Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL

Hematopoietic stem cells (HSCs) are maintained at a very low frequency in adult bone marrow under steady-state conditions. However, it is not fully understood how homeostasis of bone marrow HSCs is maintained. We attempted to identify a key molecule involved in the regulation of HSC numbers, a factor that, in the absence of Lnk, leads to HSC expansion. Here, we demonstrate that upon stimulation with thrombopoietin, expression of Bcl-xL, an antiapoptotic protein, was highly enhanced in Lnk-deficient HSCs compared to normal HSCs. As a result, Lnk-deficient HSCs underwent reduced apoptosis following exposure to lethal radiation. Downregulation of Bcl-xL expression in Lnk-deficient HSCs by short-hairpin RNA resulted in a great reduction of their capacity for reconstitution. These findings suggest that Lnk/Sh2b3 constrains the expression of Bcl-xL and that the loss of Lnk/Sh2b3 function enhances survival of HSCs by inhibiting apoptosis. Furthermore, our observations indicate that HSCs in patients with an Lnk/Sh2b3 mutation might become resistant to apoptosis due to thrombopoietin-mediated enhanced expression of Bcl-xL. Consequently, reduced apoptosis could facilitate accumulation of HSCs with oncogenic mutations leading to development of myeloproliferative disorders.     

Wernicke's encephalopathy after chemoradiotherapy for tongue cancer: Report of a case

A case of acute Wernicke's encephalopathy induced by thiamine deficiency due to malnutrition subsequent to chemoradiotherapy for tongue cancer is presented. A 63-year-old male patient had severe oral mucositis and mental stress in a long-term hospitalization for chemoradiotherapy of tongue cancer. After discharge from hospital, he had alcoholism and malnutrition. Three months later, disturbance of consciousness and ataxia followed by memory disturbance appeared. Laboratory examination revealed low serum level of thiamine. The symptoms, laboratory data, and magnetic resonance imaging suggested acute Wernicke's encephalopathy. The patient was intravenously administered thiamine and received nutritional control, thereby the symptoms were improved.     

Combined measurements of serum bile acid level and splenic volume may be useful to noninvasively assess portal venous pressure

Background

We aimed to identify a noninvasive predictor of portal venous pressure (PVP).

Methods

We directly measured the PVP in 40 consecutive patients who underwent direct percutaneous transhepatic portal vein puncture as part of the therapeutic management for liver diseases, and we evaluated the association of the PVP with noninvasive clinical parameters. The backgrounds of the liver were normal in 13 patients, chronic hepatitis in 17, and liver cirrhosis in ten.

Results

The mean PVP was 202 ± 114 mmH₂O. In a multivariate linear regression analysis, the serum bile acid level and splenic volume showed independent positive correlations with the PVP (P < 0.001 and 0.002, respectively). The formula for estimating PVP was identified as follows: PVP (mmH₂O) = serum bile acid (??mol/L) × 2.593 + splenic volume (cm³) × 0.416 + 65.929 (R ² = 0.698). In a receiver operating characteristic (ROC) analysis, the AUC values of serum bile acid and splenic volume at a PVP of 200 mmH₂O were 0.909 and 0.758, respectively. However, the AUC values of serum bile acid and splenic volume at a PVP of 250 mmH₂O were 0.792 and 0.926, respectively, suggesting that the serum bile acid level and splenic volume are sensitive predictors of early and advanced portal hypertension, respectively.

Conclusions

Combined measurements of the serum bile acid level and splenic volume may be useful to noninvasively assess the PVP prior to further invasive procedures.     

Limitation of repeated radiofrequency ablation in hepatocellular carcinoma: proposal of a three (times) × 3 (years) index

Background and Aim: Percutaneous radiofrequency ablation (RFA) has been shown to be a highly effective treatment for hepatocellular carcinoma (HCC). We investigated the controllability of HCC and explored the algorithm of therapeutic strategy for HCC in patients who met the RFA criteria. Methods: We enrolled 472 patients with HCC who met the RFA criteria (≤ 3 nodules, ≤ 3 cm) and underwent RFA for initial therapy. Patients who underwent repeated RFA were evaluated retrospectively when HCC exceeded the RFA criteria, or the functional hepatic reserve progressed to Child–Pugh grade C. Results: Overall survival rates were: 1 year, 96%; 3 years, 79%; and 5 years, 56%. In 5 years, 14% of patients progressed to Child–Pugh grade C. Meanwhile, 47% of patients exceeded the RFA criteria. Annually, 8% of patients deviated from the RFA criteria. The percentage of patients who were able to receive RFA significantly decreased at the fourth session compared with up to the third session. The survival rates decreased at the rate of 7% annually until the third year after the initial RFA. Afterwards, it shifted to a decrease at the rate of 12% annually. In a multivariate analysis, the presence of hepatitis C virus infection and the existence of a single tumor were identified as significant independent factors contributing to probabilities exceeding the RFA criteria. Conclusions: HCC was controlled by RFA up to three RFA treatments and 3 years from the initial therapy. On this basis, we propose a “three (times) × 3 (years) index” for considering a shift from RFA to other treatment modalities.     

Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B

Aim: The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately. Methods: A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL. Results: Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core‐related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis. Conclusions: It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core‐related antigens are also significant factors independently associated with relapse of hepatitis.     

Clinical outcome of up-front surgery in patients with asymptomatic, incurable synchronous peritoneal carcinomatosis

Purposes

The purpose of this study was to show the clinical features of up-front surgery of the primary tumor in asymptomatic patients with incurable colorectal PC.

Methods

Forty-six patients that were diagnosed between 1998 and 2007 with asymptomatic colorectal PC who could not be successfully cured by surgery were assessed retrospectively.

Results

A univariate analysis revealed the presence of liver metastases, without the use of oxaliplatin (OX)/irinotecan (IRI) and without a primary tumor resection to be poor prognostic factors for survival (p = 0.044, p = 0.030, p < 0.001, respectively). According to a multivariate analysis, no use of OX/IRI and no primary tumor resection, were found to be independent poor prognostic factors for survival (HR 2.57; p = 0.047, HR 6.62; p = 0.003, respectively). The median survival time of patients treated with and without OX/IRI was 18 and 7 months, respectively. The median survival time of patients with and without primary tumor resection was 10 and 2 months, respectively. The number of patients needing surgical intervention for intestinal obstruction after surgery significantly increased in patients treated with OX/IRI (p = 0.001).

Conclusion

Improvement of survival may be related to widespread use of modern systemic chemotherapy and primary tumor resection. However, an increased number of patients that needed surgery for an intestinal obstruction were observed, even after up-front surgery, when patients were treated with modern systemic chemotherapy.