[A Long-Term Survival Case of Gastric Cancer with Pyloric Stenosis and Peritoneum Dissemination That Received Intravenous and Intraperitoneal Paclitaxel Combined with S-1 Therapy after Bypass Surgery].

Although a 74-year-old man with gastric cancer with pyloric stenosis(cT4aN[+]M0, Stage Ⅲ)had undergone surgery, he was diagnosed with peritoneum dissemination. He received bypass surgery, and an intraperitoneal access port was implanted in his subcutaneous space. Postoperatively, he received 4 courses of SOX therapy. In treatment effect, the primary tumor showed no change, and ascites developed. Therefore, we changed the chemotherapy regimen in intravenous and intraperitoneal paclitaxel combined with S-1 therapy. After starting this regimen, the primary tumor decreased in size, and the pyloric stenosis improved. Currently, the patient is alive without recurrence for 5 years and 8 months after intravenous and intraperitoneal paclitaxel combined with S-1 therapy and receiving this treatment regularly.

The Organo- and Cytoprotective Effects of Heat-shock Protein in Response to Injury Due to Radiofrequency Ablation in Rat Liver.

AIM: In treating liver tumors, preserving hepatic reserve and reducing surgical invasiveness are important for minimizing postoperative complications. Geranylgeranylacetone (GGA) is reported to selectively induce heat-shock protein 70 (HSP70), which initiates a powerful cytoprotective effect. We investigated the function of HSP70 under conditions of radiofrequency ablation (RFA) of the liver. MATERIALS AND METHODS: Male Wistar rats were divided into three groups: a control group, a group administered GGA, and a group administered GGA plus quercetin, an HSP70 synthesis inhibitor. Expression of HSP70 and heat-shock factor-1 (HSF1) in the liver was measured at the protein level, and severity of liver damage was investigated using serum and hepatic tissue. RESULTS: The GGA-treated group had higher expression of HSP70 and HSF1 than the other groups. Peak liver damage in all groups occurred 6 h after RFA. The GGA-treated group also had significantly less liver damage and lower serum level of the inflammatory cytokine tumor necrosis factor-α, and a lower rate of apoptosis in tissue around post-ablation necrosis. Expression of HSP70 and HSF1 was suppressed in the group treated with GGA and quercetin, and this group had severe liver damage. CONCLUSION: Induction of HSP in the liver by GGA may be applicable in future treatments for hepatocellular carcinoma or liver metastasis. The present findings suggest that if preoperative administration of GGA can offer protective effects in the liver, treatment options could be increased and liver failure and other complications might be avoided.

Expression of HSP27 in Hepatocellular Carcinoma.

BACKGROUND/AIM: Heat-shock protein 27 (HSP27), a low molecular weight stress protein, is recognized as a molecular chaperone. The expression of HSP27 has been detected in some human tumors and while HSP27 is phosphorylated as a reresponse to stress, the function of phosphorylated HSP27 (p-HSP27) is not known. The aim of this study was to investigate what kind of effect expression of HSP27 and p-HSP27 in HCC has on clinicopathological characteristics and prognosis. MATERIALS AND METHODS: An immunohistochemical study for HSP27 and p-HSP27 was performed on 194 resected HCC cases. We analyzed the correlation of HSP27 expression with various parameters statistically. RESULTS: There was no correlation between expression of HSP27 and the clinicopathological characteristics and prognosis from the analysis of 194 cases. From the analysis of the hepatitis C virus (HCV)-positive group of 142 cases, those that were p-HSP27-positive had a larger tumor diameter and the portal vein invasion rate was high. CONCLUSION: The expression of total HSP27 may serve as a new, clinically useful marker of HCC. In addition, the present study suggests that the expression of phosphorylated HSP27 is useful in the screening and grading of HCC occurring in the setting of HCV.

Preventive effects of amino-acid-rich elemental diet Elental® on chemotherapy-induced oral mucositis in patients with colorectal cancer: a prospective pilot study.

PURPOSE: The prospective pilot study was designed to evaluate the preventive effects of amino-acid-rich elemental diet (ED), Elental(®), on chemotherapy-induced oral mucositis in patients with colorectal cancer. The factors influencing its efficacy are also investigated. METHODS: A total of 22 eligible patients with colorectal cancer experiencing grade 1-3 oral mucositis during treatment with fluorouracil-based chemotherapy entered the current study. Their average age was 67 years. There were 10 male and 12 female. The PS was 0 in the majority of patients. Patients received two courses of the same chemotherapy regimen and Elental(®) concurrently after recovery to grade 0 or 1 oral mucositis. RESULTS: FOLFOX6 + bevacizumab in 8 patients, FOLFIRI + bevacizumab in 8 patients, FOLFIRI + panitumumab in 1 patient, FOLFIRI in 1 patient, XELOX + bevacizumab in 2 patients, and S-1 + cetuximab in 2 patients were used as first-line (16 cases) or as second-line (6 cases) chemotherapy. Dose reduction of 5-fluorouracil (5-FU) or oral fluoropyrimidine was performed in the 2 patients achieving grade 3 oral mucositis and in the 3 patients achieving grade 2 oral mucositis. The maximum grade of oral mucositis decreased in 18 of the 22 patients during the first treatment course with Elental(®) (p = 0.0002) and in 20 of the 22 patients in the second course (p < 0.0001). Multivariate analyses found that the dose reduction in 5-FU or oral fluoropyrimidine, ED intake, and the prior administration of ED were each a significant factor for the preventive efficacy on oral mucositis. CONCLUSION: The amino-acid-rich elemental diet Elental(®) may be useful as a countermeasure for 5-FU-based chemotherapy-induced oral mucositis in patients with colorectal cancer.

Phase II Trial of S-1 and Oxaliplatin Plus Cetuximab for Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases (KSCC1002).

BACKGROUND: The Kyushu Study Group of Clinical Cancer (KSCC) conducted phase II trials of KSCC1002 (UMIN000001308) concerning liver resectability after first-line treatment of initially unresectable or not optimally resectable colorectal liver metastases in a prospective, multicenter study. METHODS: Patients with wild-type KRAS received 4-6 cycles of S-1 and oxaliplatin (SOX) plus cetuximab. Liver resectability was evaluated subsequently with the liver resection rate as the primary endpoint. RESULTS: Of the 33 patients enrolled between March 2010 and July 2013, the median number of administration cycles was 4 (range 0-10). The overall response rate was 63.6 % (95 % confidence interval [CI] 45.1-79.6 %). Liver resection was possible in 16 of 33 (48.5 %) patients, and there were 13 R0 cases (39.4 %). We conducted a central review of liver resectability evaluated by five liver surgeons, and the resectability increased from 18.2 to 66.7 % after chemotherapy, based on imaging. The median overall survival for all 33 cases was 31.6 months (95 % CI 14.8-not reached). The median progression-free survival was 9.7 months (95 % CI 6.2-11.8). CONCLUSIONS: SOX plus cetuximab is safe and effective for advanced colorectal cancer with limited liver metastasis, and may lead to high liver resectability.

Randomized phase II study of 5-fluorouracil hepatic arterial infusion with or without antineoplastons as an adjuvant therapy after hepatectomy for liver metastases from colorectal cancer.

BACKGROUND: Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. METHODS: Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. FINDINGS: Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm. INTERPRETATION: Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov UMIN000012099.

[Stevens-Johnson syndrome induced by regorafenib in a patient with progressive recurrent rectal carcinoma].

A 55-year-old man with rectal carcinoma underwent lower anterior resection. Eight years after surgery, multiple metastases were detected in the liver, lung, and abdominal lymph nodes. The metastatic cancers were resistant to standard chemotherapy. Thus, regorafenib was administered to the patient. The patient presented symptoms of Stevens-Johnson syndrome (SJS) nine days after regorafenib administration, and hence, treatment was terminated. To treat SJS, he received oral and topical steroid therapies. SJS is an important adverse event that hinders the continuation of regorafenib treatment. Thus, it is necessary to continually check the patient's skin condition carefully, especially at early stages of treatment. To our knowledge, this is the first report of SJS arising during the course of regorafenib treatment.

[Two Cases of Effective Hepatic Arterial Infusion Chemotherapy for Liver Metastases of Colon Cancer Resistant to Systemic Chemotherapy].

A 69-year-old man underwent right hemicolectomy for ascending colon cancer with liver metastases. Postoperative systemic chemotherapy did not reduce the metastases, and therefore, hepatic arterial infusion chemotherapy (HAI) was administered. The metastases decreased in size after 26 rounds of therapy, and the patient underwent resection. He is recurrence-free 63 months after the primary operation. A 57-year-old man underwent Hartmann's operation for sigmoid colon cancer with liver metastases. He underwent hepatic left lobe resection after metastases reduction by systemic chemotherapy. However, multiple liver metastases were detected 2 months later. Because the disease progressed despite the administration of systemic chemotherapy, HAI was utilized instead. The metastases decreased in size remarkably, and resection was performed. The patient is surviving 52 months after the primary operation while being continuously treated with HAI, resection, and systemic chemotherapy for re-recurrence. HAI is a potential alternative treatment for patients with colorectal liver metastases resistant to systemic chemotherapy.

Potential usefulness of mucin immunohistochemical staining of preoperative pancreatic biopsy or juice cytology specimens in the determination of treatment strategies for intraductal papillary mucinous neoplasm.

We classified resected intraductal papillary mucinous neoplasms (IPMNs) into four subtypes (gastric, intestinal, pancreatobiliary and oncocytic) according to their morphological features and mucin expression, determined their clinicopathological characteristics and investigated the possibility of preoperatively diagnosing these subtypes. Sixty resected tumors, 4 preoperative tumor biopsies and 10 preoperative pancreatic juice cytology specimens were analyzed. The gastric and intestinal types accounted for the majority of IPMNs. Non-gastric type IPMNs were of high-grade malignancy. Many of the pancreatobiliary-type IPMNs were in an advanced stage and were associated with a poor prognosis. The results of mucin immunohistochemical staining of preoperative biopsy and surgically resected specimens were in agreement with each other, and in close agreement with those for pancreatic juice cytology specimens obtained from 10 patients during endoscopic retrograde cholangiopancreatography (ERCP). The immunostaining of preoperative biopsy specimens and ERCP-obtained pancreatic juice cytology specimens may be useful in the differential diagnosis of gastric and intestinal types of IPMN. If such techniques enable the preoperative diagnosis of IPMN subtypes, their use in combination with conventional preoperative imaging modalities may lead to surgical treatment best suited for the biological characteristics of the four subtypes.

[A long-term survivor of advanced gallbladder carcinoma treated with curative operation and hepatic arterial infusion].

60-year-old woman was referred to us for epigastralagia under the diagnosis of chronic cholecystitis. Cholecystectomy was performed, and gallbladder carcinoma was pinpointed by postoperative pathological diagnosis. Because liver invasion should have been detected by pathological diagnosis, we conducted liver S4a+S5 resection, extrahepatic bile duct resection and D2 lymphadenectomy. The pathological diagnosis was advanced gallbladder carcinoma with liver metastasis. We treated a patient with curative operation and hepatic arterial infusion adjuvant chemotherapy by low-dose FP therapy for advanced gallbladder carcinoma, and she is doing well now without disease recurrence eight years after surgery.

[A trial using maximum preoperative chemotherapy for metastatic colorectal cancer].

There are chemotherapy methods applied before operation, before and after operation, or after operation for metastatic colorectal cancer. But the correct times and periods, etc., for their administration have not been obvious. We perform maximum preoperative chemotherapy to control micrometastases, and afterwards surgically remove the metastatic lesions[including radiofrequency ablation(RFA)]. Complications after operation and the severity of pathological liver damage etc., were investigated by comparing 14 patients who received maximum preoperative chemotherapy(group A), with 4 patients for whom 6 courses of FOLFOX+bevacizumab(BV)therapy(group B)were planned. ICG15 before liver resection and bleeding during liver resection were not significantly different(p=0. 26 and p=0. 60, respectively). No severe complication after operation was seen and pathological liver damage was minor in both groups. No interference of maximum preoperative chemotherapy with BV to metastatic colorectal cancer was suggested from the point of view of complications after operation and the severity of pathological liver damage. Further investigation with many more patients is necessary.

[A case of remnant liver metastases after resection of liver metastases from rectal cancer following treatment with 5-FU, L-OHP and CPT-11, with markedly effective treatment by cetuximab plus S-1].

FOLFOX or FOLFIRI are commonly used as first- or second-line chemotherapy for unresectable colorectal cancer or its metastases.Recently, it had become a trend to add bevacizumab or cetuximab(Cmab)limited to the K-ras wild-type or panitumumab(Pmab)limited to the K-ras wild-type.At the present time, a common third-line chemotherapy is CPT-11 plus Cmab limited to the K-ras wild-type, or Cmab/Pmab.However, the results are unsatisfactory.With Cmab plus S-1 we treated a case of remnant liver metastases from rectal cancer which was a K-ras wild-type, after treating 5-FU, L-OHP and CPT-11. The tumor marker dropped and 7 focuses of liver metastases disappeared after 6 courses of treatment(complete response: CR in)and CR was achieved after 9 courses treatment.After 10 courses of treatment, a new lesion appeared on S5 of the liver and we performed percutaneous radiofrequency ablation.

[Efficacy of Elental on prevention for chemotherapy-induced oral mucositis in colorectal cancer patients].

BACKGROUND: The present study was designed to evaluate the preventive effects of elemental diet Elental (ED) on chemotherapy-induced stomatitis in patients with colorectal cancer. MATERIALS AND METHODS: A total of 23 patients with colorectal cancer experiencing grade 1-3 stomatitis during treatment with chemotherapy (2- or 3-week per cycle) entered the current study. Their average age was 67 years, ranging from 44 to 84 years. RESULTS: A total of 22 patients received the same chemotherapy regimen, but also received more than 80 g of Elental (ED) (including 1, 932 mg of L-glutamine), per day. FOLFOX, FOLFIRI or XELOX-based chemotherapy was used. A dose reduction of 5-FU, capacitabine or S-1 was performed in 5 patients who experienced grade 2 or 3 stomatitis. The maximum grade of stomatitis decreased in 18 of the 22 patients after the first treatment course, and decreased in 20 of 22 patients after the second course with ED.The preventive efficacy of ED on stomatitis was noted in a dose-dependent manner.Similarly, the maximum grade of neutropenia decreased in 10 of 11 patients after their first or second treatment course with ED. CONCLUSION: We conclude that ED can significantly decrease the severity of chemotherapy-induced stomatitis in colorectal cancer patients in association with the control of neutropenia.

[Liver histology and surgical outcomes after preoperative chemotherapy in colorectal cancer liver metastases].

We aimed to assess hepatic histopathological responses to preoperative chemotherapy in patients with colorectal liver metastasis. We selected all patients(n=34)with colorectal liver metastases between September 2006 and March 2009. The preoperative chemotherapy group was significantly associated with tumor regression, inflammatory response, sinusoidal dilatation compared with non-chemotherapy group. There was no difference in the rate of postoperative complications and hospital stay. Prolonged preoperative systemic chemotherapy alters liver parenchyma, but it does not increase postoperative complications. This should be taken into consideration before deciding a major liver resection in patients who have received preoperative chemotherapy.

[Treatment and outcome in small bowel cancer].

In adenocarcinoma of the small intestine, delays in diagnosis are frequent, and the majority of patients present with advanced- stage disease and either lymph node involvement or distant metastatic disease. Surgical resection is a mainstay in treatment of this disease, but the role of adjuvant therapy is unclear. Recent retrospective and prospective studies have helped to clarify the optimal chemotherapy approach for advanced small bowel adenocarcinoma. The combination of capecitabine and oxaliplatin is reportedly highly effective. Further clinical studies on this rare type of tumor are needed. This article reviews the focuses on recent advances in management. The 72nd Japanese Society for Cancer of the Colon and Rectum have conducted a retrospective review of Japanese patients with adenocarcinoma of the jejunum or ileum. The data indicated that although not statistically significant, there was a trend in median overall survival favoring the chemotherapy for advanced jejunal or ileal adenocarcinoma (17 months vs. 8 months, p=0.114).

Perioperative challenges associated with a pancreaticoduodenectomy and distal pancreatectomy for pancreatic cancer in patients with situs inversus totalis: report of two cases.

Situs inversus totalis is a rare anatomic variant of a complete mirror-image transposition of the thoracic and abdominal viscera. The performance of a pancreaticoduodenectomy and distal pancreatectomy in patients with situs inversus totalis is both rare and challenging. We herein present two cases of pancreatic cancer with situs inversus totalis. The abdominal anatomy was preoperatively assessed by multidetectorrow computed tomography, three-dimensional reconstruction, and angiography. We herein report that a pancreaticoduodenectomy and distal pancreatectomy with standard regional lymphadenectomy are feasible in patients with situs inversus totalis. Due to the transposition of the viscera and major blood vessels in such cases, preoperative knowledge of the exact anatomy, mapping of anomalies, and meticulous forward planning are essential for performing these technically difficult and complex hepatobiliary-pancreatic surgeries.

[Therapeutic results of hepatic resection using thermal ablation for unresectable colorectal liver metastases].

We have retrospectively reviewed the therapeutic results of hepatic resection with or without thermal ablation therapy (TA) for colorectal liver metastases in 138 patients between 1994 and 2006. A total of 88 unresectable liver metastatic lesions were selectively treated with TA as initial treatment (42 patients) basically in combination with hepatectomy. Overall, TA achieved a high local tumor control rate of 94.3%. Multivariate analysis revealed that initial TA therapy was not a significantly predictive factor of hepatic recurrence or any recurrence. TA therapies in combination with hepatectomy may offer improving resectability without risk to intrahepatic dissemination or to extrahepatic recurrence.

[A case of intraluminal/external irradiation, chemotherapy and T-tube stent treatment for the local recurrence of the postoperative four-year bile duct cancer].

The patient was a 73-year-old man. In 2001, PPPD was performed. After confirmation of an expanded intrahepatic bile duct and anastomic stenosis in July 2005, PTBD was performed into the B3. Adenocarcinoma was detected with bile cytodiagnosis, and was diagnosed as a recurrence of the left bile-duct anastomotic site. Under the informed consent, chemo-radiotherapy was performed in addition to beam radiotherapy (30 Gy) in September 2005. Then we performed an intracavitary irradiation at 25 Gy. UFT (200 mg) was administered along with the radiation therapies. After that, an internal fistularization due to the T-tube was done. Liver metastasis was confirmed by abdominal CT in 2006. We started administering of GEM (600 mg/body) every other week after the recurrence of the bile duct cancer. The patient had survived for 24 months from the recurrence. We report a good result of the recurrent bile duct cancer treated with combined modality therapy.

[A case of hepatic eosinophilic granuloma, which needs distinction with metastatic liver cancer].

A 68-year-old man was referred to our hospital because of eosinophilia in peripheral blood and pancreatic tumor on abdominal US. He was accustomed to eating the raw flesh of wild boar and keeping wild boar, and under medical treatment for Diabetes. Pancreatic tumor was diagnosed to the pancreatic ductal cancer by the imaging examination and endoscopic transpapillary brushing cytology for pancreatic duct. The diagnosis of hepatic eosinophilic granuloma was done by aspiration biopsy for hepatic multiple small nodules. Because of the strong positive finding for nematose in the assay of multi dot-ELISA for parasite, hepatic eosinophilic granuloma caused by visceral larva migrans was accidentally complicated by pancreatic cancer, and operation for the pancreatic cancer was done. To bear this disease in mind and to research his life history, is important to diagnose hepatic multiple nodules with eosinophilia.