An open-label phase I/II study of tamibarotene in patients with advanced hepatocellular carcinoma

Aim

Tamibarotene is a synthetic retinoid expected to inhibit tumor-cell proliferation and to induce apoptosis by selective interaction with retinoic acid receptor α/β. We conducted an open-label phase I/II study to determine the maximum tolerated dose (MTD) and recommended dose (RD), and to evaluate the pharmacokinetics, efficacy, and safety profiles for advanced hepatocellular carcinoma (HCC).

Methods

Patients with histologically confirmed, measurable, unresectable HCC of Child-Pugh classification A or B and with no effective systemic or local therapies were eligible. In phase I, patients were assigned based on the 3 + 3 dose escalation criteria to receive tamibarotene at 8, 12, and 16 mg/day. The RD determined in phase I was employed for phase II. The planned sample size in phase II was 25, including the RD-treated patients in phase I.

Results

Thirty-six patients were enrolled. No patients experienced dose-limiting toxicity (DLT) at 8 mg/day. However, two out of six patients experienced the DLTs at 12 mg/day: one experienced thrombosis in a limb vein and pulmonary artery, and the other experienced an increase of γ-GTP. The MTD and RD were determined as 12 and 8 mg/day, respectively. In phase II, one patient achieved partial response, and seven achieved stable disease. The disease control rate was 32 % (95 % CI: 15.0–53.5). The following drug-related serious adverse events were reported: thrombosis in a limb vein, pulmonary artery, and portal vein; interstitial lung disease; and vomiting.

Conclusions

Tamibarotene demonstrated the inhibition of tumor cell growth in advanced HCC with acceptable tolerance.     

Early venous return in hepatic angiomyolipoma due to an intratumoral structure resembling an arteriovenous fistula

Early venous return (EVR) is an important radiological feature of hepatic angiomyolipoma (HAML) that can aid in differential diagnosis, but the pathogenic mechanisms of EVR have yet to be elucidated. We present the first HAML case for which a probable mechanism for EVR is described. The patient was a 46‐year‐old woman, who had a growing 6‐cm tumor with EVR in segment 3 of the liver as revealed by dynamic contrast‐enhanced computed tomography. Left hepatic lobectomy was performed to prevent tumor rupture. Histopathological and immunohistochemical analyses of the excised tumor indicated HAML. Successive microsections of the tumor were stained with hematoxylin–eosin and Victoria blue to visualize the vascular structure within and around the tumor. These analyses led to three major findings. First, many well‐defined thick‐walled vessels, such as arteries, were found entering the tumor. Second, many thick‐walled vessels within the tumor were connected directly to thin‐walled vessels, resembling arteriovenous fistulae. Finally, thin‐walled intratumoral vessels were connected directly to the hepatic vein. These histological findings suggested that the rich arterial flow into the tumor was being rapidly drained into the hepatic vein through intratumoral arteriovenous connections. We also detected these same anomalous circulatory pathways in tissue sections from three of four additional HAML cases with EVR. Aberrant arteriovenous fistulae within the tumor may account for many cases of EVR in HAML patients.     

Isolated splenic Mycobacterium tuberculosis complex infection in an immunocompetent individual with FDG-PET positive mass

Tuberculosis, caused by Mycobacterium tuberculosis complex, is a leading cause of mortality in the world, and 15% of the patients may present with extrapulmonary diseases, including splenic lesion. However, isolated splenic infection with M. tuberculosis complex is very rare. A 19-year-old otherwise healthy woman presented with left flank pain, revealing FDG-avid nodules in the spleen. She did not have pulmonary lesions. Histopathology of splenectomized sample showed granuloma, and subsequent PCR revealed amplification of IS6110, a genetic sequence exclusively detected in M. tuberculosis complex. A wide range of differential diagnosis of isolated splenic lesion should include M. tuberculosis infection regardless of pulmonary involvement. An elective splenectomy may be mandatory in timely manner.     

Early interventional treatment with intranasal mometasone furoate in Japanese cedar/cypress pollinosis: a randomized placebo-controlled trial

BackgroundLittle is known about the safety and effectiveness of early interventional treatment (EIT) with intranasal corticosteroids for seasonal allergic rhinitis. We designed a double-blinded, randomized, placebo-controlled 12-week trial of EIT with mometasone furoate nasal spray (MFNS) for Japanese cedar/cypress pollinosis (JCCP).MethodsA total of 50 JCCP patients received MFNS (200 ^g once daily: n = 25) or placebo (n = 25) starting on February 1, 2010. Treatments continued until the end of April. The primary endpoint was the comparison of the total nasal symptom score (TNSS) between the MFNS and placebo groups. The secondary endpoints included comparisons of QOL, daytime sleepiness, nasal ECP levels, and safety.ResultsContinuous dispersion of Japanese cedar pollen began on February 22. Although the placebo group showed a significant worsening of symptoms after the start of the continuous dispersion, no worsening occurred in the MFNS group. A significant difference in the TNSS between the two groups was seen starting at 4 weeks after the treatment. Similar results were seen for QOL and sleepiness. Nasal ECP levels in March were significantly lower in the MFNS group. A total of 56% of the MFNS group progressed to a persistent allergic rhinitis state in accordance with the ARIA classification, as opposed to 84% of the placebo group. MFNS was well tolerated, and the plasma cortisol concentrations were similar between the two groups.ConclusionsEIT with MFNS for JCCP is both safe and effective. This treatment can potentially lessen symptoms and help pollinosis patients remain in the intermittent state.     

Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience

OBJECTIVE: To compare the experience and outcome in the management of hilar cholangiocarcinoma at one American and one Japanese medical center. SUMMARY BACKGROUND DATA: Controversies surround the issues of extent of resection for hilar cholangiocarcinoma and whether the histopathology of such cancers are similar between patients treated in America and in Japan. METHODS: Records were reviewed of 100 patients treated between 1980 and 1995 at the Lahey Clinic in the United States, and of 155 patients treated between 1977 and 1995 at Nagoya University Hospital in Japan. Selected pathologic slides of resected cancers were exchanged between the two institutions and reviewed for diagnostic concordance. RESULTS: In the Lahey cohort, there were 25 resections, 53 cases of surgical exploration with biliary bypass or intubation, and 22 cases of percutaneous transhepatic biliary drainage or endoscopic biliary drainage without surgery. In the Nagoya cohort, the respective figures were 122, 10, and 23. The overall 5-year survival rate of all patients treated (surgical and nonsurgical) during the study periods was 7% in the Lahey cohort and 16% in the Nagoya cohort. The overall 10-year survival rates were 0% and 12%, respectively. In patients who underwent resection with negative margins, the 5- and 10-year survival rates were 43% and 0% for the Lahey cohort and 25% and 18% for the Nagoya cohort. The surgical death rate for patients undergoing resection was 4% for Lahey patients and 8% for Nagoya patients. Of the patients who underwent resection, en bloc caudate lobectomy was performed in 8% of the Lahey patients and 89% of the Nagoya patients. Histopathologic examination of resected cancers showed that the Nagoya patients had a higher stage of disease than the Lahey patients. CONCLUSIONS: In both Lahey and Nagoya patients, survival was most favorable when resection of hilar cholangiocarcinoma was accomplished with margin-negative resections. Combined bile duct and liver resection with caudate lobectomy contributed to a higher margin-negative resection rate in the Nagoya cohort.     

Extracorporeal bioartificial liver using the radial-flow bioreactor in treatment of fatal experimental hepatic encephalopathy

An extracorporeal bioartificial liver (BAL) that could prevent death from hepatic encephalopathy in acute hepatic insufficiency was aimed to develop. A functional human hepatocellular carcinoma cell line (FLC-4) was cultured in a radial-flow bioreactor. The function of the BAL was tested in mini-pigs with acute hepatic failure induced by alpha-amanitin and lipopolysaccharide. When the BAL system was connected with cultured FLC-4 to three pigs with hepatic dysfunction, all demonstrated electroencephalographic improvement and survived. Relatively low plasma concentrations of S-100 beta protein, as a marker of astrocytic damage, from pigs with hepatic failure during BAL therapy were noted. BAL therapy can prevent irreversible brain damage from hepatic encephalopathy in experimental acute hepatic failure.     

Suppression of Grating Lobe Artifacts in Ultrasound Images Formed from Diverging Transmitting Beams by Modulation of Receiving Beams

In linear array transducers, owing to regular spacing of the array elements, grating lobes exist in transmission and reception. In ultrasonic imaging involving the use of diverging (unfocused) transmitting beams and steered receiving beams by linear transducer arrays, aperture apodization and spatial combination of steered receiving beams from multiple transmissions are not sufficient to suppress receive-grating lobe artifacts. To further suppress receive-grating lobe artifacts in reconstructed B-mode images, we propose a technique of modulating the receiving beams by a factor that is governed by the envelope of a corresponding signal, which is formed by filtering the receiving beam with a zero-phase low-pass filter with a cut-off frequency that is determined by the receiving beam steering angle. This technique suppressed receive-grating lobe artifacts without significant loss in spatial resolution in offline reconstructed B-mode images from simulation, phantom and in vivo imaging of the carotid artery. In a simulation of point scatterers, a relative reduction in grating lobe artifacts of 40 dB was realized in images from diverging beam scanning.