A New Prognostic Model Covering All Stages of Intrahepatic Cholangiocarcinoma.

Background and Aims: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy that causes a poor survival. We aimed to identify its prognostic factors and to develop a nomogram that will predict survival of ICC patients among all stages. Methods: A total of 442 patients with pathology-proven ICC registered at the Fifth Medical Center of PLA General Hospital between July 2007 and December 2019 were enrolled. Subjects were followed for survival status until June 30, 2020. A prognostic model visualized as a nomogram was constructed in the training cohort using multivariate cox model, and was then validated in the validation cohort. Results: The median age was 55 years. With a median follow-up of 50.4 months, 337 patients died. The median survival was 11.6 months, with 1-, 3- and 5-year survival rates of 48.3%, 22.7% and 16.2%, respectively. Factors associated with overall survival were multiple tumors, lymph node involvement, vascular invasion, distant metastasis, decreased albumin, elevated lactate dehydrogenase (LDH), decreased iron, elevated fibrinogen, elevated CA125 and elevated CA19-9. A nomogram predicting survival of ICC patients at the time of diagnosis achieved a Harrel's c-statistic of 0.758, significantly higher than the 0.582 of the TNM stage alone. Predicted median survivals of those within the low, mid and high-risk subgroups were 35.6, 12.1 and 6.2 months, respectively. Conclusions: A nomogram based on imaging data and serum biomarkers at diagnosis showed good ability to predict survival in patients with all stages of ICC. Further studies are needed to validate the prognostic capability of our new model.

Tumor interstitial fluid and gastric cancer metastasis: an experimental study to verify the hypothesis of "tumor-phlegm microenvironment".

OBJECTIVE: To extract tumor interstitial fluid (TIF) from MKN-45 gastric cancer which is similar to "muddy phlegm" in Chinese medicine and observe influences of MKN-45 tumor interstitial fluid (MKN-45 TIF) intervention on metastasis of gastric cancer and on the expressions of vascular endothelial growth factor (VEGF), kinase insert domain containing receptor (KDR), epithelial-cadherin (E-cad), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1) and telomerase genes and proteins in primary tumor tissue. METHODS: An MKN-45 tumor-bearing model was established in 50 nude mice. The modeled animals were equally randomized to 5 groups: the simple tumor-bearing group (model group), the normal saline (NS) via tail vein injection (i.v.) group (NS i.v. group), MKN-45 TIF i.v. group (TIF i.v. group), NS intraperitoneal injection (i.p.) group (NS i.p. group), and MKN-45 TIF i.p. group (TIF i.p. group). The TIF and NS intervention groups received injection (i.p. or i.v.) of MKN-45 TIF or NS twice a week, 0.2 mL at a time. After 8 weeks, the primary tumors were removed, weighed and HE stained to observe tumor metastasis. The primary tumor tissues were analyzed by immunohistochemistry and real-time quantitative PCR to detect expressions of VEGF, KDR, E-cad, COX-2, ICAM-1, and telomerase genes and proteins in different groups. RESULTS: There were significant differences in tumor weight between TIF intervention groups and the model and NS intervention groups. Tumor metastasis was observed in all 5 groups, but the tumor metastasis rate in TIF intervention groups was significantly higher than those in the model and NS intervention groups. The gene and protein expressions of gastric cancer-related factors VEGF, KDR, COX-2, ICAM-1 and telomerase were unregulated while the gene and protein expressions of E-cad were downregulated in TIF intervention groups. CONCLUSIONS: TIF promotes tumor growth, invasion and metastasis of gastric cancer. These findings provide preliminary experimental clues for verifying the hypothesis of "tumor-phlegm microenvironment".

Tumor interstitial fluid and postoperative recurrence of tumors: An experimental study for verifying hypothesis of "tumor-phlegm microenvironment".

OBJECTIVE: To explore a method of extracting tumor interstitial fluid (TIF) which is similar to muddy phlegm in Chinese medicine (CM), interleukin-8 (IL-8) in concentration was taken as the representative of the content of TIF, analyzed in the extracted TIF and the original tumor tissue, and examined to see whether TIF has an interfering effect on tumor recurrence. METHODS: Tumor tissue was ground, centrifuged, and filtered for intercellular substances. Tumor-bearing Kunming S180 mice were raised for 21 days and then the tumors were removed to observe the influence of intervention with TIF, normal saline (NS) and a blank control on tumor recurrence. RESULTS: The content of IL-8 in the filtered and unfiltered tumor tissue was not significantly different (P>0.05). Postoperative tumor recurrence in TIF intervention group was significantly higher than that in the NS intervention and control groups (60%, 12/20 vs. 20%, 4/20. vs. 15%, 3/20, χ(2) =11.058, P<0.01). Tumor cells grew vigorously and infiltrated to muscular tissue in TIF intervention group. Large numbers of tumor cells were seen necrotic in the NS intervention group, and small numbers of tumor cells were seen necrotic in the blank control group. CONCLUSIONS: TIF can be effectively extracted by the means described. It does not contain tumor cells, but its contents such as IL-8 may stimulate tumor cell growth and promote postoperative tumor recurrence, which provided preliminary experimental basis for hypothesis of "tumor-phlegm microenvironment".

[Effects of Xiaotan Sanjie Decoction on expressions of interleukin-8 and its receptors in gastric tumor xenografts and gastric tissue adjacent to the tumor in mice].

OBJECTIVE: To explore the mechanisms of Xiaotan Sanjie Decoction (XTSJD), a compound traditional Chinese herbal medicine, in inhibiting the tumor growth and preventing recurrence by testing the protein expressions of interleukin-8 (IL-8) and its receptors chemokine receptor 1 (CXCR1) and chemokine receptor 2 (CXCR2) in gastric tumor xenografts and gastric tissue adjacent to the tumor in mice. METHODS: Fifty Kunming mice were randomly divided into normal group, normal saline (NS) group, Heat-clearing and Detoxicating Decoction (HCDD) group, tegafur (FT-207) group and XTSJD group. Except for mice in the normal group, S180 tumor block was transplanted into the gastric walls of the mice, and the mice were administered with corresponding medicine for 3 weeks. Weight of tumor xenografts was measured and tumor inhibition rate was calculated. IL-8 protein expression was tested by enzyme-linked immunosorbent assay. Expressions of CXCR1 and CXCR2 were tested by immunohistochemical method. RESULTS: The protein expressions of IL-8 and its receptors in tumor xenografts and gastric tissue adjacent to the tumor were markedly higher than those in the gastric tissue in normal mice (P<0.01); compared with HCDD and FT-207, XTSJD could significantly decrease the IL-8 protein expression in tumor xenografts and gastric tissue adjacent to the tumor (P<0.05); compared with FT-207, XTSJD could significantly decrease the CXCR1 protein expression in tumor xenografts (P<0.01), and XTSJD could also significantly decrease the CXCR1 protein expression in gastric tissue adjacent to the tumor as compared with HCDD and FT-207 (P<0.01); compared with HCDD and FT-207, XTSJD could significantly decrease the CXCR2 protein expression in tumor xenografts (P<0.01), and there was no significant difference among the three drug-treated groups in CXCR2 protein expression in gastric tissue adjacent to the tumor (P>0.05). CONCLUSION: XTSJD can decrease the protein expressions of IL-8 and its receptors in tumor xenografts and gastric tissue adjacent to the tumor. It may be one of the mechanisms of XTSJD in inhibiting the tumor growth and preventing recurrence.

Mechanisms of treatment of cancer pain with a topical Chinese herbal formula in rats.

BACKGROUND: Pain has a substantial impact on patients' activities and overall quality of life, but current conventional drugs have debilitating side effects, including gastrointestinal disorders. Thus there is a pressing need for new therapies with fewer side effects to alleviate cancer pain. We recently developed a topical herbal formula Xiaotan Tongluo analgesic gel (XTTL gel) based on the principles of traditional Chinese herbalism, and we have received positive feedback from bone cancer pain patients. The aim of this study was to determine the analgesic effects and explore the mechanisms of XTTL gel in a rat model of bone cancer pain. METHODS: The rat model of bone cancer pain was established by inoculating Walker-256 rat carcinoma cells directly into the right tibial medullary cavity of Wistar rats. The rats were randomly assigned to three groups (n = 10 per group): (1) sham bone cancer control (sham group): vehicle (PBS) inoculation without carcinoma cells plus topical administration of blank gel; (2) Sham treatment control (vehicle group): Walker-256 cell inoculation plus topical administration of blank gel; (3) XTTL gel treatment (treatment group): Walker-256 cell inoculation plus topical administration of XTTL gel. XTTL gel treatments were applied daily for 7 days starting on day 14 following inoculation. Outcomes were assessed 21 days after inoculation by mechanical allodynia, histological staining, and by measuring concentrations of type I collagen carboxy-terminal telopeptide (ICTP) and bone-specific alkaline phosphatase (BAP) in serum. RESULTS: Fourteen days after cancer cell incubation, significant mechanical allodynia in the ipsilateral hind paw and tumor growth in proximal end of the tibia were observed in the vehicle and treatment groups but not in the sham group. At day 21, mechanical withdrawal thresholds in treatment group rats were significantly higher ((4.8557 +/- 0.8336) g) compared with those of the vehicle group ((1.8630 +/- 1.4369) g, P < 0.05). ICTP and BAP levels increased significantly in vehicle group rats ((101.5176+/- 11.0694) U/L and (370.7838 +/- 12.8273) U/L, respectively) compared with those of the sham group ((11.7553 +/- 1.1885) U/L and (185.7338 +/- 3.6761) U/L, respectively; P < 0.05). XTTL gel decreased the level of blood serum ICTP ((41.8998 +/- 6.4970) U/L, P < 0.05) but had little effect on blood serum BAP ((365.5338 +/- 18.5361) U/L, P > 0.05). CONCLUSION: Topical use of XTTL gel may have an analgesic effect on bone cancer pain, an effect mediated by lowering of ICTP levels and inhibiting bone resorption.