more than expected in the context of its functional relevance.

Cancer-specific promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene as an important prognostic biomarker of gastric cancer.

BACKGROUND: There have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer. METHODS: Quantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010. RESULTS: (1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability. CONCLUSIONS: Promoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.

Critical relevance of genomic gains of PRL-3/EGFR/c-myc pathway genes in liver metastasis of colorectal cancer.

The PRL-3 gene is involved in the liver metastasis of colorectal cancer (CRC) and oncogene addiction to anticancer therapy. In the present study genomic gains in PRL-3 and its pathway genes, c-myc and EGFR, were investigated in order to determine their clinical relevance during metastatic formation in primary CRC and corresponding liver metastases. The genomic gain statuses of PRL-3, EGFR, and c-myc were investigated using quantitative polymerase chain reaction (qPCR) analysis in 35 samples of CRC and corresponding liver metastases. In the primary CRC specimens, genomic gains in PRL-3, c-myc, and EGFR were observed in 4, 4, and 13 cases, respectively. A genomic gain in one gene was observed in 18 cases, and these genomic gains were mutually exclusive. In the liver metastasis specimens, genomic gains were observed in 14, 8, and 13 cases, respectively. The copy numbers of PRL-3 and c-myc were significantly higher in the liver metastases than in the primary CRC specimens (P=0.03, P=0.009, respectively). A genomic gain in PRL-3 was the most frequent gain in the liver metastases (P=0.004) and was partially redundant with a c-myc genomic gain. EGFR genomic gains were consistent between the primary CRC and the liver metastases (P=0.0000008). In addition, a genomic gain in any of the 3 genes was observed in 23 cases (66%). Among the clinicopathological factors that were assessed, an EGFR genomic gain was significantly associated with tumour size in the primary CRC and the liver metastases (P=0.04). A c-myc genomic gain was also significantly associated with the v factor of the primary tumours in the liver metastases (P<0.01). In conclusion, the genomic copy numbers of PRL-3, c-myc and EGFR were frequently characterised by aberrations in genomic gain in liver metastases from CRC; thus, these gene statuses exhibit potential for the identification of patients who are likely to respond positively to anticancer therapies.

[Chemoradiotherapy with S-1 for Recurrence Cases of Colorectal Cancer].

INTRODUCTION: Although chemotherapy is the main treatment for recurrent colorectal cancer, the utility of radiotherapy as a local treatment has been widely reported. We performed chemoradiotherapy with S-1 for cases with recurrence after surgery, and the outcomes are reported herein. MATERIALS AND METHODS: Chemoradiotherapy with S-1 was performed in 4 cases. S-1 was administered for 2 weeks during the irradiation period, and the off period provided was 1 week. RESULTS: X-ray irradiation was performed in 2 cases and proton beam irradiation in the other 2. The progression free periods of the 2 cases receiving proton beam irradiation were 31 months and 36 months. In contrast, the progression free periods of the 2 cases given X-ray irradiation were 24 months and 21 months. DISCUSSION: It is known that S-1 not only achieves a high anticancer effect via dihydropyrimidine dehydrogenase(DPD)inhibition, which is a major metabolic pathway of 5-FU, but also increases the radiation susceptibility of malignancies. S-1 is regarded as an ideal anticancer agent when used in combination with radiation therapy. Since the local control achieved in our 4 cases was good, chemoradiotherapy with S-1 was considered to be a useful treatment.

[Examination of Cases of Hepatectomy for Metastatic Colorectal Cancer].

OBJECTIVES: Resection of liver metastasis from colorectal cancer is known to improve prognosis; therefore, surgical treatment is recommended for resectable metastases in the Japanese Society for Cancer of the Colon and Rectum Guidelines for the Treatment of Colorectal Cancer. In this study, we investigated factors that affect the prognosis of resection of such metastatic liver tumors. RESULTS: Thirty-three cases of liver resection performed during the period from 1998 to 2017 were investigated. The 5-year overall survival rate after liver resection was 47.3%, and the 5-year recurrence-free survival rate after liver resection was 29.9%. Univariate analysis identified CA19-9(p=0.02)and operative procedure(p=0.0046)as prognostic factors, while multivariate analysis revealed operative procedure(p=0.03)to be a prognostic factor. When prognosis was examined in terms of operative procedure(ie, lobectomy, segmental resection, or partial resection), the prognosis of patients undergoing lobectomy was significantly poorer compared to those undergoing segmental resection(p=0.0092, RR=28.94)and partial resection(p=0.0092, RR=25.37). CONCLUSION: In this study, operative procedure was identified as a poor prognostic factor. The prognosis of liver metastasis requiring lobectomy is considered to be poor. Further accumulation of cases is needed to investigate the effects of other factors in the choice of operative procedure.

[Perioperative Effect of Intraoperative Fluid Restriction with the Same Fixed Volume of 5 ml · kg(-1) · h(-1) in Patients Undergoing Major Abdominal Versus Thoracic Surgery].

BACKGROUND: Major abdominal surgery accompanies the higher magnitude of physiological stress response and may require an additional replacement fluid for the redistributed volume. Intraoperative volume restriction strategy is recommended to avoid fluid overload leading to increased mortality. We conducted a comparative study of the perioperative effects of intraoperative fluid restriction in abdominal versus thoracic surgery. METHODS: Each 15 patients having major abdominal or thoracic surgery were studied prospectively. All participants were identically given intraoperative iv crystalloid of 5 ml · kg(-1) · hr(-1) under combined epidural/general anesthesia. Plasma level of AVP, aldosterone, angiotensin II and IL-6 as well as body water composition by bioelectrical impedance analysis was examined at preoperative period, at the end of surgery and on the first postoperative day. RESULTS: In abdominal surgery group there was significantly less intraoperative urine output compared with thoracic surgery group. No significant differences were found between two groups in extracellular water volume chnages, AVP, aldosterone angiotensin II, IL-6 level and postoperative renal function. CONCLUSIONS: Restrictive fluid therapy with intraoperative crystalloid of 5 ml · kg(-1) · hr(-1) can be safely used with no serious adverse events in abdominal surgery. In conclusion we had better not make any traditional difference in intraoperative fluid management between abdominal and thoracic surgery even if their stress response differs in magnitude.

Laparoscopic mesh repair of a Morgagni hernia using the double-crown technique: A case study.

We report a case of Morgagni hernia in which the patient underwent laparoscopic mesh repair. A 65-year-old woman presented with an abnormal shadow in the right lower lung field on a routine medical checkup. CT showed that the transverse colon passed between the liver and abdominal wall, and herniated into the thoracic cavity. Simple closure was precluded by the large hernial orifice. We therefore performed laparoscopic repair using a Parietex Optimized Composite Mesh. The double-crown technique was used to fix the margin of the mesh to the region around the hernial orifice. Our procedure for repair of a Morgagni hernia with a large hernial orifice is safe and minimally invasive, and it may effectively prevent recurrence.

[Efficacy and safety of remifentanil-based regimen for postoperative pain management in abdominal surgery patients: a double-blind study with low-dose remifentanil infusion of 0.02 microg x kg(-1) x min(-1)].

BACKGROUND: Remifentanil is a powerful analgesic with fast onset and ultra-short duration of action. Its context-sensitive half-time is consistently short even after a prolonged infusion. Remifentanil is effective for providing better postoperative analgesia, but this method is not generally accepted in Japan. The present study was conducted to document efficacy and safety of low-dose remifentanil infusion in postoperative patients. METHODS: Forty patients undergoing abdominal surgery were studied prospectively. They were randomly assigned to either remifentanil (0.02 microg x kg(-1) x min(-1)) or placebo group. Postoperatively all patients received continuous epidural anesthesia with lidocaine and IV patient-controlled analgesia with fentanyl. Flurbiprofen was administered only when no pain relief was achieved. Visual analogue scale (VAS), requirement of fentanyl and flurbiprofen, and the incidence of remifentanil-related adverse effects (respiratory depression, nausea, vomiting, pruritus) were examined at 3 hourly intervals for 12 hours. RESULTS: There are no statistical differences between two groups in pain scores. No adverse events including respiratory depression occurred throughout the study in both groups. CONCLUSIONS: Remifentanil infusion at 0.02 microg x kg(-1) x min(-1) can safely be used without any serious adverse events, while it may not be enough for postoperative analgesia. The best dosage of this drug for postoperative analgesia remains to be elucidated.

[Postoperative pain management in video-assisted thoracic surgery using a continuous unilateral intercostal analgesia].

BACKGROUND: Optimal pain management after video-assisted thoracic surgery (VATS) remains an open issue. We prospectively studied the analgesic effect of intercostal analgegia (ICA) by comparison with epidural analgesia. METHODS: Twenty-two patients undergoing VATS procedures were randomly divided into ICA (n = 8) or epidural (n = 14) group. Postoperatively 2 ml x hr(-1) of 0.2% ropivacaine was delivered continuously through intercostal or epidural catheter. Moreover, each group received the equal dose of fentanyl (0.25 x µg(-1). kg(-1) x hr(-1)) intravenously or epidurally. When no pain relief was achieved, iv fentanyl was given as a rescue. Requirement of additional fentanyl and pain score using a visual analogue scale (VAS) were documented for 19 hours. RESULTS: The mean pain scores at rest, mobilization and with coghing were slightly higher in the ICA group. Total additional dose of iv fentanyl was significantly different between the groups (ICA 147 ± 41 vs Epidural 39 ± 15 µg; P = 0.015). Pain scores and fentanyl requirements spread over the lower range. The mean of VAS in ICA group was less than 5 even at coughing, suggesting clinically irrelevant. CONCLUSIONS: In patients with coagulopathy, multimodal approach using intercostal analgesia supplemented by intravenous patient-controlled analgesia may be an alternative to epidural analgesia for postoperative pain management.

[Intraperitoneal irrigation for pseudomyxoma peritonei-a case of critical metabolic alkalosis precipitated by irrigation with 101 of sodium bicarbonate--].

Pseudomyxoma peritonei causes marked accumulation of jelly-like ascites in the peritoneal cavity. Removal of much mucinous ascites by irrigating the cavity appears to be an effective treatment. We describe a patient who underwent the irrigation with sodium bicarbonate solution and developed critical alkalemia. A 68-year-old woman with normal renal function was operated on for recurrent pseudomyxoma peritonei. Fol- lowing the excision of primary lesion, her intraperitoneal cavity was irrigated with 10 1 of 7% sodium bicarbonate in about 45 minutes. Thirty minutes after irrigation, blood gas analysis revealed severe metabolic alkalosis (pH 7.714, BE 25.6 mmol x l-1 ) with electrolyte disorder (Na 157.8 mmol x l-1 K 2.31mmol x l-1, Ca 0.73 mmol x l-1). Hypotension (<60 mmHg) and sinus tachycardia (>130 beats x min -1) supervened 75 minutes later. Transferring to the ICU, she was given KC1 solution intravenously based on serial blood analysis while on mechanical ventilation. The next day acid-base disturbance returned spontaneously to normal (pH 7.45, BE 8.0mmol x l-1), leading to endotracheal extubation. Electrolyte imbalance was gradually resolved on 2nd POD and she was discharged from the ICU. Intraperitoneal irrigation with sodium bicarbonate requires special perioperative considerations for lifethreatening alkalemia, especially in a patient with renal impairment.

[Anesthetic considerations for spine surgery in 71 patients with infectious spondylitis: effects of different pathogen either pyogenic or tuberculous on intraoperative blood loss].

BACKGROUND: Little information is available about anesthetic management in spine surgery for infectious spondylitis, in which major bleeding can be expected. The amount of blood loss may vary somewhat with pyogenic or tuberculous spondylitis. Limited data prompted us to get a clue to determine how best to care for these patients. METHODS: To examine the amount of intraoperative bleeding, 71 patients with either pyogenic (group A; 44 patients) or tuberculous spondylitis (group B; 27 patients) were retrospectively reviewed using hospital records. They underwent posterior fusion with instrumentation and anterior radical resection of the lesion. RESULTS: No significant differences were observed between the groups in age, gender, comorbidity or length of hospital stay. Operative time was longer in patients with group B (A: 126 +/- 41 vs B: 197 +/- 76 min, P<0.01). There was a trend toward greater blood loss in group B, especially massive bleeding (>1.5 l) occurred at a higher rate (13.6 vs 33.3%, P=0.05). The number of involved vertebrae was more in group B (1.8 +/- 0.9 vs 2.9 +/- 1.3, P<0.01). Both operative time and blood loss volume showed a good correlation with the number of vertebrae infected, suggesting that extensive eradication over several spinal segments may be indicated for tuberculous spondylitis. CONCLUSIONS: Spine surgery for tuberculous spondylitis is more likely to carry risks of longer operative time and higher rate of blood loss.

[Case of obstructive sleep apnea possibly having led to postoperative appearance of generalized convulsion].

Adverse surgical outcomes appear to be more frequent in patients with known obstructive sleep apnea (OSA). However, OSA patients may present for surgery without a prior diagnosis. A 37-year-old man underwent craniotomy for surgical direct neck clipping of the right ruptured internal carotid aneurysm. His intraoperative and early postoperative courses were uneventful. At night, about 48 hr after surgery, he developed sudden generalized tonic-clonic convulsion and temporary depressed consciousness resulting in marked hypercapnea (Pa(CO2)>100 mmHg). His respiration was transiently supported by PSV mode via LMA. He soon got well without neurologic deficits. At night, about 74 hr postoperatively, a generalized convulsion was again observed with hypercapnea. Aside from the respiratory support, percutaneous cricothyroidotomy was performed using Minitrach II system for his airway control, leading to no further recurrence of seizure. He was suspected to have unrecognized OSA due to such characteristic findings of sleep apnea as obesity (BMI>30) and witnessed apneas by his family. Postoperative rapid eye movement (REM) sleep rebound has been suggested to contribute to two consecutive night appearance of seizure. Clinical suspicion for OSA should be required preoperatively and perioperative heightened awareness is recommended.