Frequency and proliferative response of circulating invariant natural killer T cells in pediatric patients with malignant solid tumors

Background

Invariant natural killer T (iNKT) cells play an important role in tumor immunity, enhancing both innate and acquired immunity. We have previously shown the enhancement of antibody-dependent cellular cytotoxicity against neuroblastoma by activated iNKT cells. As a first step towards clinical application, we studied the frequency and proliferative response of circulating iNKT cells in children with and without cancer.

Methods

Blood samples were collected from 10 patients with pediatric malignant solid tumors and 11 patients with non-neoplastic diseases (control). The frequency of circulating iNKT cells was quantified by flow cytometry. Whole peripheral blood mononuclear cells were then stimulated with α-galactosylceramide (α-GalCer) for 7 days, and the expansion rate of the iNKT-cell fraction was assessed.

Results

The frequency of iNKT cells in the patients of the cancer and control group did not differ to a statistically significant extent. The iNKT-cell population increased after α-GalCer stimulation in all cases. The iNKT cells of patients who had undergone intensive chemotherapy also had the potential to expand in vitro.

Conclusions

Unlike adult cancer patients, the numbers of circulating iNKT cells were not decreased in pediatric cancer patients. α-GalCer stimulation induced a proliferative response in all of the patients.

     

Invariant natural killer T infiltration in neuroblastoma with favorable outcome

Background

Tumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics.

Methods

Using real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients’ outcome.

Results

Vα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P?=?0.0099), in tumors with low or intermediate risk (P?=?0.0050), with high TrkA expression (P?=?0.0229), with favorable histology (P?=?0.0026), with aneuploidy (P?=?0.0348), and in younger patients (P?=?0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P?=?0.0089).

Conclusions

Since tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.

     

Comparison of Premortem Magnetic Resonance Imaging and Postmortem Autopsy Findings of a Cortical Microinfarct

An 85-year-old woman diagnosed with amyotrophic lateral sclerosis died of pneumonia and was autopsied. Magnetic resonance imaging (MRI) performed 16 days before death revealed an intracortical high-intensity lesion in her right temporal cortex on three-dimensional (3D)-double inversion recovery (DIR) and 3D-fluid-attenuated inversion recovery (FLAIR) images. Histopathological examination indicated a cortical microinfarct (CMI) juxtaposed to cerebral amyloid angiopathy. Recently, in vivo detection of CMIs using 3D-DIR and 3D-FLAIR on 3-tesla MRI has been reported, and postmortem MRI study confirmed the presence of CMIs. This is the first case study to compare CMI findings detected upon premortem MRI to the CMI itself discovered upon postmortem neuropathological examination.     

Arterio-biliary fistula as rare complication of chemoradiation therapy for intrahepatic cholangiocarcinoma

Significant hemobilia due to arterio-biliary fistula is a very rare complication of chemoradiation therapy (CRT) for unresectable intrahepatic cholangiocarcinoma (ICC). Here we report a case of arterio-biliary fistula after CRT for unresectable ICC demonstrated by angiographic examinations. This fistula was successfully treated by endovascular embolization. Hemobilia is a rare complication, but arterio-biliary fistula should be considered after CRT of ICC.     

HIF‐1α is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5‐FU chemotherapy

Among several chemotherapeutic agents, 5‐fluorouracil (5‐FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5‐FU in an adjuvant setting, has been identified. Hypoxia‐induced drug resistance, via upregulation of HIF‐1α, is a major obstacle in the development of effective cancer therapy. However, few clinical studies have so far assessed the relationship between the HIF‐1α expression and the chemo‐resistance of gastric cancer patients in an adjuvant setting. We established 2 HIF‐1α knockdown gastric cancer cell lines in order to clarify the role of HIF‐1α in chemo‐resistance against 5‐FU. Furthermore, expression of HIF‐1α was immunohistochemically assessed in 91 resected specimens. Sixty‐four of 91 patients received 5‐FU adjuvant chemotherapy after surgery. HIF‐1α expression was associated with the significantly shorter relapse‐free survival and disease‐specific survival in the 64 patients of adjuvant group (p = 0.026, 0.014, respectively), but not in the 27 of surgery group. Multivariate analysis showed that HIF‐1α was an independent risk factor for relapse in 64 patients in the adjuvant group (p = 0.029). In conclusion, the current study confirmed, for the first time that HIF‐1α expression is an independent risk factor for relapse in high‐risk gastric cancer patients who underwent curative surgery followed by adjuvant 5‐FU chemotherapy. A favorable effect of 5‐FU might therefore be expected in patients that do not express HIF‐1α, whereas, other types of chemotherapy or additional treatments, such as HIF‐1α inhibitors, should be considered in patients that do express HIF‐1α.     

High incidence of meropenem resistance among α-hemolytic streptococci in children with cancer

Background:  Infections caused by antibiotics-resistant Gram-positive bacteria have been reported from many pediatric hematology–oncology centers.
Methods:  The susceptibility profiles to meropenem, piperacillin, and vancomycin among oral flora isolates of α-hemolytic streptococci (AHS) obtained from six children with cancer who received several empirical therapies (ET) against febrile neutropenia, were investigated.
Results:  Meropenem minimum inhibitory concentration (MIC) of AHS isolated from ET patients was 2.167 ± 0.258 μg/mL (mean ± SD), which was significantly higher than the MIC of AHS isolated from control groups. Intriguingly, AHS isolated approximately 6 months after hospital discharge indicated recovery of susceptibility to meropenem.
Conclusions:  AHS isolates from neutropenic children with cancer should be checked for antibiotic susceptibility, even against carbapenems.     

Change in salivary levels of chromogranin A in children by hearing dental air turbine noise

Dental fear in children can be a psychological barrier for maintenance of oral health, thus it is important to objectively evaluate the responses to stress stimuli produced during dental treatments. In this study, we analyzed the stress responses of 15 preschool (3- to 6-year) and 22 school-aged (6- to 12-year) children to dental air turbine noise by measuring salivary levels of chromogranin A (CgA), a marker of psychological stress. Salivary CgA was significantly increased during exposure to the noise in the school-aged subjects, especially in those who had previously experienced tooth excavation, while there was no significant difference in CgA levels before and during noise exposure in those without such experience. In the preschool children, the noise did not induce increased secretion of CgA even in those with previous excavation experience. In addition, the levels of dental fear were assessed using a dental subscale of children's fear survey schedule (CFSS-DS), while reactions during dental care were scored according to the Frankl Behavior Rating scale. In the school-aged children, change in salivary CgA level was not correlated with CFSS-DS (r = 0), while there was a weak negative correlation with Frankl score (r = ?10.202). Our results indicate that air turbine noise causes psychological stress in school-aged children, especially in those who have previously received dental treatments.