Tumor vascularity on contrast-enhanced computed tomography as a predictive marker of metastatic potential for small nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: Although surgical resection is generally suggested for nonfunctioning pancreatic neuroendocrine tumors, observation can be proposed for carefully selected patients with small tumors. However, the indications for observation remain unclear. METHODS: This retrospective study included 77 patients with nonfunctioning pancreatic neuroendocrine tumors, including small tumors (≤2.0 cm, n = 41), who received pancreatectomy. The ratio of the mean computed tomography value of a tumor in the late arterial/equilibrium phase (computed tomography a/e ratio) was used to evaluate tumor vascularity. Pathologic examinations of small tumors were conducted. The associations among the computed tomography a/e ratio, pathologic findings, and survival outcomes were investigated. RESULTS: Small tumors were pathologically categorized by the degree of fibrosis as follows: medullary (n = 20), intermediate (n = 11), and fibrotic (n = 10). The fibrotic type had significantly lower computed tomography a/e ratios than the medullary type (median, 1.42 vs 2.03, P < .001). The median number of vessels with microscopic venous invasion was significantly higher in the fibrotic type than in the medullary type (4.5 vs 0.0, P < .001). The cutoff value of the computed tomography a/e ratio for predicting microscopic venous invasion was determined to be 1.54 by the receiver operating characteristic curve (area under the curve, 0.832; sensitivity, 80.0%; specificity, 83.9%; accuracy, 82.9%). Microscopic venous invasion was an independent prognostic factor for relapse-free survival in overall patients (hazard ratio 5.18, P = .017). CONCLUSION: The computed tomography a/e ratio may be a useful predictor of the metastatic potential of nonfunctioning pancreatic neuroendocrine tumors and may help decide the indications of observation for small nonfunctioning pancreatic neuroendocrine tumors.

Acquired hemophilia A developing in the perioperative period of pancreatoduodenectomy: a report of two cases.

BACKGROUND: Acquired hemophilia A (AHA) is a rare disease characterized by a prolonged activated partial thromboplastin time (aPTT) and the production of coagulation factor VIII inhibitors. We encountered two cases of AHA in the perioperative period of pancreatoduodenectomy (PD). CASE PRESENTATION: Case 1: A 76-year-old woman with intraductal papillary mucinous carcinoma developed acute cholecystitis 5 days before PD. Despite immediate improvement in her acute cholecystitis with biliary drainage and antibiotics, her aPTT level was prolonged (55.9 s). PD was performed as scheduled. On postoperative day (POD) 2, she developed intra-abdominal hemorrhaging that required reoperation. However, intra-abdominal bleeding and concomitant anemia persisted after reoperation. On POD 13, she was diagnosed with AHA based on the detection of an inhibitor of coagulation factor VIII. Despite hemostatic and immunosuppressive treatment, including massive blood transfusion, her general condition gradually worsened due to continuous bleeding and secondary infections. She ultimately died of multiple organ failure on POD 71. Case 2: An 82-year-old man received PD for distal cholangiocarcinoma. On POD 3, a small amount of blood via abdominal drainage was observed. On POD 4, his aPTT level was prolonged (61.5 s). On POD 8, subcutaneous hemorrhaging of the median wound was observed, and corticosteroids were administered under suspicion of AHA on POD 9. On POD 15, an inhibitor of FVIII was detected, and he was diagnosed with AHA. On POD 17, the aPTT level had normalized, and an inhibitor of FVIII was undetectable. On POD 41, he was discharged without any serious hemorrhagic events. CONCLUSIONS: AHA may be more frequent than previously reported. When unexplained prolonged aPTT or bleeding symptoms are observed, it is important to keep AHA in mind during the perioperative period of invasive surgery.

Clinical significance of immunocytochemical staining for peritoneal lavage cytology in pancreatic cancer.

BACKGROUND: Peritoneal lavage cytology for pancreatic ductal adenocarcinoma is conducted with both an intraoperative rapid diagnosis by Papanicolaou staining (cytology-rapid) and a final diagnosis by immunocytochemical staining at a later date (cytology-final) in our hospital. However, the clinical significance of cytology-final has not yet been elucidated. METHODS: A total of 675 pancreatic ductal adenocarcinoma patients who underwent pancreatectomy and cytology between 2002 and 2018 were retrospectively reviewed. Diagnostic results of cytology-rapid and cytology-final and survival outcomes were analyzed. RESULTS: A total of 43 patients (6.4%) were diagnosed as cytology-rapid (+), and all of them were ultimately diagnosed as cytology-final (+). Among the 632 patients with cytology-rapid (-), 19 (3.0%) were eventually diagnosed as cytology-final (+). The overall survival of patients with cytology-rapid (+) and that of patients with cytology-rapid (-) did not differ to a statistically significant extent (median survival time 26.4 vs 32.9 months; P = .106). In contrast, the overall survival of patients who were diagnosed as a false-negative result by cytology-rapid was significantly worse than that of patients diagnosed as a true negative (18.7 vs 34.8 months; P = .031). The overall survival of patients with cytology-final (+) was significantly worse than that of patients with cytology-final (-) (23.6 vs 34.8 months; P = .012). A multivariate analysis showed that cytology-final (+) was an independent prognostic factor for the OS (hazard ratio = 1.43; P = .049), whereas cytology-rapid (+) was not. CONCLUSION: Immunocytochemical staining may be a useful complement to a diagnosis of cytology by conventional Papanicolaou staining in pancreatic ductal adenocarcinoma patients.

The Association Between Neoadjuvant Therapy and Pathological Outcomes in Pancreatic Cancer Patients After Resection: Prognostic Significance of Microscopic Venous Invasion.

BACKGROUND: The impact of neoadjuvant therapy (NAT) on pathological outcomes, including microscopic venous invasion (MVI), remains unclear in pancreatic cancer. METHODS: A total of 456 patients who underwent pancreatectomy for resectable and borderline resectable pancreatic cancer between July 2012 and February 2020 were retrospectively reviewed. Patients were divided into two groups: patients with NAT (n = 120, 26%) and those without NAT (n = 336, 74%). Clinicopathological factors, survival outcomes and recurrence patterns were analyzed. RESULTS: Regarding pathological findings, the proportion of MVI was significantly lower in patients with NAT than in those without NAT (43% vs 62%, P = 0.001). The 5-year survival rate in patients with NAT was significantly better than that in those without NAT (54% vs 45%, P = 0.030). A multivariate analysis showed that MVI was an independent prognostic factor for the overall survival (OS) (hazard ratio 2.86, P = 0.003) in patients who underwent NAT. MVI was an independent risk factor for liver recurrence (odds ratio [OR] 2.38, P = 0.016) and multiple-site recurrence (OR 1.92, P = 0.027) according to a multivariate analysis. The OS in patients with liver recurrence was significantly worse than that in patients with other recurrence patterns (vs lymph node, P = 0.047; vs local, P < 0.001; vs lung, P < 0.001). The absence of NAT was a significant risk factor for MVI (OR 1.93, P = 0.007). CONCLUSION: MVI was a crucial prognostic factor associated with liver and multiple-site recurrence in pancreatic cancer patients with NAT. MVI may be reduced by NAT, which may contribute to the improvement of survival in pancreatic cancer patients.

Rapid fluorescence imaging of human hepatocellular carcinoma using the ß-galactosidase-activatable fluorescence probe SPiDER-ßGal.

Fluorescence imaging of tumours facilitates rapid intraoperative diagnosis. Thus far, a promising activatable fluorescence probe for hepatocellular carcinoma (HCC) has not been developed. Herein, the utility of the fluorescence imaging of HCC using a ß-galactosidase (ß-Gal)-activatable fluorescence probe SPiDER-ßGal was examined. ß-Gal activity was measured in cryopreserved tissues from 68 patients. Live cell imaging of HCC cell lines and imaging of tumour-bearing model mice were performed using SPiDER-ßGal. Furthermore, fluorescence imaging was performed in 27 freshly resected human HCC specimens. In cryopreserved samples, ß-Gal activity was significantly higher in tumour tissues than in non-tumour tissues. Fluorescence was observed in HCC cell lines. In mouse models, tumours displayed stronger fluorescence than normal liver tissue. In freshly resected specimens, fluorescence intensity in the tumour was significantly higher than that in non-tumour liver specimens as early as 2 min after spraying. Receiver operating characteristic curves were generated to determine the diagnostic value of SPiDER-ßGal 10 min after its spraying; an area under the curve of 0.864, sensitivity of 85.2%, and specificity of 74.1% were observed for SPiDER-ßGal. SPiDER-ßGal is useful for the rapid fluorescence imaging of HCC. Fluorescence imaging guided by SPiDER-ßGal would help surgeons detect tumours rapidly and achieve complete liver resection.

Matrix metalloprotease-14 is a target enzyme for detecting peritoneal metastasis in gastric cancer.

BACKGROUND: Accurate diagnosis of peritoneal metastasis in gastric cancer (GC) is important to determine the appropriate treatment. This study aimed to examine whether matrix metalloprotease-14 (MMP-14) was a candidate enzyme in fluorescence imaging for the diagnosis of peritoneal metastasis in GC. METHODS: GC and normal peritoneal (NP) tissues from 96 and 20 patients, respectively were evaluated for MMP-14 expression. Live cell imaging of GC cell lines (NUGC4, MKN45, MKN74, HGC-27, and Kato-III) was performed using the MMP-14-activatable fluorescence probe; BODIPY-MMP. Furthermore, the overall survival (OS) was calculated in all patients (n = 96). RESULTS: MMP-14 expression was significantly higher in GC tissues (median: 3.57 ng/mg protein; range:0.64-24.4 ng/mg protein) than in NP tissues (median: 1.34 ng/mg protein; median: 0.53-3.09 ng/mg protein) (P < 0.01). Receiver operating characteristic curves showed that the area under the curve, sensitivity, and specificity were 0.907, 84.4%, and 90.0%, respectively. In live cell imaging using the BODIPY-MMP, fluorescence was observed in five GC cell lines. In the analysis of OS, the high expression of the MMP-14 group had a significantly poorer OS rate than the low expression of the MMP-14 group (P = 0.02). In the multivariate analyses, MMP-14 expression was an independent risk factor for OS (hazard ratio: 2.33; 95 % confidence interval: 1.05-5.45; P = 0.04). CONCLUSION: MMP-14 is a promising enzyme in intraoperative fluorescence imaging for peritoneal metastasis in GC, especially in patients with poor prognosis.

Therapeutic Strategy of Colorectal Liver Metastasis Using Modified-JHBPS Nomogram.

BACKGROUND/AIM: We attempted to stratify prognosis using the modified Journal of Hepato-Biliary-Pancreatic Sciences (mJHBPS) nomogram upon identification of colorectal liver metastasis (CRLM) and to investigate which strategy is better, surgery first (SF) or chemotherapy first (CF), in each risk group. PATIENTS AND METHODS: A total of 137 patients with CRLM who underwent resection of the primary tumor were included. Patients with brain, bone, or perihilar lymph node metastases were excluded. Patients were scored using the mJHBPS nomogram upon identification of CRLM. Prognosis was investigated using event-free survival (EFS) and overall survival (OS). RESULTS: The nomogram allowed stratification of patients using EFS and OS: low-risk (0-6 score, n=38), medium-risk (7-11 score, n=42), and high-risk (12≥ score, n=57). In the low-risk group, the EFS and OS of the CF group were significantly poorer than those of the SF group (p=0.019 and p=0.014, respectively). CF was an independent prognostic factor for both EFS and OS. CONCLUSION: The mJHBPS nomogram can stratify CRLM patients with sufficient differences in EFS and OS. SF was recommended for patients in the low-risk group.

Laparoscopic cholecystectomy for gangrenous cholecystitis in around nineties: Two case reports.

BACKGROUND: Gangrenous cholecystitis is a form of acute cholecystitis which involves gangrenous alterations in the gallbladder wall and it often follows an acute and serious course. We herein report on two cases of very elderly people diagnosed early with gangrenous cholecystitis, who safely underwent laparoscopic cholecystectomy (LC) and both demonstrated a good outcome. CASE SUMMARY: Case 1: An 89-year-old female. She underwent abdominal contrast-enhanced computed tomography (CECT) due to abdominal pain and diarrhea. Her gallbladder wall indicated the absence of contrast enhancement, thus leading to diagnosis of gangrenous cholecystitis and she therefore underwent LC. Although her gallbladder demonstrated diffuse necrosis and it was also partly perforated, she was able to be discharged without any serious complications. Case 2: A 91-year-old female. She made an emergency visit with a chief complaint of abdominal pain. Abdominal CECT revealed swelling of the gallbladder and an ambiguous continuity of the gallbladder wall. She was diagnosed with gangrenous cholecystitis and underwent LC. Her gallbladder had swelling and diffuse necrosis. Although her preoperative blood culture was positive, she showed a good outcome following surgery. CONCLUSION: Although a definite diagnosis of gangrenous cholecystitis is difficult to make prior to surgery, if an early diagnosis can be made and appropriate treatment can be carried out, then even very elderly individuals may be discharged without major complications.

ß-Galactosidase is a target enzyme for detecting peritoneal metastasis of gastric cancer.

Diagnosis of peritoneal metastasis in gastric cancer (GC) is essential for determining appropriate therapeutic strategies and avoiding non-essential laparotomy or gastrectomy. Recently, a variety of activatable fluorescence probes that can detect enzyme activities have been developed for cancer imaging. The aim of this study was to identify the key enzyme involved in peritoneal metastasis in GC. The enzymatic activity of gamma-glutamyl transpeptidase, dipeptidyl peptidase IV, and ß-galactosidase (ß-Gal) was assessed in lysates prepared from preserved human GC (n = 89) and normal peritoneal (NP; n = 20) samples. ß-Gal activity was significantly higher in the human GC samples than in NP samples, whereas no differences were observed in the activities of the other enzymes. Therefore, we used SPiDER-ßGal, a fluorescent probe that can be activated by ß-Gal, for imaging GC cell lines, peritoneal metastasis in a mouse model, and fresh human resected GC samples (n = 13). All cell lines showed fluorescence after applying SPiDER-ßGal, and metastatic nodules in the mice gradually developed high fluorescence that could be visualized with SPiDER-ßGal. The human GC samples showed significantly higher fluorescence than NP samples. ß-Gal is a useful target enzyme for fluorescence imaging of peritoneal metastasis in GC.

Geriatric Nutritional Risk Index Predicts Poor Prognosis of Patients After Curative Surgery for Gastric Cancer.

Background: The Geriatric Nutritional Risk Index (GNRI) is a nutritional measure for predicting the risk of morbidity and mortality in hospitalized patients. We evaluated the utility of the GNRI to predict the short-term and long-term outcomes after curative surgery for gastric cancer (GC). Patients and Methods: Patients who underwent curative surgery for GC between 2008 and 2016 were reviewed (n=795). We classified patients into two groups according to the GNRI (high GNRI: low and no risk; low GNRI: major and moderate risk) and compared the utility of the GNRI. Results: A low GNRI was an independent prognostic factor for poorer overall survival (hazard ratio=2.34, p<0.001). The GNRI tended to be a better prognostic indicator in elderly patients with GC. Low GNRI was associated with postoperative complications (odds ratio=2.27, p=0.002), especially in patients aged ≥75 (odds ratio=2.26, p=0.042). Conclusion: Low GNRI was associated with poor prognosis and occurrence of postoperative complications in patients with GC, especially in elderly patients.

Prognostic impact of the preoperative hemoglobin A1c levels in patients with gastric cancer surgery depends on postoperative complications.

PURPOSE: The long-term prognostic impact of the hemoglobin A1c levels has not yet been evaluated in patients with gastric cancer. The present study investigated the clinical significance of the hemoglobin A1c levels in patients with gastric cancer. METHODS: We enrolled 294 patients with stage II, III, or IV gastric cancer who underwent gastrectomy. The patients were divided into high preoperative hemoglobin A1c (> 6.0%) and low preoperative hemoglobin A1c (≤ 6.0%) groups. RESULTS: In patients with stage III gastric cancer with severe postoperative complications, the high preoperative hemoglobin A1c group had a significantly worse prognosis than the low preoperative hemoglobin A1c group (p = 0.0409). In patients without severe postoperative complications, the high preoperative hemoglobin A1c group had a significantly favorable prognosis compared with the low preoperative hemoglobin A1c group (p = 0.0348). CONCLUSION: The prognosis of patients with stage III gastric cancer having high preoperative hemoglobin A1c levels greatly depended on the presence or absence of postoperative complications. To avoid postoperative complications, optimal perioperative management and personalized treatments are critical, particularly for these patients.

Efficacy of 5-aminolevulinic acid-mediated photodynamic therapy in a mouse model of esophageal cancer.

5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is a minimally invasive therapeutic modality used in the management of various cancers, but to a lesser extent for esophageal cancer (EC). The current study investigated the antitumor effects of ALA-PDT. Human EC cells were treated with ALA, after which ALA-induced fluorescence was examined under a fluorescence microscope. The cytotoxic effects of ALA-PDT were assessed using three types of LEDs (blue, green and red) in vitro and in vivo. Subcutaneous tumor model mice was constructed with KYSE150 cells. ALA-PDT was performed once a week for 4 weeks and tumor weights were measured. A popliteal lymph node (PLN) metastasis murine model was generated using KYSE150 cells. KYSE150 cells were inoculated into the left footpad of nude mice. ALA-PDT was performed on the footpad once a week for 4 weeks. PLNs were then removed 3 weeks after the last treatment. The lymph nodes were evaluated by hematoxylin and eosin staining. Red fluorescence of protoporphyrin IX (PpIX) was observed in all EC cell lines. ALA-PDT using LEDs exerted significant antitumor effects in vitro and in vivo. The antitumor effects of ALA-PDT with blue LED were the strongest, followed by green and red LEDs. The number of metastasized PLNs was significantly smaller in the ALA-PDT group (0%) than in the control group (37.5%). The present results indicated that ALA-PDT is effective for EC.

Oncological Safety of Ultrasonically Activated Surgical Devices During Gastric Cancer Surgery.

BACKGROUND/AIM: Ultrasonically activated surgical devices (USADs) have become indispensable instruments for gastrointestinal surgery. In this study, we investigated the oncological safety of the use of USADs. MATERIALS AND METHODS: We harvested and cultivated the splashes and mist scattered from an USAD when cutting MKN45-derived cancer nodules. Seven days later, we observed viable cancer cells and the total number of cells was counted. The histopathology of the nodules cut by the USAD was also examined. RESULTS: The existence of viable cancer cells was confirmed by ex vivo cell culture. The number of viable cancer cells was reduced by slow grasping of the USAD. The surface of cancerous tissue cut by the USAD was partially heat-denatured, however, there were some parts in which cancerous tissue was exposed on the surface. CONCLUSION: Surgeons should recognize the possibility that cancer cells may be scattered by USAD use.

Laparoscopic splenectomy for polysplenia with splenic torsion: a case report.

BACKGROUND: Polysplenia refers to the presence of two or more equal-sized spleens. Very rarely, one of the multiple spleens may develop torsion and infarction. CASE PRESENTATION: A 21-year-old woman presented with left upper quadrant pain, the cause of which could not be diagnosed. She returned to our hospital, 2 days later, without any pain improvement. Enhanced computed tomography showed splenic infarction and polysplenia. Initially, we could not identify the cause of the infarction and started conservative therapy, which did not result in any improvement. Hence, we performed a splenectomy, after securing informed consent. Because the patient was a young woman, we opted for a laparoscopic approach. During surgery, we identified the cause of the infarction as spleen pedicle torsion; the infarcted spleen was excised using an automated suturing device. We completed the laparoscopic surgery without converting it to an open laparotomy, and the patient was discharged 4 days later. This was a rare case of polysplenia with splenic torsion. CONCLUSION: Laparoscopic splenectomy is minimally invasive and has cosmetic advantages. Thus, this approach may be considered as a treatment option for this condition.

Rapid detection of metastatic lymph nodes of colorectal cancer with a gamma-glutamyl transpeptidase-activatable fluorescence probe.

Rapid diagnosis of metastatic lymph nodes (mLNs) of colorectal cancer (CRC) is desirable either intraoperatively or in resected fresh specimens. We have developed a series of activatable fluorescence probes for peptidase activities that are specifically upregulated in various tumors. We aimed to discover a target enzyme for detecting mLNs of CRC. Among our probes, we found that gGlu-HMRG, a gamma-glutamyl transpeptidase (GGT)-activatable fluorescence probe, could detect mLNs. This was unexpected, because we have previously reported that gGlu-HMRG could not detect primary CRC. We confirmed that the GGT activity of mLNs was high, whereas that of non-metastatic lymph nodes and CRC cell lines was low. We investigated the reason why GGT activity was upregulated in mLNs, and found that GGT was induced under conditions of hypoxia or low nutritional status. We utilized this feature to achieve rapid detection of mLNs with gGlu-HMRG. GGT appears to be a promising candidate enzyme for fluorescence imaging of mLNs.

Photodynamic diagnosis of peritoneal metastasis in human pancreatic cancer using 5-aminolevulinic acid during staging laparoscopy.

Peritoneal metastasis is an important prognostic factor for pancreatic cancer. The present study evaluated the possibility of diagnosing peritoneal metastasis by a photodynamic diagnosis using 5-aminolevulinic acid (5-ALA-PDD). In vitro, protoporphyrin IX (PpIX) accumulation was examined in the AsPC-1-GFP cell line following 5-ALA hydrochloride administration. In vivo, AsPC-1-GFP cells were injected into the peritoneal cavities of mice. Three weeks later 5-ALA hydrochloride was intraperitoneally administered to the mice. The peritoneal nodules were observed under fluorescence excitation. A total of 34 patients were enrolled in the present study who were clinically diagnosed with pancreatic malignancy. 5-ALA hydrochloride was orally administered to the patients prior to surgery. During the operation the abdominal cavity was observed under white light and fluorescence. In vitro and in vivo, it was confirmed that PpIX-induced red fluorescence. In 9 patients peritoneal nodules suspected to be peritoneal metastasis were observed under white light. In 4 of the 9 patients nodules were detected on the basis of the fluorescence images. Fluorescent nodules were histopathologically diagnosed as metastatic. In the present study it was confirmed that 5-ALA-PDD holds promise for the rapid diagnosis of peritoneal metastasis in patients with pancreatic cancer.

Establishment of Molecular Design Strategy To Obtain Activatable Fluorescent Probes for Carboxypeptidases.

Carboxypeptidases (CPs) are a family of hydrolases that cleave one or more amino acids from the C-terminal of peptides or proteins. However, methodology to monitor the activities of CPs is poorly developed. Here, we present the first versatile design strategy to obtain activatable fluorescent probes for CPs by utilizing intramolecular spirocyclization of rhodamine to translate the "aliphatic carboxamide to aliphatic carboxylate" structural conversion catalyzed by CPs into dynamic fluorescence activation. Based on this novel strategy, we developed probes for carboxypeptidases A and B. One of these probes was able to detect pancreatic juice leakage in mice ex vivo, suggesting that its suitability for intraoperative diagnosis of pancreatic fistula. This design strategy should be broadly applicable to CPs, as well as other previously untargetable enzymes, enabling development of fluorescent probes to study various pathological and biological processes.

The Prognostic Value of Preoperative Neutrophil-to-Lymphocyte Ratio in Colorectal Cancer.

BACKGROUND: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) has been reported in several cancers included colorectal cancer; however, it is not clear if there is an association between NLR and cancer-specific survival in colorectal cancer. And the optimal cut-off value is controversial. This study was designed to assess the prognostic value of preoperative NLR in colorectal cancer patients. METHODS: Total 823 consecutive patients who underwent surgery for all stages of colorectal cancer in our hospital between January 2006 and December 2011 were included in the study. Preoperative NLR was calculated from their hospital records. RESULTS: Using the receiver-operating characteristic curve, we found that the optimal preoperative NLR cut-off value that was strongly associated with cancer-specific survival was 2.1. Using this value, 505 patients were identified as having high NLR (≥2.1) and 397 patients were identified as having low NLR (<2.1). High NLR was associated with preoperative serum albumin values <4.0 g/dl (p < 0.001), positive preoperative serum C-reactive protein (CRP; p < 0.001), preoperative carcinoembryonic antigen (CEA) values ≥5.0 ng/dl (p = 0.003), and stage progression (p = 0.002). Cox proportional hazard analyses identified preoperative high NLR as an independent poor prognostic factor (p = 0.020, HR 1.66 (95 % CI: 1.08-2.63)). When comparing stage of disease, preoperative high-NLR patients with Stage III disease (p = 0.024) and Stage IV disease (p = 0.036) had significantly poorer prognoses. CONCLUSIONS: In this study, we have demonstrated that preoperative NLR ≥2.1 was a prognostic indicator for cancer-specific survival of colorectal cancer patients.