Efficacy and Safety of Lenvatinib for Patients With Advanced Hepatocellular Carcinoma: A Retrospective, Real-world Study Conducted in Japan.

AIM: We evaluated real-world efficacy and toxicity of lenvatinib in 142 patients with advanced hepatocellular carcinoma (HCC) at six tertiary referral centres. PATIENTS AND METHODS: The patients with advanced HCC treated with lenvatinib were grouped into two categories based on REFLECT criteria for analysis of efficacy and safety. The primary endpoint was progression-free survival (PFS). RESULTS: The objective response rate (ORR) at week 12 of therapy was 41.5%, with a median PFS of 176 days. Child-Pugh score of 5 points, the presence of extrahepatic metastasis and adverse effects grade 2 or higher were considered independent factors associated with both better PFS and ORR. The ORR for patients who fulfilled the REFLECT inclusion criteria was significantly higher than that for those who did not. However, no significant differences in PFS were observed between the two groups. The incidence rate of adverse effects grade 3 or higher was 40.1%, which was similar for the two groups. CONCLUSION: Lenvatinib is safe and effective for patients, whether or not they satisfy REFLECT criteria. The result warrants replication in a larger study.

A Case of Pathological Complete Response Following FOLFIRINOX Therapy for Pancreatic Adenocarcinoma with Synchronous Distant Lymph Node Metastases.

INTRODUCTION: We report a case of conversion surgery for pancreatic ductal adenocarcinoma (PDAC) with synchronous distant metastases showing pathological complete response (pCR) after FOLFIRINOX therapy. PRESENTATION OF CASE: A 46-year-old woman with obstructive jaundice was referred to our hospital. A CT scan revealed a hypo-vascular mass in the head of the pancreas with multiple para-aortic lymph nodes and a Virchow's node swollen. The serum CA 19-9 level was 71795.1 U/mL. The result of tumor biopsy from the biliary stenotic site was concordant with adenocarcinoma. She was diagnosed with PDAC with distant metastases. After 10 courses of FOLFIRINOX followed by 4 courses of FOLFIRI, a CT scan showed that distant lymph node swellings disappeared, and CA19-9 level became almost normal. She underwent pancreaticoduodenectomy with dissection of para-aortic lymph nodes 8 months after the initiation of chemotherapy. Pathologically, no evidence of residual adenocarcinoma was observed in neither pancreas nor lymph nodes. Adjuvant chemotherapy using S-1 was administered for 6 months, and no recurrence has been observed 4 years after surgery. BRCA1/2 mutations were not detected in patient's DNA. DISCUSSION: With the induction of intensive chemotherapies such as FOLFIRINOX, an increasing number of patients with synchronous distant metastases could become suitable candidates for surgery of the primary lesion because of the potential complete response of metastatic lesions. CONCLUSION: This case presented a rare occurrence of pCR in a patient with unresectable PDAC with distant metastases who received FOLFIRINOX. The feasibility and benefits of conversion surgery in such patients must be investigated in future trials.

Isolated myeloid sarcoma presenting with small bowel obstruction: a case report.

BACKGROUND: Myeloid sarcoma (MS) is a solid tumor consisting of myeloid blasts or immature myeloid cells, which are unusual outside the bone marrow. CASE PRESENTATION: We present a rare case of isolated myeloid sarcoma of the small bowel in a 54-year-old man who was admitted to our hospital with repeated symptoms of intestinal obstruction. A small bowel series via an ileus tube revealed severe jejunal obstruction. Computed tomography revealed that the obstruction was likely caused by a jejunal tumor. The patient underwent laparoscopy-assisted partial resection of the jejunum with lymphadenectomy. Histopathological examination of the surgical specimen confirmed that MS had been responsible for the obstruction. CONCLUSIONS: Patients with MS require systemic chemotherapy, as do patients with acute myeloid leukemia. Hence, an early, accurate diagnosis is imperative for treating this malignancy. It is also important to list MS in the differential diagnosis of a small bowel tumor, even in nonleukemic patients.

[A Resected Case of Angiomyolipoma Difficult to Be Distinguished from Hepatocellular Carcinoma].

A 42-year-old man complaining of left back pain was admitted to our hospital. The hepatis B and C surface antigens were negative. The serum levels of tumor markers were within the reference ranges. Abdominal ultrasound revealed an 8 cm-sized, primarily round and hyperechoic mass in the left lateral segment. Contrast-echo showed non-uniform enhancement in the arterial phase and uniform enhancement in the portal phase. This mass did not indicate"wash-out"on contrast- enhanced CT. It showed hypointensity in the hepatobiliary phase on MRI. The definitive diagnosis could not be obtained, and the patient was suspected with malignancy, such as hepatocellular carcinoma(HCC). Therefore, left hemi-hepatectomy was performed for the diagnostic treatment. Based on the immunochemical staining results, he was diagnosed with angiomyolipoma( AML). AML is composed of fat, blood vessels, and smooth muscles. It is regarded as a tumor of perivascular epithelioid cell tumor(PEComa). Early venous return and adipose tissues in the tumor were the distinctive features of this tumor. The preoperative diagnosis of AML without any fatty component as in this case is very difficult.

[A Case of Resected Peritoneal Metastasis from Hepatocellular Carcinoma after Surgery].

A 69-year-old woman with a hepatocellular carcinoma(HCC)was followed-up for type B chronic hepatitis and underwent partial hepatectomy(S6)at our hospital. Afterwards, she underwent radiofrequency ablation(RFA)therapy twice because of intrahepatic recurrence. Seven months after the first hepatectomy, a left adrenalectomy was performed for a left adrenal metastasis. Seventeen months after the first hepatectomy, a splenectomy was performed for a splenic metastasis. Forty-three months after the first hepatectomy, a second hepatectomy was performed for intrahepatic recurrence, and a right adrenalectomy was performed for an adrenal metastasis. Sixty-eight months after the first hepatectomy, an abdominal CT revealed a growing solitary lesion in the ascending colon, which was diagnosed as a peritoneal metastasis. The peritoneal dissemination was removed because there were no other extrahepatic or intrahepatic recurrences. Histologically, the resected specimen was diagnosed as a peritoneal metastasis from a HCC. The patient survived, and there were no recurrences for 6 months after the operation. We report this case of a peritoneal metastasis from a HCC after surgery with a review of the literature.

Solid pseudopapillary neoplasm of the pancreas showing marked distal atrophy: A case report.

INTRODUCTION: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm, affecting primarily young females. Because SPNs are of low-malignancy, they rarely obstruct the main pancreatic duct (MPD) and cause atrophy of the distal pancreas even if their tumor sizes are large. PRESENTATION OF CASE: A 35-year-old female was referred to our hospital due to pancreatic tumor. Imaging findings showed the presence of well-defined round tumor in the body of the pancreas with 25-mm in diameter. The pancreas parenchyma distal to the tumor was markedly atrophic, and MPD dilatation was not observed. The lesion was diagnosed as SPN by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), and central pancreatectomy was performed. Intraoperative frozen section of the distal atrophic pancreas showed no evidence of acinar cells, indicating exocrine dysfunction. Therefore, we closed distal pancreas stump instead of reconstruction. In the distal atrophic parenchyma, scattered foci of islets of Langerhans and the vestige of dilated MPD were observed. She has shown neither endocrine nor exocrine insufficiency after surgery. DISCUSSION: SPNs are usually found without atrophic change of distal pancreas. To the best of our knowledge, this is the first report of SPN in which exocrine dysfunction of atrophic pancreas was demonstrated pathologically and central pancreatectomy without anastomosis of distal pancreas was chosen for the surgical treatment. CONCLUSION: We reported a very rare case of SPN with marked distal parenchymal atrophy. We successfully performed central pancreatectomy without reconstruction.

Radiofrequency Ablation Guided by Contrast-Enhanced Sonography versus B-Mode Sonography for Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization.

PURPOSE: Contrast-enhanced sonography increases negative enhancement in the Kupffer phase after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We compared contrast-enhanced sonography with B-mode sonography for guidance of radiofrequency ablation (RFA) of HCC after TACE. METHODS: After TACE was performed, 18 nodules in 12 patients were treated by B-mode sonography guided RFA, while 22 nodules in 18 patients were treated by contrast-enhanced sonography-guided RFA. RESULTS: The success rate of initial RFA was 83.3% (15/18 nodules) in the B-mode sonography group. On the other hand, the success rate was 100% (22/22 nodules) in the contrast-enhanced sonography group and the difference was significant (p = 0.046). CONCLUSION: These findings suggest that RFA guided by Kupffer phase contrast-enhanced sonography after TACE is a promising therapeutic option for curing HCC.

Primary diffuse large B cell lymphoma of the common bile duct causing obstructive jaundice.

We report a rare case of a diffuse large B-cell lymphoma (DLBCL) arising from the common bile duct (CBD). A 77-year old man presented with general fatigue and obstructive jaundice. Abdominal computed tomography revealed a well-circumscribed enhancing mass in the midportion of the CBD with proximal bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) also showed a midportion of the CBD stricture. Direct peroral cholangioscopy revealed smooth mass in the midportion of the CBD, and narrow-band imaging (NBI) showed irregular tortuous microvessels. The brushing cytology of the CBD was performed, and it was diagnosed as suspicious for poorly differentiated adenocarcinoma or malignant lymphoma. We performed extrahepatic bile duct resection for accurate diagnosis. Histological and immunohistochemical examination of the resected specimen revealed DLBCL. Although systemic chemotherapy is the mainstay of treatment for DLBCL, he refused scheduled subsequent chemotherapy, and died of multiple liver metastases 6 months after surgery.

Hepatic metastasis from bile duct cancer of the ampulla is effectively controlled by multidisciplinary treatment including S-1, gemcitabine and bevacizumab: A case report.

The liver is the most common site for recurrent metastases from bile duct cancer (BDC) in the ampullary area. However, the optimal chemotherapy regimen for recurrent hepatic metastases has not yet been established. An oral combined fluoropyrimidine drug, S-1 (tegafur, gimeracil and oteracil), has recently been introduced alone or in combination with gemcitabine for BDC. A 67-year-old man underwent a pancreaticoduodenectomy (PD) for early stage distal BDC in the ampullary area. A small hepatic metastasis developed 8 months after the PD. Combined chemotherapy of S-1 (80 mg/m(2)) and gemcitabine (1000 mg/m(2)) was started after radiofrequency ablation (RFA) of the hepatic tumor. Although complete response was achieved and maintained for 4 months with chemotherapy, there was regrowth of the tumor. We performed hepatic segmentectomy for radical treatment. Fourteen months after the hepatectomy, metastasis developed again in the remnant liver. Bevacizumab was added to the combination chemotherapy with S-1 and gemcitabine, since the cancer seemed resistant to the chemotherapy alone. The patient has been well managed for 3 years by a multidisciplinary treatment with surgery, RFA and the combination chemo-therapy on an outpatient basis. This case indicates that distal BDC even in an early stage has a more malignant potential than anticipated. The multidisciplinary treatment including surgery, RFA and combination chemotherapy of S-1, gemcitabine and bevacizumab was effective for BDC with hepatic metastasis. This chemotherapy is feasible on an outpatient basis and may be one of the treatment options for metastatic BDC.

Tumor markers after radiofrequency ablation therapy for hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study was to evaluate the clinical value of measurement of the AFP-L3 fraction before and after radiofrequency ablation (RFA) therapy for HCC, compared with the measurement of total AFP and des-gamma-carboxy prothrombin (DCP). METHODOLOGY: One hundred and twenty-four patients with HCCs were evaluated for their complete response with a 5-mm-thick safety margin around the tumor. Three tumor markers (AFP, DCP, AFP-L3) were measured after RFA therapy, and their clinical significance was studied. RESULTS: Multivariate analysis revealed that of the three tumor makers only AFP-L3 showed significant differences in the survival and disease-free rates. CONCLUSIONS: AFP-L3 is the most reliable tumor marker for estimating overall survival and disease-free survival in patients with HCC effectively treated by RFA in contrast to AFP and DCP.

Radiofrequency ablation combined with reduction of hepatic blood flow: effect of Lipiodol on coagulation diameter and ablation time in normal pig liver.

BACKGROUND/AIMS: We evaluated the effectiveness of radiofrequency (RF) ablation combined with transarterial embolization using Lipiodol and gelatin sponge. METHODOLOGY: A total of 18 normal pig liver lobes were randomly assigned to the following three different RF ablation groups, 1) combined with TAE using Lipiodol and gelatin sponge as "LpTAE group"; 2) combined with TAE using gelatin sponge only as "TAE group"; 3) ablation alone as "control group". Ablations were performed under open laparotomy using an RF generator and a 2-cm expandable needle. The diameter of coagulation and the ablation time were compared among the three groups. RESULTS: The characteristic shape of coagulated area differed among the three groups. The long-axis diameter showed no significant difference among the three groups (27.5mm, 27.5mm, 26.7mm; respectively), while the short-axis diameter was significantly larger in the LpTAE group compared with the control groups (25.2mm vs. 20.5mm; p < 0.05). The total ablation time was significantly shorter in the LpTAE and TAE groups compared with the control group (166, 204 seconds vs. 309 seconds; p = 0.001, p = 0.01). CONCLUSIONS: RF ablation combined with LpTAE produced larger and more spherical areas of coagulation in a shorter ablation time. Such an advantage could potentially enhance the clinical effectiveness of RF ablation.

Diagnosis of gallbladder diseases by contrast-enhanced phase-inversion harmonic ultrasonography.

We evaluated the usefulness of contrast-enhanced ultrasonography(US) for detecting and differentiating gallbladder lesions. Contrast-enhanced coded phase-inversion harmonic US was performed on 90 patients with gallbladder abnormalities. After administering Levovist, we observed the gallbladders in real time. Contrast-enhanced coded phase-inversion harmonic ultrasonography was compared with B-mode US and contrast-enhanced computer tomography (CT) with regard to the sensitivity and specificity in depicting the elevated gallbladder lesions. Furthermore, we assessed how the vascular patterns of the elevated gallbladder lesions depicted by contrast-enhanced US correlated with the diagnosis. Contrast-enhanced US efficiently discriminated true lesions from biliary sludge, unlike B-mode US. Consequently, contrast-enhanced US was more specific (100%) than B-mode US (81%), although their sensitivities were similar (98% and 96%, respectively). Contrast-enhanced US was also more sensitive that contrast-enhanced CT (98% versus 79%), although the two methods were equally sensitive (100% versus 95%). We classified the vascular patterns of the abnormalities depicted by contrast-enhanced US in the 90 cases into types 1 to 4, which represent branch-like, heterogeneous, homogeneous, and avascular patterns, respectively. All type 1 and 2 lesions were over 10 mm in size while most (88%) type 3 lesions were 10 mm or less in size. While the majority of carcinomas (86%) were type 1 or 2, three benign lesions also showed these patterns. Thus, the vascular pattern may simply reflect the size of the lesion and therefore its usefulness in diagnosing gallbladder lesions may be limited. Nevertheless, contrast-enhanced US is clearly superior to the other techniques in discriminating biliary sludge from other lesions.

Contrast harmonic sonography-guided radiofrequency ablation therapy versus B-mode sonography in hepatocellular carcinoma: prospective randomized controlled trial.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of contrast harmonic sonographic guidance in radiofrequency ablation of locally progressive hepatocellular carcinoma poorly depicted with B-mode sonography. SUBJECTS AND METHODS: A series of 40 patients with hepatocellular carcinoma with local tumor progression poorly depicted with B-mode sonography were randomly treated with radiofrequency ablation guided by either contrast harmonic sonography (n = 20) or conventional B-mode sonography (n = 20). Unpaired Student's t tests were performed to compare numbers of treatment sessions. RESULTS: Treatment analysis showed that the complete ablation rate after a single treatment session was significantly higher in the contrast harmonic sonography group than in the B-mode sonography group (94.7% vs 65.0%; p = 0.043) and that the number of treatment sessions was significantly lower in the contrast harmonic sonography group (mean, 1.1 +/- 0.2 vs 1.4 +/- 0.6; p =0.037). CONCLUSION: Contrast harmonic sonography-guided radiofrequency ablation is an efficient technique for guiding further ablation of local tumor progression not clearly demarcated with B-mode sonography.

Treatment of large and/or multiple hepatic malignancies: open surgical approaches of radiofrequency ablation.

BACKGROUND/AIMS: Patients with hepatic malignancies are often poor candidates for resection because of the lack of hepatic reserve as a result of coexisting cirrhosis or the presence of multiple tumors. The purpose of this study was to determine the safety and efficacy of open intraoperative radiofrequency ablation of unresectable hepatic malignancies with size larger than 4 cm in diameter and/or more than three in number. METHODOLOGY: Between May 2000 and September 2003, 30 patients (24 men, 6 women; age range, 59-72 years; mean age, 63 years) with 51 hepatic malignancies. The maximal diameter of all tumors ranged from 1.0 to 10cm (mean +/- SD, 3.2 +/- 1.8). RESULTS: All tumors achieved necrosis completely in a single session. The mean follow-up from the initial ablation in this study was 18.9 +/- 10.1 months (range, 0-41). The 1-, 2 and 3-year overall survival rates were 86.1%, 71.6% and 71.6%, respectively. The 1-, 2 and 3-year disease-free survival rates were 70.9%, 37.6% and 25.1%, respectively. CONCLUSIONS: Open radiofrequency ablation is a safety and efficient approach for hepatic malignancies sized more than 4 cm in diameter and/or located more than three in number.

Serum proinflammatory cytokines and adhesion molecules in ulcerative colitis.

BACKGROUND/AIMS: The aim of this study was to define the correlation between serum markers, such as proinflammatory cytokines and adhesion molecules, and disease activity in ulcerative colitis (UC). METHODOLOGY: Nineteen patients with UC treated in our hospital from April 2003 to June 2004, were enrolled into this study. We measured serum interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule (VCAM-1) from a blood sample. We investigated the correlation between these cytokine molecules and clinical activity. RESULTS: Serum levels of IL-6 after treatment were significantly decreased proportionately as disease activity improved. Serum levels of IL-8 also significantly correlated with disease activity. On the other hand, serum levels of TNF-alpha were within the normal range in most of cases despite being in the active phase. There were also no significant differences between before and after treatment in serum levels of ICAM-1 or VCAM-1. CONCLUSIONS: Serum IL-6 and IL-8 significantly reflected disease activity in patients with UC.

Prognostic factors for portal venous invasion in patients with hepatocellular carcinoma.

BACKGROUND: Factors involved in portal venous invasion (PVI) must be clarified to enable better determination of therapeutic strategies and outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Of 365 patients with HCC who consulted our department between January 1999 and January 2003, 53 with PVI at the initial consultation were excluded, and the other 312 without PVI were included in this study. Of these patients, we compared liver function, tumor markers, and initial treatment between 287 patients without PVI during follow-up (until December 2004) and 25 patients who developed PVI, and investigated prognostic factors. RESULTS: Multivariate analysis using a COX regression model showed that a Lens culinaris A-reactive fraction of alpha-fetoprotein (AFP-L3) rate of 15% or more, a des-gamma-carboxy prothrombin (DCP) level of 100 mAU/ml or more, multiple tumors, and a platelet count of 130 000/mm(3) or more were correlated with PVI. CONCLUSIONS: HCC frequently infiltrated the portal vein in patients with a high rate of AFP-L3, a high level of DCP, or multiple tumors. Furthermore, the incidence of PVI was significantly higher in patients with a platelet count of 130 000/mm(3) or more.

Differential diagnosis of nodular lesions in cirrhotic liver by post-vascular phase contrast-enhanced US with Levovist: comparison with superparamagnetic iron oxide magnetic resonance images.

BACKGROUND: We investigated the diagnostic utility of post-vascular phase contrast-enhanced ultrasonography (US) and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) as compared to the histological diagnosis of differential grades of hepatocellular carcinomas (HCCs). METHODS: Forty-nine patients with histologically characterized liver nodules (well-differentiated HCC, n = 20; moderately differentiated HCC, n = 19; poorly differentiated HCC, n = 1; dysplastic nodule, n = 9) received contrast-enhanced US and SPIO-MRI. Subsequently, we quantitatively evaluated the relationships between the images of the nodules and their histological diagnosis and differential grades. RESULTS: The ratio of the echogenicity of the tumorous area to that of the nontumorous area with post-vascular phase contrast-enhanced US (post-vascular phase ratio) decreased as nodules became less differentiated (P < 0.05; Kruskal-Wallis test). The ratio of the intensity of the nontumorous area to that of the tumorous area on SPIO-enhanced MR images (SPIO intensity index) also decreased as nodules became less differentiated (P < 0.01). The post-vascular phase ratio correlated with the SPIO intensity index for HCCs and dysplastic nodules (r = 0.76). The conformity of the result from the post-vascular phase contrast-enhanced US and SPIO-MRI was 96%. CONCLUSIONS: Contrast-enhanced US is a valuable method for predicting the histological grade of HCCs in cirrhotic patients, and may be a good alternative to SPIO-enhanced MRI.

Low-dose, long-term, intermittent interferon-alpha-2b therapy after radical treatment by radiofrequency ablation delays clinical recurrence in patients with hepatitis C virus-related hepatocellular carcinoma.

OBJECTIVE: To assess whether or not interferon (IFN) therapy prevents recurrence, and eventually improves the prognosis of patients with hepatocellular carcinoma (HCC) after completion of radical radiofrequency ablation (RFA) therapy. METHODS: Included as the IFN group in this study were 24 patients in total, who received radical RFA therapy first, followed by medication with IFN-alpha2b at such a low dose of 3 MIU x 2/week for as long as possible. On the other hand, the control group comprised 33 patients in total, who received radical RFA therapy without subsequent treatment with IFN. The control group was matched to the IFN group in age, platelet counts and size of nodules. RESULTS: Of the 24 patients treated with IFN, only one patient showed sustained virologic response. The median tumor-free period until the first recurrence after radical RFA therapy was 3.4 years in the IFN group and 1.4 years in the control group (p = 0.02). During the first 3 years after commencement of IFN administration, the cumulative recurrence rate in the IFN group was found to be lower than in the control group (p = 0.01); however, with the lapse of time over 3 years, the recurrence rate in the IFN group increased. There was no difference in the cumulative survival rates between the IFN group and the control group (p = 0.25). CONCLUSION: Subsequently after radical RFA therapy, long-term, low-dose, intermittent IFN therapy successfully delayed clinical recurrence of HCC.

Vascularity of gastric carcinoma: evaluation using color Doppler ultrasonography.

PURPOSE: The purpose of this study was to investigate the vascularity of primary gastric cancer lesions using color Doppler ultrasonography. METHODS: We used color Doppler ultrasonography to study 78 patients with gastric cancer detected on B-mode ultrasonographic examination and 14 patients without gastric tumors but with a slightly thickened gastric wall that was also detected on B-mode ultrasound. The color Doppler signals of the gastric lesions were graded as (-), no color signals; (+), slight increase in number of color signals; and (++), an obvious increase in number of color signals. The vessel area outside the tumor area in the microscopic pathological specimens was also calculated. RESULTS: The color signals of 13 (18%) of the 71 gastric cancer patients were graded (-); those of 14 (20%) patients were graded (+); and those of 44 (62%) patients were graded (++). The color signals for 9 (65%) of 14 patients without gastric tumors were graded (-); those of 4 (28%) patients were graded (+), and those of 1 patient (7%) were graded (++). These differences were significant (P = 0.0002). The vessel count ratio in the microscopic pathologic specimens was also significantly higher in patients with an increased number of color signals than in those without an increased number of color signals (P = 0.002). CONCLUSION: Color Doppler ultrasound showed increased vascularity in the gastric cancers in most of the subjects (82%, 58/71). Furthermore, color Doppler ultrasound also showed no increase in vascularity in most subjects (65%, 9/14) whose B-mode ultrasonograms showed thickened gastric walls but who did not have gastric cancer. Thus, color Doppler imaging may prove useful as a screening modality for gastric cancer.