Association of iron metabolic enzyme hepcidin expression levels with the prognosis of patients with pancreatic cancer.

Hepcidin and ferroportin, which are known as key iron regulators, may be used in future treatments of pancreatic ductal adenocarcinoma. Iron is essential for life support; it helps oxygen molecules bind to hemoglobin and acts as an important catalytic enzyme center. However, iron overload is a risk factor for cancer, possibly through the generation of reactive oxygen species (ROS). Hepcidin, which is a peptide hormone mainly generated by the liver, inhibits iron absorption via enterocytes and iron release from macrophages. Notably, hepcidin regulates iron homeostasis in the body by regulating the iron transporter ferroportin. In the present study, it was assumed that high hepcidin expression and low ferroportin expression result in malignancy. Therefore, it was examined whether hepcidin and ferroportin expression levels were correlated with the prognosis of pancreatic cancer in patients. Results revealed that high hepcidin expression levels and low ferroportin expression levels in pancreatic cancer tissue were significantly associated with poor prognosis in the analyses of overall survival (P=0.0140 and 0.0478, respectively). Additionally, there was no significant difference in disease-free survival in the hepcidin- and ferroportin-staining groups. Hepcidin expression correlated with the pathological stage and vascular invasion (P=0.0493 and 0.0400, respectively), and ferroportin expression was correlated with age (P=0.0372). Multivariate analysis of overall survival in the hepcidin-staining group revealed that pathological N factor (pN), adjuvant chemotherapy, and hepcidin expression were independent prognostic factors (P=0.0450, 0.0002, and 0.0049, respectively). Similarly, multivariate analysis of overall survival in the ferroportin-staining group revealed that vascular invasion, and ferroportin expression were independent prognostic factors (P=0.0028, P<0.0001, and P=0.0056, respectively). Thus, hepcidin and ferroportin expressions might be novel prognostic indicators for pancreatic cancer.

Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy.

BACKGROUND: The cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) are well known to play a dominant role in distant metastasis. Nevertheless, the effect on CAFs with current chemoradiation therapies remains uncertain. OBJECTIVE: This study aimed to reveal the role of CAFs under current chemoradiation therapy (CRT) and investigate the factors regulating CAFs. METHODS: α-SMA-positive cells in 86 resected PDAC specimens with/without preoperative CRT were evaluated by immunohistochemistry. Various factors, including the plasma levels of vitamin D, were investigated for association with the number of CAFs or distant metastasis-free survival (DMFS). Human pancreatic satellite cells (hPSCs) extracted from clinical specimens were used to validate the factors. RESULTS: All PDAC samples contained CAFs but the number varied widely. Multivariate analysis for DMFS indicated a larger number of CAFs was a significant risk factor. Univariate analysis for the number of CAFs identified two clinical factors: preoperative CRT and lower plasma levels of vitamin D. In subgroup analysis, the higher plasma level of vitamin D was a dominant factor for longer DMFS in PDAC patients after preoperative CRT. These results were validated by using extracted hPSCs. Irradiation activated stromal cells into CAFs facilitating malignant characteristics of PDAC and the change was inhibited by vitamin D supplementation in vitro. CONCLUSION: In conjunction with established current therapies, vitamin D supplementation may be an effective treatment for PDAC patients by inactivating CAFs.

Patients Treated with Preoperative Chemoradiation for Pancreatic Ductal Adenocarcinoma have Impaired Bone Density, a Predictor of Distant Metastasis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm that spreads to surrounding tissue or distant sites. This study investigated distant metastases in PDAC patients with or without preoperative chemoradiation therapy (CRT), focusing on vitamin D levels and bone density. METHODS: This study included 146 patients with PDAC who underwent surgery from 2007 to 2014. Bone density was evaluated using computed tomography, and the preoperative vitamin D level was calculated by enzyme-linked immunosorbent assay (ELISA) for patients with available plasma (48 cases). RESULTS: When the patients were divided into two groups according to the change in bone density, the group with decreased bone density had a shorter distant metastasis-free survival time (DMFS) after surgery than the other group (p < 0.05). Low vitamin D was a weak predictor of DMFS, but the difference was not significant (p = 0.08), perhaps because of the sample size. Multivariate analysis indicated three significant factors associated with distant metastasis: a decrease in bone density (hazard ratio [HR], 2.17; p = 0.04), normalization of the Dupan-2 value after surgery (hazard ratio [HR], 0.39; p = 0.02), and completion of adjuvant chemotherapy (HR, 0.29; p < 0.01). Univariate analysis showed that a low vitamin D concentration (<20 pg/ml) was a risk factor (p = 0.04) for bone density change. Multivariate analysis found that preoperative CRT was the only factor associated (±, OR, 5.8; p = 0.04) with bone density change, suggesting that preoperative CRT significantly decreases bone density in patients with insufficient vitamin D. CONCLUSION: Patients treated with preoperative CRT tend to have impaired bone density, which is a predictor of distant metastasis. Thus, vitamin D supplementation may decrease distant metastasis.

The basal nutritional state of PDAC patients is the dominant factor for completing adjuvant chemotherapy.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and several clinical trials have shown that adjuvant chemotherapy after curative resection can improve the prognosis of these patients. However, the adjuvant chemotherapy completion rate is less than satisfactory. If this rate could be increased then the overall prognosis of PDAC might be improved; however, reports addressing this problem are insufficient. To elucidate the factors, we retrospectively investigated PDAC patients. METHODS: Various factors of 121 PDAC patients undergoing R0 resection, including preoperatively treated patients, were investigated. Univariate and multivariate analyses were performed to investigate the factors that were associated with the completion of adjuvant chemotherapy. RESULTS: The analysis identified age and the prognostic nutritional index (PNI) as significant independent factors. A receiver operating characteristic curve analysis of age yielded a cutoff value of 67 years (sensitivity, 64%; specificity, 78%). Univariate and multivariate analyses of the 61 patients who were over 67 years of age revealed that the PNI (odds ratio, 0.85; P = 0.048) and Evans grade (odds ratio, 0.041; P = 0.0010) were significant factors for the completion of chemotherapy. CONCLUSIONS: The results of our investigation suggest that nutrition should be controlled in older PDAC patients to facilitate the completion of adjuvant chemotherapy.

[Complete Surgical Resection of a Huge Hepatocellular Carcinoma Invading the Diaphragm and Lung after Transcatheter Arterial Chemoembolization (TACE) and Sorafenib--A Case Report].

We report a case of locally advanced huge hepatocellular carcinoma (HCC) invading the diaphragm and the right lung, which was controlled by sorafenib, thereby allowing curative resection. A 72-year-old man was diagnosed with advanced HCC invading the diaphragm and the right lung. At the time of diagnosis, his tumor was considered unresectable and he underwent transarterial embolization (TAE)/transcatheter arterial chemoembolization (TACE) 3 times. Assessment with enhanced CT after TAE/TACE showed that a viable lesion remained. Subsequently, he was treated with sorafenib for 15 months. Reassessment showed that the main tumor remained stable in size, and he was admitted to our hospital for surgery. Preoperative evaluation by enhanced CT and MRI detected an intrahepatic metastasis in segment 4 of the liver. After TACE was performed for this nodule, extended right hemihepatectomy with right diaphragmatic and right lung partial resection was performed. He had no postoperative complications and was discharged 27 days after surgery. He remains alive without recurrence 10 months after surgery.

[A case report of hepatectomy for liver metastasis of colon cancer after heavy particle radiotherapy].

A 51-year-old female patient was admitted to our hospital with a diagnosis of sigmoid colon cancer, and a sigmoidectomy and D3 lymphadenectomy was performed. The tumor was a moderately differentiated tubular adenocarcinoma (pT3N0M0, pStage II). No adjuvant therapy was administered. An abdominal computed tomography (CT) performed 11 months after the sigmoidectomy revealed a hepatic metastasis. The patient chose to undergo carbon ion radiotherapy (53.0 GyE/1 Fr). However, a second CT performed 10 months later indicated regrowth of the hepatic metastasis. A partial liver resection was performed, and severe deformity was observed in the irradiated region of the liver. The borderline between the tumor and surrounding tissue was not clearly discriminated. Histopathological examinations indicated increased numbers of fibrous cells in the irradiated region. To perform hepatic resection safely for liver metastasis of colorectal cancer following heavy particle radiotherapy, it is necessary to accurately determine the resection line before and during surgery. When feasible, resection of the whole irradiated area should be considered.

[A case of HER2-positive advanced gastric cancer with extensive lymph node metastasis treated via chemotherapy with a trastuzumab-containing regimen followed by conversion surgery].

A 62-year-old man presented with type 3 gastric cancer (tub1, HER2 positive) in the cardia, with 10-cm direct invasion into the lower esophagus, and extensive lymph node metastasis (Virchow and paraaortic nodes). Trastuzumab (Her), in the XP regimen (capecitabine and cisplatin [CDDP] plus Her; Xeloda®: 2,000 mg/m² on day 1-14, CDDP: 80 mg/m² on day 1, Her: 8(6) mg/kg on day 1), was administered every 3 weeks and repeated for 6 courses. After administering 6 courses of the XP plus Her regimen, without severe adverse events in the patient, computed tomography (CT) revealed shrinkage of both the main tumor and the metastatic sites, by 51%. Esophagectomy and proximal gastrectomy with 3-field lymphadenectomy and gastric tube reconstruction was performed via right thoracotomy and laparotomy (R0). However, Grade 3 pneumonia occurred postoperatively, and the patient was discharged on day 67 after surgery. After treatment, the tumor was histologically evaluated as Grade 1b gastric cancer, and remnant cancer cells also expressed HER2. The patient was too frail to receive adjuvant chemotherapy, and he died of pneumonia 11 months after surgery, without obvious relapse. Perioperative chemotherapy with a regimen containing Her has a possible role in treating advanced HER2-positive gastric cancer. Multiple invasive conversion surgeries might decrease the feasibility of adjuvant chemotherapy and worsen the prognosis.