Takehiro Kukitsu

Primary intestinal lymphangiectasia successfully treated with octreotide

Abstract: A 21-year-old man with diarrhea and edema was admitted to our hospital and diagnosed with protein-losing enteropathy caused by primary intestinal lymphangiectasia. He was placed, in turn, on a low-fat diet, an elemental diet, and, subsequently, fasting therapy with total parenteral nutrition (TPN) support. However, his symptoms were not relieved, but, rather were exacerbated. On the 45th day of hospitalization, octreotide therapy was initiated. After 2 weeks of treatment, his clinical symptoms, as well as hypoproteinemia and hypoalbuminemia, gradually became alleviated. The improvement was confirmed in terms of scintigraphy, endoscopy, and histology of the duodenum. The patient remained healthy until 6 months after the commencement of octreotide treatment, when he discontinued octreotide at his own discretion, at which point the symptoms recurred. Resumption of the drug; however, again brought about remission, which has continued until the present, March 2000. Thus, octreotide therapy is one modality which may be useful for refractory primary intestinal lymphangiectasia.

Effect of transjugular intrahepatic portosystemic shunt formation on portal hypertensive gastropathy and gastric circulation

OBJECTIVES:The aim of this study was to investigate the effect of a transjugular intrahepatic portosystemic shunt (TIPS) on portal hypertensive gastropathy (PHG) and gastric hemodynamics.METHODS:A total of 16 patients with cirrhosis and portal hypertensive gastropathy were prospectively studied. Of these, 12 patients underwent TIPS for esophageal varices and four for refractory ascites. Gastric mucosal blood flow (GMBF) was assessed by laser Doppler flowmeter, and total blood flow (TBF) in submucosa and mucosa by near-infrared endoscopy. Portal venous pressure was obtained by a transducer during the TIPS procedure. The severity of portal hypertensive gastropathy was classified as none, mild, or severe. The examinations were performed before and 2 wk after the procedure.RESULTS:TIPS significantly reduced portal venous pressure. PHG improved in all four patients with severe PHG and in five of 12 patients with mild PHG after treatment. Gastric mucosal blood flow increased from 49.0 to 55.6 ml/min/100 g after TIPS. In contrast, TBF decreased from 0.35/s to 0.27/s after treatment. Liver function tests showed no significant changes before and after the procedure.CONCLUSIONS:It is considered that TIPS may have a beneficial effect on PHG at least for a short time. The mechanism by which PHG improves may be closely related to the improvement of the injured gastric perfusion in cirrhotic patients with PHG.

Aberrant Crypt Foci as Precursors of the Dysplasia-Carcinoma Sequence in Patients with Ulcerative Colitis

Purpose: Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. Experimental Design: ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro–synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. Results: ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. Conclusions: We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.

Aberrant Crypt Foci: Detection, Gene Abnormalities, and Clinical Usefulness

Human aberrant crypt foci (ACF) were first identified as lesions consisting of large thick crypts in colonic mucosa of surgical specimens after staining with methylene blue. Previously we succeeded in identifying ACF by using magnifying endoscopy and analyzed the number, size, and dysplastic features of ACF in normal controls and patients with adenoma or cancer patients. On the basis of these analyses, we strongly suggested that ACF, particularly dysplastic ACF, are precursor lesions of the adenoma-carcinoma sequence in humans. In most sporadic ACF, K-ras mutations were positive, but APC mutations were negative irrespective of nondysplastic or dysplastic features. Conversely, in most ACF from familial adenomatous polyposis patients, APC mutations were positive but K-ras mutations were negative. These results may suggest that the molecular mechanism of sporadic colon carcinogenesis is not necessarily the same as that of familial adenomatous polyposis. It was shown that ACF acquired resistance to apoptosis induced by bile salts, whereas normal colonic epithelial cells are turning over consistently by apoptosis. This apoptosis resistance was closely associated with glutathione S-transferase P1-1 expression. One of the most important clinical applications of ACF observation with magnifying endoscopy is its use as a target lesion for chemoprevention. Because ACF are tiny lesions, they should be eradicated during a short time by administration of chemopreventive agents. In fact, we performed an open chemopreventive trial of sulindac and found that the number of ACF was reduced markedly in 2 months. We currently are proceeding with a randomized double-blind trial targeting ACF.

Chemoprevention of colorectal cancer

Colorectal cancer is a disease with a high mortality rate and it has been increasing in prevalence worldwide. Chemoprevention, as well as primary and secondary prevention, for colorectal cancer have attracted much attention. Many chemopreventive trials have been performed, and several agents, including nonsteroidal antiinflammatory drugs, such as aspirin and sulindac, cyclooxygenase-2 selective inhibitors, such as celecoxib, vitamin D, folate, and calcium, have been shown to have some effect. In these chemopreventive trials, the targeted lesions used for evaluation were mainly polyps. However, the chemopreventive effects of some agents on polyps may require several years to evaluate. Further, larger polyps may not be susceptible to chemopreventive agents. Aberrant crypt foci (ACF) are tiny lesions at the earliest stage of colorectal carcinogenesis, which consist of large, thick crypts identified by dense, methylene blue staining. We succeeded in identifying human ACF in situ using magnifying endoscopy and found that the number of ACF, particularly dysplastic ACF, increased significantly from normal subjects to adenoma patients and then to cancer patients. We also found that the number, size, and dysplastic features of ACF are significantly correlated with the number of adenomas in adenoma patients. Thus, it was surmised that ACF are precursor lesions of the adenoma-carcinoma sequence in humans and that ACF may be the most appropriate lesions as targets for chemoprevention. We have shown that the number of ACF was significantly reduced in patients treated with sulindac. We are currently proceeding with a randomized, double-blind, chemopreventive trial targeting ACF.

A case of successful management of portosystemic shunt with autosomal dominant polycystic kidney disease by balloon-occluded retrograde transvenous obliteration and partial splenic embolization.

We describe a patient with autosomal dominant polycystic kidney disease who was successfully managed for severe abdominal distension, impaired liver function and a portosystemic shunt by interventional therapies. The patients intra-hepatic portal vein was compressed and narrowed by multiple liver cysts, which resulted in a decrease of the portal blood flow and portal hypertension due to a huge gastro-renal shunt These haemodynamic changes were assumed to contribute to insufficient protein synthesis in the liver. Therefore, we first repeatedly performed minocycline hydrochloride instillations to treat the multiple liver cysts. Then, we conducted a partial splenic embolization to prevent elevation of the portal vein pressure prior to balloon-occluded retrograde transvenous obliteration which was performed to increase the portal blood flow. The portal blood flow markedly increased, and protein synthesis in the liver also recovered and the clinical symptoms improved. The patient has been monitored for more than two years up to the present and her liver function parameters have remained within the normal range. Renal insufficiency is known to be a major prognostic factor in autosomal dominant polycystic kidney disease. In some cases, however, liver involvement with multiple cysts may result in a fatal outcome. In such cases, interventional therapies, as provided to this patient, should be considered.

Re: Spontaneous rupture of renal metastasis of hepatocellular carcinoma: management by emergency transcatheter arterial embolization.

Spontaneous rupture of a primary lesion in hepatocellular carcinoma (HCC) is not unusual, and may be one of the defining factors in the prognosis [1]. However, rupture of an HCC metastatic lesion is very rare [2–4]. There are no reports in the literature describing cases with ruptured renal HCC metastasis. We report a case of massive retroperitoneal hemorrhage from the site of a right renal HCC metastasis. The bleeding was successfully controlled by transcatheter arterial embolization (TAE). In August 1997 a 67-year-old man with liver cirrhosis associated with hepatitis C virus had undergone TAE for an HCC in S1 measuring 3.5 3.8 cm. Following the first treatment, repeat TAE therapy was performed three times for recurrent HCC in S1. In December 1998, a chest X-ray showed lung metastasis in the right middle lobe, for which 48 Gy radiotherapy was performed. In January 1999, he was readmitted to our hospital with a chief complaint of severe headache. Brain computed tomography (CT) revealed a tumor in the left occipital lobe, suggesting HCC metastasis. He underwent surgery on the 4th hospital day. Histological examination of the tumor showed poorly differentiated HCC. He had no headache after the operation and was then discharged on the 15th hospital day. In March 1999, CT scan revealed new lesions in the bilateral kidney (Fig. 1A) and the left lung, suggesting HCC metastases. We decided that further treatment would be futile, so we followed him conservatively. On April 16, 1999, he was brought to our hospital by ambulance, presenting with right flank pain and hypovolemic shock. Abdominal CT scan showed a retroperitoneal hematoma in contact with the right kidney which was displaced ventrally (Fig. 1B). Enhancement with contrast material was seen in the hematoma, suggesting persistent bleeding. Three hours after the admission, emergency angiography was performed. A selective right renal arteriogram showed tortuous arteries and a 2-cm tumor at the lower pole of the right kidney (Fig. 2A), where extravasation of contrast material was observed. This suggested a tumor rupture causing continued bleeding. In order to achieve hemostasis, TAE was performed using Gelform and coils. A right renal arteriogram after TAE showed occlusion of the feeding artery to the tumor and preservation of normal renal parenchyma (Fig. 2B). Subsequently, his blood pressure stabilized and his general condition improved. Three months after TAE the patient died from recurrence of brain metastasis. Tumor rupture, however, never recurred. At autopsy we discovered HCC in the liver, bilateral lung, right parietal pleura, brain, spleen, and left kidney. The liver showed macronodular cirrhosis and a 3-cm diameter lesion of poorly differentiated HCC, exposed to the inferior vena cava, in S1 with necrotic tissue due to treatment. The tumor of the right kidney was thoroughly necrotic. All tumor cells found at autopsy had the same histological appearance as the primary tumor. Renal metastasis of HCC is often observed at autopsy, but it is rarely clinically diagnosed. Nakashima et al. [5] reported that extrahepatic metastasis was found in 144 (64%) of 225 autopsies in patients with HCC and renal metastasis in five (2.2%). Systemic metastasis was observed in our patient, probably because the HCC was exposed to the inferior vena cava and consisted of poorly differentiated cells, although primary HCC was localized in S1. Spontaneous rupture of primary HCC into the peritoneal cavity is reported to occur in 10% of cases [1]. In contrast, spontaneous rupture of metastatic lesions is very rare but has been previously reported in the lung, rib, spleen, pleura, and peritoneum [2–4]. All of these reported cases were treated conservatively and the patient died of hemorrhagic shock or hepatic failure. It is thought that massive hemorrhage may become one of the causes of hepatic failure in cirrhotic patients with ruptured HCC, who often have limited hepatic reserve for ischemia. An early diagnosis of the rupture site is required. In our case, dynamic CT scan showed the presence of the hematoma and active bleeding and was useful for an early diagnosis. Control of bleeding from a ruptured HCC is often difficult. Recently, several reports have described the usefulness of TAE, tolerable for patients with severe liver dysfunction in contrast to surgery, for the management of spontaneous rupture of primary HCC [6]. TAE is effective in achieving immediate hemostasis in almost all patients. Its immediate mortality rate is far less than that of surgery. As to the kidney, there have been many reports on the effectiveness of TAE for rupture of renal angiomyolipoma [7]. TAE is a minimally invasive therapy and can preserve the normal renal parenchyma by selective embolization of the feeding artery to the tumor. In conclusion, selective arterial embolization is an effective and safe procedure to manage tumor rupture. It is thought that TAE may be appropriate therapy even for ruptured renal HCC metastasis.

Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial.

BACKGROUND AND STUDY AIMS Endoscopic bile duct stone (BDS) removal is a well-established treatment; however, the preference for basket or balloon catheters for extraction is operator-dependent. We therefore conducted a multicenter prospective randomized trial to compare catheter performance. PATIENTS AND METHODS We enrolled patients with a BDS diameter ≤ 10 mm and common bile duct diameter ≤ 15 mm. Participants were randomly assigned to groups that were treated with basket or balloon catheters between October 2013 and September 2014. The primary endpoint was the rate of complete clearance of the duct; the secondary endpoints were the rate and time to complete clearance in one endoscopic session. RESULTS We initially enrolled 172 consecutive patients; 14 were excluded after randomization. The complete clearance rates were 92.3 % (72/78) in the balloon group and 80.0 % (64 /80) in the basket group. The difference in the rates between the two groups was 12.3 percentage points, indicating non-inferiority of the balloon method (non-inferiority limit -10 %; P < 0.001 for non-inferiority). Moreover, the balloon was superior to the basket (P = 0.037). The rate of complete clearance in one endoscopic session was 97.4 % using the balloon and 97.5 % using the basket (P = 1.00). The median times to complete clearance in one endoscopic session were 6.0 minutes (1 - 30) and 7.8 minutes (1 - 37) in the balloon and basket groups, respectively (P = 0.15). CONCLUSIONS For extraction of BDSs ≤ 10 mm, complete endoscopic treatment with a single catheter is more likely when choosing a balloon catheter over a basket catheter.University Hospital Medical Information Network Trials Registry: UMIN000011887.

Efficacy and Feasibility of Combination Chemotherapy with S-1 and Cisplatin (2 Weeks Regimen) for Advanced Gastric Cancer

OBJECTIVE Although combination chemotherapy with 3 weeks of S-1 and cisplatin is effective for advanced gastric cancer, the toxicities of S-1 which mostly occur during the third week of administration are a major problem. To achieve fewer adverse effects with S-1 and higher dose intensity of cisplatin, we performed combination chemotherapy with 2 weeks of S-1 and cisplatin as first line. The aim of this retrospective study was to analyse the efficacy and feasibility of this regimen. METHODS S-1 (40-60 mg depending on patients body surface area) was given orally twice daily for 2 consecutive weeks, and 70 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period. RESULTS Forty-eight patients received a total of 184 courses of chemotherapy. Overall response rate was 40.6% and median survival time was 411 days. Dose intensities were 257.6 mg/m(2)/week for S-1 and 16.4 mg/m(2)/week for cisplatin. The incidences of grade 3/4 haematological toxicities were leucopenia (19%), neutropenia (29%) and anaemia (17%), and those of grade 3 non-haematological toxicities were anorexia (31%) and nausea (21%). The rate of treatment discontinuation owing to toxicity was 10%. CONCLUSIONS This regimen may be effective as an alternative therapy to 3 weeks of S-1 and cisplatin to reduce the toxicity of chemotherapy for advanced gastric cancer.

Reply to Kadayifci et al.

We appreciate the comments made by Dr. Kadayifci regarding our study inwhich we concluded that complete endoscopic treatment with a single catheter is more likely when choosing a balloon catheter over a basket catheter for the extraction of bile duct stones ≤10mm [1]. In the basket group, the basket catheter was switched to a balloon catheter when the endoscopist had judged the duct clearance to be complete by the basket catheter. First, the balloon was inflated at the perihilar bile duct and pulled to the bottom of the bile duct, and then balloon-occluded cholangiography (BOC) was performed. During this procedure, if a stone emerged from the papilla of Vater, this was judged to be “incomplete clearance.” In addition, when a defect on BOC was confirmed to be a stone by subsequent endoscopic observation, the outcome was also judged to be “incomplete clearance.” Therefore, “residual stones on BOC (n=9)” were confirmed during this procedure. These failure cases meant that duct clearance had not been completed by basket catheter alone. “Complete clearance by the assigned catheter” in the basket group represented the result obtained by the basket catheter alone, not by the basket catheter plus the balloon catheter. Therefore, we think that using the balloon after the basket for stone extraction was not a confounding factor of our study. As mentioned by Dr. Kadayifci, it is sometimes difficult to check stone removal by direct endoscopic observation after balloon sweep of the duct. Therefore, the performance of the balloon catheter may be overestimated. The actual success rate of each catheter might be lower than the rates determined in our study because BOC and balloon sweep were used to confirm duct clearance in both groups. For true comparison of the two catheters, other modalities, such as peroral cholangioscopy, should be used to evaluate the efficacy of individual catheters. However, it was not realistic to use cholangioscopy to evaluate residual stones in our study because participants included patients with normal common bile ducts, with diameters ≤8mm in general. In addition, evaluating the end point by the same method in both groups is crucial in a randomized controlled trial. When considering clinical trial feasibility, BOC was selected to evaluate the end point in both groups to minimize the methodological bias. However, we identified this issue as a limitation of our study.