A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer.

BACKGROUND: It is unclear whether treating brain metastasis before starting systemic chemotherapy can improve survival compared with upfront chemotherapy in non-small-cell lung cancer (NSCLC) with asymptomatic cerebral oligo-metastases. PATIENTS AND METHODS: We undertook a randomized, controlled trial of 105 patients with one to four brain metastases, admitted to Samsung Medical Center between 2008 and 2013. Patients were randomly assigned to receive stereotactic radiosurgery (SRS) (49 patients) followed by chemotherapy or upfront chemotherapy (49 patients). The primary end point was overall survival (OS) and secondary end points included central nervous system (CNS) progression-free survival, progression to symptomatic brain metastasis and brain functional outcome. RESULTS: The median age was 58 years (range, 29-85) with ECOG 0-1 performance status, and 40% of patients were never smokers. Most patients had adenocarcinoma, and about half of patients had only one brain metastasis, while the rest had multiple cerebral metastases. The median OS time was 14.6 months [95% confidence interval (CI), 9.2-20.0] in the SRS group and 15.3 months (95% CI, 7.2-23.4) for the upfront chemotherapy group (P = 0.418). There was no significant difference in time to CNS disease progression [median, 9.4 months (SRS) versus 6.6 months (upfront chemotherapy), P = 0.248]. Symptomatic progression of brain metastases was observed more frequently in the upfront chemotherapy group (26.5%) than the SRS group (18.4%) but without statistical significance. CONCLUSIONS: Although this study included smaller sample size than initially anticipated due to early termination, SRS followed by chemotherapy did not improve OS in oligo-brain metastases NSCLC patients compared with upfront chemotherapy. Further study with large number of patients should be needed to confirm the use of upfront chemotherapy alone in this subgroup of patients. CLINICAL TRIALS NUMBER: NCT01301560.

Identification of a novel HLA-B*40 variant allele, B*40:301, by sequence-based typing.

The new allele, HLA-B*40:301 differs from B*40:01:02 by one nucleotide substitution at codon 239 (AGA → AAA).

Identification of a novel HLA-A*29 allele, HLA-A*29:01:09, by sequence-based typing in a Korean individual.

HLA-A*29:01:09 differs from A*29:01:01:01 by one nucleotide difference at nucleotide position 414.

Identification of a novel HLA-C*03 variant allele, C*03:280 by sequence-based typing.

The new allele, HLA-C*03:280 differs from C*03:04:01 by one nucleotide substitution at codon 35 (CGG→CAG).

Identification of the novel allele, HLA-C*15:02:01:03, by full-length genomic sequencing.

The HLA-C*15:02:01:03 allele differs from the HLA-C*15:02:01:01 allele by a single-nucleotide substitution in the 5' untranslated region (-42 C>A).

Identification of a new HLA-DRB1*04 allele, DRB1*04:10:03.

The new allele, DRB1*04:10:03, showed one nucleotide difference with DRB1*04:10:01 (705C>T).

A new HLA-B*15 allele, HLA-B*15:263, identified in a Korean individual.

HLA-B*15:263 differs from HLA-B*15:18:01 by a single nucleotide exchange at position 824, C>G (codon 251 TCT>TGT).

Sequence variations of the locus-specific 5' untranslated regions of SLA class I genes and the development of a comprehensive genomic DNA-based high-resolution typing method for SLA-2.

The genetic diversity of the major histocompatibility complex (MHC) class I molecules of pigs has not been well characterized. Therefore, the influence of MHC genetic diversity on the immune-related traits of pigs, including disease resistance and other MHC-dependent traits, is not well understood. Here, we attempted to develop an efficient method for systemic analysis of the polymorphisms in the epitope-binding region of swine leukocyte antigens (SLA) class I genes. We performed a comparative analysis of the last 92 bp of the 5' untranslated region (UTR) to the beginning of exon 4 of six SLA classical class I-related genes, SLA-1, -2, -3, -4, -5, and -9, from 36 different sequences. Based on this information, we developed a genomic polymerase chain reaction (PCR) and direct sequencing-based comprehensive typing method for SLA-2. We successfully typed SLA-2 from 400 pigs and 8 cell lines, consisting of 9 different pig breeds, and identified 49 SLA-2 alleles, including 31 previously reported alleles and 18 new alleles. We observed differences in the composition of SLA-2 alleles among different breeds. Our method can be used to study other SLA class I loci and to deepen our knowledge of MHC class I genes in pigs.

Changes in serum immunomolecules during antibiotic therapy for Mycobacterium avium complex lung disease.

Little information is available regarding changes in immune status for patients with Mycobacterium avium complex (MAC) lung disease during antibiotic therapy. Serum immunomolecules from 42 patients with MAC lung disease were assayed comparatively using an array-based system according to (i) patients with MAC lung disease at the time of diagnosis versus healthy controls and (ii) alterations after 12 months of antibiotic therapy in the MAC lung disease group. In addition, cytokine analyses were performed to determine whether cytokine responses were associated specifically with the disease phenotype, treatment outcome and aetiological agent. Notably, the serum concentrations of type 1 cytokine-associated molecules, such as CD40L, interferon (IFN)-γ, interleukin (IL)-8 and IL-23, were decreased significantly in patients at the time of diagnosis, suggesting that these molecules may serve as indicators of host susceptibility to MAC disease. Although the overall serum level of T helper type 1 (Th1)-related molecules, such as CD40L and IFN-γ, was restored after treatment, Th17-related cytokines, such as IL-17 and IL-23, were down-regulated significantly at 12 months post-treatment compared to pretreatment. Furthermore, these cytokine patterns differed among patient subgroups. Decreased serum concentrations of IL-17 and/or IL-23 were associated with failure of sputum conversion, the fibrocavitary disease phenotype and M. intracellulare lung disease. Thus, the reciprocal balance between Th1 and Th17 immunity during antibiotic therapy for MAC lung disease is critical for dictating the treatment response. In conclusion, a low level of Th1-related immunomolecules may perpetuate MAC lung disease, and the serum concentrations of Th17-related cytokines can reflect the treatment outcome, disease phenotype and aetiological agent.

A new allele, HLA-DQB1*05:50, identified by sequence-based typing in a Korean individual.

The new allele DQB1*05:50 showed one nucleotide difference with DQB1*05:03:01:01 at codon 39 (CGC/CAC).

The novel HLA-C*03:02:02:03 identified by cloning and genomic full-length sequencing.

The sequence of the C*03:02:02:03 differs from that of C*03:02:02:01 by one nucleotide substitution in the 5' UTR at position -57 (C>A).

HLA-B*40:02:18, a new HLA-B*40 allele.

The new allele B*40:02:18 showed one nucleotide difference with B*40:02:01 at codon 111 (CGC/CGT).

A new HLA-A*02 allele, A*02:465.

The new allele A*02:465 showed one nucleotide difference with A*02:06:01 (172G>A).

A new HLA-C allele, C*06:99, identified by sequence-based typing in a Korean individual.

The C*06:99 allele substitutes one nucleotide of C*06:02:01:01 at codon 50 (CCG→CTG), Pro to Leu.

Identification of a novel HLA-C*08 allele, HLA-C*08:78, by sequence-based typing in a Korean individual.

HLA-C*08:78 differs from C*08:01:01 by a nonsynonymous mutation at codon 239 (GGA to AGA) in exon 4.

Identification of a novel HLA-A*02 allele, A*02:428, by sequence-based typing.

HLA-A*02:428 differs from A*02:06:01 by a non-synonymous mutation at codon 260 (CAT to GAT) in exon 4.

Local sustained delivery of oncolytic adenovirus with injectable alginate gel for cancer virotherapy.

Adenoviruses (Ad) have been investigated for their efficacy in reducing primary tumors after local intratumoral administration. Despite high Ad concentrations and repetitive administration, the therapeutic efficacy of Ad has been limited because of rapid dissemination of the Ad into the surrounding normal tissues and short maintenance of Ad biological activity in vivo. To maximize the therapeutic potential of Ad-mediated gene therapeutics, we investigated the efficacy of local, sustained Ad delivery, using an injectable alginate gel matrix system. The biological activity of Ad loaded in alginate gel was prolonged compared with naked Ad, as evidenced by the high green fluorescent protein gene transduction efficiency over an extended time period. Moreover, oncolytic Ad encapsulated in alginate gel elicited 1.9- to 2.4-fold greater antitumor activity than naked Ad in both C33A and U343 human tumor xenograft models. Histological and quantitative PCR analysis confirmed that the oncolytic Ad/alginate gel matrix system significantly increased preferential replication and dissemination of oncolytic Ad in a larger area of tumor tissue in vivo. Taken together, these results show that local sustained delivery of oncolytic Ad in alginate gel augments therapeutic effect through selective infection of tumor cells, sustained release and prolonged maintenance of Ad activity.

A new HLA-C*07:244 allele identified by sequence-based typing in a Korean individual.

The C*07:244 changes single nucleotide of C*07:02:01 at codon 75 (CGA → CAA), Arg to Gln.

HLA-A*02:07:02, a new allele identified by sequence-based typing in a Korean individual.

The new allele A*02:07:02 shows a single nucleotide substitution compared with A*02:07:01 at codon 233 (ACC → ACT) without any amino acid change.