Impact of early elevation of serum bilirubin during treatment with pegylated interferon and ribavirin in patients with chronic hepatitis C

Aim: Hemolytic anemia is a well‐known adverse effect of interferon and ribavirin combination treatment. Herein, we analyzed the impact of early elevation of serum bilirubin level as a marker for predicting severe anemia during treatment. Methods: We studied 245 chronic hepatitis C patients who received pegylated interferon and ribavirin combination treatment, and divided them using two different threshold levels: (i) elevation of total bilirubin of 0.5 mg/dL or more within 1 week of starting treatment; and (ii) drop of hemoglobin (Hb) by 3 g/dL or more within 4 weeks of starting treatment. We compared the dynamics in each group and then investigated independent factors for predicting a severe Hb drop (≥3 g/dL) at 4 weeks after beginning treatment and dose reduction of ribavirin. Results: Total bilirubin levels at 1 week were significantly higher in patients with a Hb drop of 3 g/dL or more as compared to those with a drop of less than 3 g/dL (P < 0.0001). Hb levels at 4 weeks were significantly lower in the group of 0.5 mg/dL or more increase of total bilirubin levels than in the group with a less than 0.5 mg/dL increase (P < 0.0001). Therefore, elevation of total bilirubin after 1 week of treatment was shown to be an independent factor for predicting severe Hb drop (≥3 g/dL) at 4 weeks (P < 0.0001), and dose reduction of ribavirin during treatment (P = 0.0321). Conclusion: Early elevation of serum bilirubin level was found to be a possible predictive marker of both a severe drop of Hb in the early phase of treatment and dose reduction of ribavirin.     

Prediction of invasive carcinoma in branch type intraductal papillary mucinous neoplasms of the pancreas

Background  

Patients with branch duct type intraductal papillary mucinous neoplasm (BD-IPMN) without invasion usually show favorable prognosis. However, the prognosis becomes poor when the IPMN lesions give rise to invasive carcinoma cells. In addition, recent studies have revealed that BD-IPMN is frequently complicated by common type pancreatic ductal carcinoma. Thus, the prognosis of BD-IPMN depends on the occurrence of these two types of invasive carcinoma. However, little is known about the risk factors for the development of these invasive carcinomas in BD-IPMN. This study aims to identify the factors which predict the development of invasive carcinoma in BD-IPMN.     

L157X nonsense mutation of the succinate dehydrogenase subunit B gene in a Japanese patient with right paraaortic paraganglioma

Nuclear genes succinate dehydrogenase B subunit and succinate dehydrogenase D subunit, which encode two mitochondrial complex II subunits, are associated with the development of familial paraganglioma (PGL). Succinate dehydrogenase B subunit gene mutation is highly associated with extraadrenal PGL and subsequent distant metastasis. We describe the case of a 29-year-old Japanese man with a 3-year history of hypertension, headache, and palpitation. Endocrinological examinations showed that the patient had elevated levels of catecholamines, and imaging studies revealed a right paraaortic PGL without distant metastases. The PGL was surgically removed. Genetic analysis of the patient showed a heterozygous thymine deletion at position 470 (c.470delT) in exon 5 of the succinate dehydrogenase B subunit gene complementary DNA. This thymine deletion changed TTG (leucine) to TGA (stop codon) at codon 157 (L157X). It remains unclear whether this mutation was associated with PGL malignancy because the patient has had no metastases for the past 3 years. It has been recently reported that L157X is associated with malignant paraaortic PGL. Thus, strict follow-up is required because this succinate dehydrogenase B subunit gene's nonsense mutation (L157X) may be related to the malignancy.     

Prognostic analysis and a new risk model for Hodgkin lymphoma in Japan

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated β2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15–9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07–5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.     

The pivotal role of intracellular calcium in oxaliplatin-induced inhibition of neurite outgrowth but not cell death in differentiated PC12 cells

The antineoplastic efficacy of oxaliplatin, a widely used anticancer drug, is restricted by its adverse effects such as peripheral neuropathy. Infusing a combination of calcium gluconate and magnesium sulfate (Ca/Mg) suppresses the acute neurotoxic side effects of oxaliplatin, although the mechanism is unclear. To elucidate the molecular mechanisms of oxaliplatin-induced neurotoxicity and the effects of Ca/Mg against this toxicity, we examined the effect of Ca/Mg on oxaliplatin-induced inhibition of neurite outgrowth in PC12 cells, a commonly used neuronal cell model. Oxaliplatin and oxalate suppressed nerve growth factor (NGF)-induced neurite outgrowth and reduced the NGF-mediated increase in the intracellular calcium concentration [Ca(2+)](i). A calcium-chelating agent, BAPTA/AM, also exhibited similar inhibitory effects on neurite outgrowth and [Ca(2+)](i). The addition of Ca/Mg attenuated these inhibitions induced by oxaliplatin and oxalate. The NGF-induced upregulation of growth-associated protein-43 (GAP-43) was suppressed by oxaliplatin and oxalate. Oxaliplatin, but not oxalate, suppressed NGF-stimulated extracellular signal-regulated kinase activation, and this inhibition was not affected by Ca/Mg. Ca/Mg did not modify the oxaliplatin-induced loss of cell viability or apoptosis in PC12 or HCT-116 cells, a human colorectal cancer cell line. These results suggest that the inhibition of neurite outgrowth but not tumor cell death induced by oxaliplatin is partly associated with reductions in [Ca(2+)](i) and GAP-43 expression, and this inhibition was suppressed by the addition of Ca/Mg. Therefore, it may be assumed that Ca/Mg is useful for protecting against oxaliplatin-induced neurotoxicity without reducing the antitumor activity of oxaliplatin.     

Carrageenan gels for oral sustained delivery of acetaminophen to dysphagic patients

We have designed gel formulations for the oral administration of acetaminophen with suitable rheological characteristics for ease of administration to patients with swallowing difficulties and sufficient integrity in the stomach to achieve a sustained release of this drug. Gels formed by agar and ι-carrageenan were assessed for suitable gel strength and in vitro and in vivo release characteristics. Comparison of 1.5% ι-carrageenan gel with 0.5% agar gel demonstrated improved sustained release properties of the ι-carrageenan gel. Gel formed by ι-carrageenan has suitable rheological and sustained release characteristics for potential use as vehicles for oral delivery of drugs to dysphagic patients.