[FOLFIRINOX for Locally Advanced and Recurrent Pancreatic Cancer with UGT1A1 *6 and or UGT1A1*28 Polymorphisms-A Report of Two Cases].

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.

Prognostic impact of elevated preoperative C-reactive protein on patients with differentiated thyroid carcinoma.

BACKGROUND: C-reactive protein (CRP) has been reported to be associated with poorer prognosis in various malignancies. However, the relationship between CRP and differentiated thyroid carcinoma (DTC) remains to be elucidated. METHODS: A total of 45 patients, including 32 patients with preoperative DTC and 13 DTC patients with metastatic disease, were included in the study. The relationships between CRP levels and clinicopathological features were retrospectively analyzed. RESULTS: Analysis using a receiver operating characteristic curve revealed a preoperative CRP cutoff value of 0.155 mg/dL. Patients with preoperative CRP ≥ 0.155 mg/dL, those with T3 + T4, those with extrathyroidal invasion, or those with stage II, showed a statistically shorter recurrent-free survival than those with preoperative CRP < 0.155 mg/dL, those with T1 + T2, those without extrathyroidal invasion, or those with stage I (P = 0.001, P = 0.004, P = 0.024, and P = 0.025, respectively). Preoperative CRP ≥ 0.155 mg/dL was an independent prognostic factor for recurrent-free survival in the DTC patients (hazard ratio = 6.334, 95% confidence interval: 1.023-39.234, P = 0.037). The proportion of patients aged ≥55 y, and those with T3 + T4, was statistically higher in those with preoperative CRP ≥ 0.155 mg/dL than in those with preoperative CRP < 0.155 mg/dL (P = 0.037 and P = 0.038, respectively). CONCLUSIONS: Higher preoperative CRP levels have a robust prognostic impact on recurrence-free survival in DTC patients. In addition, higher preoperative CRP levels were associated with age ≥ 55 y and T3 + T4.

Serum transthyretin level is associated with prognosis of patients with gastric cancer.

BACKGROUND: The goal of the present study was to determine whether serum transthyretin level can be used as a novel prognostic biomarker for patients with gastric cancer. PATIENTS AND METHODS: Serum levels of transthyretin were examined before treatment in 42 patients with gastric cancer, 30 of whom underwent curative operation and had their prognostic factors analyzed. RESULTS: In an analysis using a receiver operating characteristic curve, transthyretin was evaluated as a useful biomarker to predict the overall survival of the patients (P = 0.033), and a level of 22.8 mg/dL was determined as the cut off value. The transthyretin levels exhibited statistically significant correlations with total protein (r = 0.598, P < 0.001), albumin (r = 0.626, P < 0.001), and retinol binding protein (r = 0.753, P < 0.001). On the other hand, the transthyretin levels showed statistically significant inverse correlations with tumor size (r = -0.753, P < 0.001) and the numbers of involved lymph nodes (r = -0.453, P = 0.012). The patients with serum transthyretin levels of <22.8 mg/dL showed poorer prognosis than those with levels of ≥22.8 mg/dL (P = 0.033); therefore, serum transthyretin level was an independent prognostic factor for the gastric cancer patients (hazard ratio: 0.420, 95% confidence interval: 0.180-0.985, P = 0.042). CONCLUSIONS: Anthropometric measurement of serum transthyretin can be useful for predicting the prognosis of patients with gastric cancer.

[A Case of Long-Term Survival of the Pancreatic Tail Cancer with the Concomitant Small Liver Metastasis].

We hereby report a case of long-term survival of the pancreatic tail cancer with a synchronous small liver metastasis. A 62- year-old male with pancreatic tail cancer was incidentally diagnosed with single tiny metastasis in the left medial section of the liver duringthe distal pancreatectomy. The lesion was also resected together with primary lesion. Since then, systemic chemotherapies such as gemcitabine(GEM)plus S-1 combination therapy, GEM alone therapy and S-1 alone therapy had been given to escape from recurrence. However, the recurrences were found in the liver at 21 months after surgery. Left hepatectomy was performed for metastatic lesions. Afterwards, proton radiation therapy was twice performed for the metastatic lesions in the liver which were unable to be removed by surgery alone. Partial resection of transverse colon was also needed to be performed for the bowel obstruction caused by recurrence on the surgical margin of the liver. Systemic chemotherapies includingS -1 therapy, FOLFIRINOX therapy and GEM plus nab-paclitaxel therapy have been continued throughout his entire treatment history after recurrence. He has been keepingin good physical condition with these multidisciplinary therapies, even though 51 months have passed since the first evidence of liver metastasis was diagnosed.

[A Case of Long-Term Survival of Metastatic and Recurrent Duodenal Gastrointestinal Stromal Tumor Treated with Multimodality Managements].

We hereby report a case of long-term survival of metastatic and recurrent duodenal gastrointestinal stromal tumor(GIST) treated with multimodality managements. A 59-year-old man was diagnosed with duodenal GIST and underwent surgical resection of a primary lesion of the duodenum. Since the pathological findings on mitotic rate indicated its high risk of recurrence, the systemic treatment by imatinib mesylate was given shortly after the surgery. Six months later, metastatic lesions being considered to be imatinib-resistant were observed in the remnant liver. Since there were no other drugs available for GISTs in clinic at that time, surgery of central bisegmentectomy with partial resection of the liver was performed to eliminate all metastatic lesions. However, recurrences had been repeatedly diagnosed afterward. In response to them, four more surgery for recurrent liver or peritoneal tumors, two transcatheter arterial chemoembolizations(TACE)and one radiofrequency ablation(RFA)were performed on the basis of its resectability. Sunitinib malate had been given since it was approved for imatinib-resistant GISTs in clinic. Eventually, as long as 99 months had passed since we observed the first evidence of the resistance to imatinib mesylate when he died from the GIST.

[Treating Side Effects of FOLFIRINOX--A Study of the Effect of Hange-Shashin-To on Preventing Diarrhea].

OBJECTIVES: FOLFIRINOX is an effective therapy for unresectable advanced pancreatic cancer. However, FOLFIRINOX has side effects of blood and gastrointestinal toxicity. Diarrhea, one of the side effects of CPT-11, sometimes becomes serious. We studied whether Hange-shashin-to could prevent diarrhea caused by CPT-11. METHODS: Seven patients who were diagnosed with unresectable pancreatic cancer, either Stage Ⅳor recurrent disease, were enrolled. They took 2.5 g of Hange-shashin-to before each meal starting one day before FOLFIRINOX, and continued taking it for one week. We examined the occurrence of diarrhea by using CTCAE retrospectively. RESULTS: The median age was 61 years. The median number of chemotherapy courses was 4. The frequency of diarrhea was lower, compared to the results of ACCORD11 trial and the domestic phaseⅡ clinical trials. In addition, Grade 3 or more serious diarrhea was not observed, even in the patients with genetic polymorphisms of UGT1A1. CONCLUSION: The incidence of diarrhea in patients treated with Hange-shashin-to in our department was lower compared to the ACCORD11 trial and domestic phase Ⅱ clinical trials. Hange-shashin-to is useful to allay the severity of diarrhea caused by CPT-11 in FOLFIRINOX therapy.

[A Long-Term Survival Case of Unresectable Hilar Bile Duct Cancer Treated with Gemcitabine].

A 69-year-old woman was diagnosed with liver dysfunction on blood testing in a nearby clinic. Computed tomography revealed stenosis of the hilar bile duct. Accordingly, an endoscopic nasobiliary drainage tube was inserted in the left hepatic duct and she was referred to our hospital for diagnostic examinations and treatment. The endoscopic retrograde cholangiopancreatography findings revealed obstruction of the cystic duct and stenosis of the hilar bile duct due to inflammation of the cystic duct or inflammation of the clamping type by cholecystitis. Considering the possibility of malignant tumor, surgical operation was performed. Radical resection was considered impossible and we instead performed cholecystectomy and resection of a bile duct wall specimen for diagnosis. The pathological diagnosis was poorly differentiated tubular adenocarcinoma. The patient was treated with gemcitabine as systemic chemotherapy for unresectable hilar bile duct cancer. Currently, 78 months after the start of chemotherapy, the patient is alive and well, without tumor progression.

To Stent or Not To Stent Hepaticojejunostomy--Analysis of Risk Factors for Postoperative Bile Leaks and Surgical Complication.

BACKGROUND/AIMS: Hepaticojejunostomy (HJ) has remained an important component of many surgical procedures. Biliary leaks after HJ represent a major complication carrying a high risk for prolonged hospital stay, biliary peritonitis, and the need for placing interventional drains or even conducting a re-laparotomy. The aims of this study were to define predictive factors associated with the incidence of bile leaks and to compare the results of anastomotic stenting of HJ with those obtained without stenting. METHODOLOGY: A retrospective study was performed on patients who underwent HJ between January 2000 and December 2010 at Gunma University Hospital, Department of Surgery I. A bile leak was defined as a bilirubin concentration in the drains exceeding serum bilirubin or occurrence of a biloma requiring drainage. Transanastomotic techniques for HJ were compared between the stented (external diverting stent, internal stent) and non-stented groups with respect to bile leaks. RESULTS: An HJ leak was demonstrated in 15 patients (12.4%); the overall surgical morbidity was 29.2%. The incidence of clinically relevant bile leaks after HJ was significantly associated with simultaneous liver resection, preoperative biliary drainage (PBD) and the placement of stents through the anastomosis. CONCLUSIONS: We conclude that the routine use of a biliary stent is not justified before and after surgery. We consider that stenting is unnecessary when a full anastomosis of the bile duct to the jejuna mucosa is performed. However, when an anastomosis of the intrahepatic bile duct to the jejuna mucosa is performed, more careful method must be exercised during an anastomotic procedure.

[An inflammatory pseudotumor of the liver mimicking a metastatic lesion of gallbladder cancer - a case report].

An inflammatory pseudotumor (IPT) of the liver is a rare benign disorder.As its characteristics based on computer tomography and magnetic resonance imaging findings are still unclear, it is difficult to distinguish IPT from malignant diseases of the liver.Herein, we report a case of IPT of the liver concurrent with advanced gallbladder cancer, which we could not diagnose preoperatively.First, we performed lateral segmentectomy of the liver.Second, a radical operation for gallbladder cancer was performed after confirming that the hepatic tumor was IPT via intraoperative pathological diagnosis.Therefore, modalities less invasive than surgical resection should be innovated, even though surgical resection is accurate.

IgG4-related intrahepatic sclerosing cholangitis resulting in sepsis caused by secondary suppurative inflammation: report of a case.

We report a case of pre-disseminated intravascular coagulation caused by secondary suppurative inflammation in a patient with immunoglobulin (Ig) G4-related sclerosing cholangitis. The patient was a 78-year-old man in whom a localized stenosis of the intrahepatic bile duct was found without any other bile duct stricture or symptoms. He underwent surgical resection 6 months later for acute severe cholangitis and sepsis caused by bile duct obstruction. The resected specimen contained an abscess and nodulary mass in the liver. Immunohistochemical analysis revealed IgG4-positive plasma cell infiltration, whereby we diagnosed IgG4-related sclerosing cholangitis. As IgG4-related sclerosing cholangitis limited to within the intrahepatic portion is extremely rare, we present this case with a review of the literature.

Description of pylorus-preserving pancreaticoduodenectomy in elderly patients.

BACKGROUND/AIMS: The aim of this paper is to examine the safety and feasibility of pylorus-preserving pancreaticoduodenectomy in elderly patients. METHODOLOGY: The study population consisted of 40 consecutive patients. They were divided into two groups: Group A (<75 years old) and Group B (=75 years old). Reconstruction with a vertical duodenojejunostomy and internal pancreatic drainage with an omental wrapping was performed on the patients in both the groups. RESULTS: Less time was required to complete the operations in Group B (280±20min) than in Group A (386±88min; p=0.0006). Intraoperative blood loss in Group B was significantly lesser (365±109g) than that in Group A (629±249g; p=0.0026). No statistically significant difference was observed between both groups, in terms of the length of time required until food intake resumed and length of hospital stay. Although the rate of postoperative complication was higher in Group B (10.0%), no statistically significant difference was observed. CONCLUSIONS: Pylorus-preserving pancreaticoduodenectomy with a vertical duodenojejunostomy and internal pancreatic drainage with an omental wrapping seems safe and can be performed on elderly patients without a significant risk of complications.

[A case of metastatic liver carcinoma treated with radiofrequency ablation and hepatectomy].

We report a case of metastatic liver carcinoma treated by radiofrequency ablation (RFA) and hepatectomy. A 53-year-old man suffering from sigmoid colon carcinoma and unresectable multiple liver metastases was treated with capecitabine and oxaliplatin and bevacizumab. After the seventh course, tumor reduction was confirmed but liver dysfunction meant that it was difficult to continue the same regimen. Because preoperative evaluation of liver function showed a high risk of postoperative liver failure, a combination of partial hepatectomy and RFA was planned in order to reduce the amount of liver resection. High anterior resection, partial hepatectomy and RFA were performed as planned. He underwent S-1 therapy following 7 courses of irinotecan, S-1, and bevacizumab therapy. To date, no recurrence has been observed 18 months after the operation. A combination of hepatectomy and RFA is expected to be an effective local treatment for multiple liver metastases of colorectal cancer, although the evidence is currently insufficient.

[Changes in myeloid-derived suppressor cells in malignant effusions of cancer patients following cancer chemotherapy].

Myeloid-derived suppressor cells(MDSCs) have been reported to be induced by inflammation, to suppress immune function, and promote tumor progression, and to be found in circulating blood, tumor tissue, and lymph nodes. MDSCs were found in pleural effusions and ascites of patients with malignant diseases and these results are described in this report. Changes in the levels of MDSCs during clinical responses to cancer chemotherapy are also reported. MDSC levels in malignant effusions have also been shown to change with the levels of MDSCs in peripheral blood and with clinical responses. MDSCs seem to play an important role in inflammation that is strongly related to advancing malignant diseases. The results also suggested that MDSCs may be reduced after effective chemotherapy, which may be effective as an adjuvant treatment with cancer immunotherapy.

Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of ß-catenin.

Pancreatic cancer is a leading cause of cancer-related mortality and often has a poor prognosis because of its late diagnosis, aggressive local invasion, early metastasis and poor response to chemotherapy. The chemotherapeutic agent gemcitabine is effective for treating advanced pancreatic cancer, but its efficacy remains less than satisfactory. It is expected that further investigation of pancreatic cancer cell invasion and development of strategies to block this process should improve the disease prognosis. In this study, we tested our hypothesis that galectin-3 (gal-3), a multifunctional member of the ß-galactoside-binding protein family, may regulate pancreatic cancer cell motility and silencing of it inhibit cell motility. Previous studies demonstrated that this protein is associated with tumor cell adhesion, proliferation, differentiation, angiogenesis, apoptosis and metastasis. Here, we used gal-3 small interfering RNA (siRNA) to silence its expression in various pancreatic cancer cell lines to determine whether gal-3 regulates cell proliferation, migration and invasion in vitro. We found that silencing gal-3 reduced cellular migration and invasion, but failed to affect proliferation. In gal-3 siRNA-transfected cells, we detected a decrease in ß-catenin expression, an important signal for cancer cell invasion, which was caused by downregulation of phosphorylated Akt and GSK-3ß. We also found that matrix metalloproteinase (MMP)-2 expression was reduced by gal-3 silencing. These results indicate that gal-3-mediated invasion via MMP-2 regulated by ß-catenin degradation is initiated by Akt phosphorylation in pancreatic cancer cells. Our results suggest that gal-3 can be a novel therapeutic target in pancreatic cancer.

Mixed ductal-endocrine carcinoma of the pancreas occurring as a double cancer: report of a case.

We present a successfully treated case of mixed ductal-endocrine carcinoma of the pancreas complicated by right renal cell carcinoma. The patient had no symptoms, and laboratory data were close to the normal range. Enhanced computed tomography demonstrated a marked enhanced tumor, which appeared to be an endocrine tumor, at the pancreas uncus. We performed pyrolus-preserving pancreaticoduodenectomy, regional lymph node resection, and right nephrectomy. Histologically and immunohistochemically, the pancreas tumor had both a ductal (exocrine) and an endocrine component. The renal tumor was a typical clear cell carcinoma. A diagnosis of synchronous double cancer was made. As demonstrated in previously published reports, this type of mixed tumor has malignant potential for invasive ductal carcinoma. We propose that mixed ductal-endocrine carcinoma of the pancreas should be treated by surgical resection with a sufficient surgical margin and regional lymph node resection to improve the patient's prognosis.

Liver hemorrhage due to idiopathic peliosis hepatis successfully treated with hepatic artery embolization.

Peliosis hepatis is an extremely rare condition that may cause fatal hepatic hemorrhage and liver failure. We report a case of liver hemorrhage due to idiopathic peliosis hepatis. A 60-year-old woman was admitted to our hospital with slight right hypochondriac pain. She went into hemorrhagic shock, and computed tomography (CT) showed multiple low-density areas in the right liver with massive subcapsular blood collection. Selective transfemoral arteriography of the celiac artery revealed no signs of vascular malformation or tumor stain, but showed signs of pooling in the right posterior segmental artery. The artery was embolized with particles of gelatin sponge, and hemostatic control was successful. Although peliosis hepatis is extremely rare, the diagnosis is significant because of its urgent clinical status, and transarterial embolization is a useful and minimally invasive procedure for liver hemorrhage due to peliosis hepatis.

[PSK decreased FOLFOX4-induced peripheral neuropathy and bone marrow suppression in patients with metastatic colorectal cancer].

FOLFOX4 has been proven to be effective for metastatic colorectal cancer and is now used as a postoperative adjuvant therapy. However, adverse effects such as cold-sensitive paresthesia and bone marrow suppression are common, and this may necessitate a change of chemotherapy regimen even though FOLFOX is effective. PSK, a polysaccharide derived from mushrooms, has been developed in Japan as an immune-enhancing agent, and is widely used in patients with gastric, colorectal and pulmonary cancer. PSK has also been reported to decrease some adverse effects of chemotherapy. FOLFOX4 combined with PSK was administered to patients with metastatic colorectal cancer and the results were evaluated. Eight cycles of FOLFOX4 and PSK (3.0 g/day, po) were given to 25 patients with metastatic (19 hepatic, 3 pulmonary and 3 peritoneal) colorectal cancer. There was no CR (0%), while PR, SD and PD were 48, 36 and 16%, respectively. The response rate was 48%, and the disease control rate was 84%. There were significantly lower frequencies of adverse effects in comparison with published data. Grades 1 and 3 neutropenia occurred in 48 and 24%, respectively, of the patients; grades 1 and 3 nausea in 48 and 4%; and grades 1, 2 and 3 sensory neurotoxicity in 52, 4 and 0%. No patient dropped out due to adverse effect in this study. PSK plus FOLFOX4 seemed to be as effective as FOLFOX4 monotherapy as has been published, and significantly less toxic. These results suggest that this combination therapy may be more effective than FOLFOX4 monotherapy when given over a longer period, with a lower incidence of adverse effects.

Phosphoglucose isomerase/autocrine motility factor promotes melanoma cell migration through ERK activation dependent on autocrine production of interleukin-8.

It is well known that phosphoglucose isomerase/autocrine motility factor (AMF) promotes cell migration in an autocrine manner in various tumor cells. However, it remains unclear whether certain cytokines modulate the effects of AMF on tumor cell migration. Because interleukin (IL)-8, a proinflammatory cytokine, is produced by melanoma cells and has been correlated with melanoma migration, the migratory ability of melanoma cells induced by AMF may also involve induction of IL-8 expression. In the present study, we assessed whether AMF promotes melanoma cell migration through autocrine production of IL-8. We found that AMF stimulation increased IL-8 production through up-regulation of IL-8 mRNA transcription, especially in biologically early stage melanoma cells. AMF-induced migration of these cells was inhibited by a specific neutralizing antibody against IL-8. The IL-8 production induced by AMF was mediated by the ERK1/2 pathways. These findings suggest that melanoma migration induced by AMF is mediated by autocrine production of IL-8 as a novel downstream modulator of the AMF signaling pathway.

Peptides derived from a soluble molecule of the human leukocyte antigen (HLA) class I cause apoptosis in gastric cancer cell lines.

We have reported that the levels of the soluble molecule of the human leukocyte antigen class I (sHLA-I) in patients with advanced gastric cancer were significantly lower than those in patients with cancer in the early stages. However, the effect of sHLA-I on gastric cancer cells has not been elucidated. Using human gastric cancer cell lines, MKN28, MKN45, and MKN74, we evaluated the effects of sHLA-I on cell growth, DNA synthesis, and apoptosis induction. Three types of synthesized peptides derived from HLA-I were also examined for their capacity to induce apoptosis. sHLA-I and a synthesized peptide, nos. 220-232 of the alpha3 domain of HLA-B7, caused cell growth inhibition by inducing apoptosis in human gastric cancer cells. This peptide also inhibited the in vivo growth of cancer dissemination caused by an intraperitoneal injection of MKN45 into severe combined immunodeficient mice. In conclusion, sHLA-I and the peptides derived from HLA-I cause apoptosis in human gastric cancer cell lines.