SPARC accelerates biliary tract cancer progression through CTGF-mediated tumor-stroma interactions: SPARC as a prognostic marker of survival after neoadjuvant therapy.

PURPOSE: In biliary tract cancer (BTC), malignancy is strongest at the invasion front. To improve the BTC prognosis, the invasion front should be controlled. We evaluated tumor-stroma crosstalk at the tumor center and at the invasion front of BTC lesions. We investigated the expression of SPARC, a marker of cancer-associated fibroblasts, and determined its ability to predict BTC prognosis after neoadjuvant chemoradiotherapy (NAC-RT). METHODS: We performed immunohistochemistry to evaluate SPARC expression in resected specimens from patients that underwent BTC surgery. We established highly invasive (HI) clones in two BTC cell lines (NOZ, CCLP1), and performed mRNA microarrays to compare gene expression in parental and HI cells. RESULTS: Among 92 specimens, stromal SPARC expression was higher at the invasion front than at the lesion center (p = 0.014). Among 50 specimens from patients treated with surgery alone, high stromal SPARC expression at the invasion front was associated with a poor prognosis (recurrence-free survival: p = 0.033; overall survival: p = 0.017). Coculturing fibroblasts with NOZ-HI cells upregulated fibroblast SPARC expression. mRNA microarrays showed that connective tissue growth factor (CTGF) was upregulated in NOZ-HI and CCLP1-HI cells. A CTGF knockdown suppressed cell invasion in NOZ-HI cells. Exogeneous CTGF upregulated SPARC expression in fibroblasts. SPARC expression at the invasion front was significantly lower after NAC-RT, compared to surgery alone (p = 0.003). CONCLUSION: CTGF was associated with tumor-stroma crosstalk in BTC. CTGF activated stromal SPARC expression, which promoted tumor progression, particularly at the invasion front. SPARC expression at the invasion front after NAC-RT may serve as a prognosis predictor.

Prognostic value of functional SMAD4 localization in extrahepatic bile duct cancer.

BACKGROUND: SMAD4 is a key mediator of TGFß signaling and one of the mutated genes in extrahepatic bile duct cancer (eBDC). It has been also reported that SMAD4 has dual functions, in carcinogenesis via silencing and in tumor invasion/metastasis via signaling, depending on tumor stage. We previously visualized more nuclear transitioning functional SMAD4 at the tumor invasion front than the central lesion. So, we investigated the localization of functional SMAD4 (e.g., invasion area or metastasis lesion) and its association with chemotherapy and chemo-radiation therapy. METHODS: We performed SMAD4 immunostaining on 98 resected eBDC specimens and evaluated the presence of the functional form of nuclear SMAD4 at the central lesion, invasion front, and metastatic lymph node. We also examined the influence on chemotherapy after recurrence (n = 33) and neoadjuvant chemo-radiation therapy (NAC-RT, n = 21) and the prognostic value of using retrospective data. RESULTS: In 73 patients without NAC-RT, 8.2% had loss of SMAD4 expression and 23.3% had heterogeneous expression. Patients without SMAD4 expression at any site had significantly poorer overall survival (OS) than other patients (P = 0.014). Expression of SMAD4 at the invasion front was related to better survival (recurrence-free survival [RFS] P = 0.033; OS P = 0.047), and no SMAD4 expression at the metastatic lymph node was related to poorer OS (P = 0.011). The patients who had high SMAD4 expression had poorer prognosis after recurrence (RFS P = 0.011; OS P = 0.056). At the residual cancer in the resected specimen, SMAD4 was highly expressed after NAC-RT (P = 0.039). CONCLUSIONS: Loss of SMAD4 protein expression was a poor prognostic factor in eBDC at resectable stage. However, the intensity of functional SMAD4 in eBDC is a marker of resistance to chemo-radiotherapy and malignant potential at advanced stages.

Preoperative FDG-Positive Lymph Nodes Predict the Postoperative Prognosis in Resectable Biliary Tract Cancers.

BACKGROUND: F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) has been used to diagnose and stage various cancers. In regard to biliary tract cancer (BTC), due to cholangitis it is difficult to evaluate FDG uptake caused by cancer. We previously showed that FDG-positive lymph nodes (LNs) of resectable BTC had a possibility of predicting postoperative prognosis. OBJECTIVE: This study aimed to validate the usability of FDG-PET for LNs using another cohort and to investigate in detail the relationship between FDG-positive LNs and the prognosis of BTC. METHODS: We measured the preoperative maximum standardized uptake value (SUVmax) at each of the 190 surgically dissected LN areas in 67 patients and investigated the prognosis using our previously determined SUVmax cut-off values of ≥ 2.8. RESULTS: Regarding the prognosis of patients with resectable BTC, a LN SUVmax ≥ 2.8 [PET N (+)] was a poor prognostic factor for recurrence-free survival (RFS) compared with a LN SUVmax < 2.8 [PET N (-)]. It was confirmed that the hazard ratio forest plot [PET N (+)/PET N (-)] for RFS indicated a similar tendency among subcategories. Moreover, we investigated patients with pN0 disease and demonstrated that the PET N (+) group also had a significantly worse RFS outcome compared with the PET N (-) group. Recurrence of the PET N (+) group has significantly occurred more often in LNs than that of the PET N (-) group. CONCLUSION: High LN SUVmax was confirmed to be the preoperatively diagnosed prognostic risk factor for RFS in resectable BTC and could be helpful for clinical decision making regarding the perioperative treatment strategy.

[Clinical Outcome of Eight Patients with Perforated Colorectal Cancer].

We studied the clinicopathological findings of 8 patients with perforated colorectal cancer. Four patients were male. In 7 patients, the primary cancer site was left side colon. Chief complaints were abdominal pain in 7 patients and diarrhea in 1 patient. The emergent operation was performed in all cases. The final stages of 8 patients were as follows: 5 patients with Stage II, 2 patients with Stage III, 1 patient with Stage IV. All patients were discharged from our hospital. Postoperative chemotherapy was performed for 5 patients. Of these 8 patients, 1 patient had peritoneal dissemination and 1 patient had local recurrence. Two patients were died of cancer and 6 patients were alive. In conclusion, patient with perforated colorectal cancer were high risk cases for recurrence.

[An Analysis of Perforated Gastric Cancer with Acute Peritonitis in Our Hospital].

Perforated gastric cancer is relatively rare and the incidence is reported about 1% of all the cases of gastric cancer. We retrospectively analyzed the clinical data of the consecutive 12 patients with perforated gastric cancer who underwent operation in our hospital between January 2005 and December 2016. There were 5 men and 7 women, with an average age of 65.8 years old(34-87). Perforated gastric cancer occurred in the region U(1 cases), M(6 cases), L(5 cases). There were 11 cases with distant metastasis. We could successfully diagnosed as perforated gastric cancer in 8 cases before emergency operation. Gastrectomy was performed in 5 cases. However, the curative resection was performed only 1 case. Prognosis of perforated gastric cancer is poor. We considered as an appropriate two-step surgical strategy that the first step of surgery is an acute peritonitis treatment followed by radical gastrectomy with lymphadenectomy.

[A Case of Transverse Colon Cancer in Which Long-Term Chemotherapy Was Performed after Palliative Colonic Stent Placement].

We report a case involving a 76-year-old woman with transverse colon cancer undergoing long-term chemotherapy following palliative colonic stent placement. She visited our hospital with a diagnosis of colonic obstruction. Her abdomen was evidently distended and tender. CT revealed the apple core sign in the transverse colon-hepatic flexure area, and then bowel obstruction. The disseminated lesion occluded the superior mesenteric vein. Multiple masses were found on both lungs; a single tumor was detected in liver S6. Hence, we diagnosed her with unresectable obstructive transverse colon cancer. A colonic stent was inserted to remove the obstruction. Because primary tumor resection was rendered impossible, mFOLFOX6 was initiated with the colonic stent intact. After 5 courses, CT revealed that the liver metastasis disappeared, and lung metastases exhibited SD of a therapeutic effect. She further received 5 courses of mFOLFOX6 and 20 courses of maintenance therapy using FU. However, single liver metastasis recurred, exhibiting PD of a therapeutic effect. Histological diagnosis of liver metastasis was a consistent finding due to metastatic colorectal cancer; RAS mutation was not detected. Currently, 2 years after the diagnosis, FOLFIRI and panitumumab are being administered as the second-line treatment, with no colonic stentrelated complications.

[Case of Central Venous Catheter Laceration of the Pectoralis Minor Muscle].

A 50's underwent gastrectomy for gastric cancer 4 years before. He had received chemotherapy for para-aortic lymph node metastases. A central venous catheter with a subcutaneous port was implanted via the right subclavian vein, under ultrasonographic guidance, 1 year 3 months earlier. The patient complained of swelling in his right chest during intravenous injection of ramucirumab and paclitaxel via the port. A chest radiograph revealed that a catheter fracture. A CT scan showed that the fractured catheter had lacerated the pectoralis minor muscle and the tip was in the right inferior pulmonary artery. The catheter fragment was removed using a pigtail catheter and a snare catheter via a percutaneous transfemoral approach, without any complication. The catheter was cut at 15.5 cm from the tip. This fracture was thought to be caused by a kink in the pectoralis muscle.

Prognostic Factors of Oral Intake After Endoscopic Gastroduodenal Stent Placement for Advanced Gastric Cancer.

Gastroduodenal stents are effective for gastric outlet obstruction (GOO) due to gastric cancer. However, some patients are unable to eat again soon. We retrospectively analyzed the cause of short-feeding periods. Between 2011 and 2015, we performed stent placement in 22 patients who could not eat solids. The effects of clinical characteristics on duration of oral intake were analyzed using Cox proportional hazards models. Univariate analyses revealed that the degree of GOO [no oral intake/liquids only; hazard ratio (HR), 10.9; 95% confidence interval (CI), 2.5-48.1; P=0.003], performance status score (2 or 3/0 or 1; HR, 5.7; 95% CI, 1.8-16.9; P=0.004), and poststenting chemotherapy (no/yes; HR, 5.7; 95% CI, 1.9-18.9; P=0.002) were significant factors for cessation of oral intake. Multivariate analysis showed that GOO and chemotherapy were significant factors. Gastroduodenal stents were less effective for patients with severe stenosis or without poststenting chemotherapy.