Anti-Tumor Effects of Heat-Killed L. reuteri MG5346 and L. casei MG4584 against Human Colorectal Carcinoma through Caspase-9-Dependent Apoptosis in Xenograft Model.

In this study, we examined the anti-tumor effects of heat-killed Bifidobacterium and Lactobacillus strains on human colorectal carcinoma RKO cells in in vitro and in vivo xenograft models. First, the cytotoxic and apoptotic effects of 11 different strains were examined using an MTT assay and flow cytometry, respectively. Then, xenograft BALB/c nude mice were implanted with RKO cells and orally administered with single or mixed heat-killed bacterial strains to examine their inhibitory effects on tumor growth. Additionally, the levels of cleaved caspase-9, -3, and -7 and PARP in tumor tissues were analyzed using Western blotting or immunohistochemistry staining. The results showed that RKO cells were highly susceptible to heat-killed B. bifidum MG731 and L. reuteri MG5346 and that L. casei MG4584 induced apoptosis to a greater extent than other strains. The oral administration of individual MG731, MG5346, or MG4584 significantly delayed tumor growth, and mixtures of MG5346 and MG4584 or MG731, MG5346, and MG4584 synergistically inhibited the tumor growth in the xenograft model. The expression of cleaved caspase-3, -7, and -9 and PARP in the tumor tissues was increased in Western blotting, and the expression of cleaved caspase-3 and PARP in immunohistochemistry staining was also increased. Therefore, we suggest that the use of the combination of MG5346 and MG4584 as parabiotics could effectively inhibit the growth of colorectal cancer.

Identification of T-cell receptor expression in EBV-positive neoplastic cells in extranodal NK/T-cell lymphoma, nasal-type, and comparison with T-cell receptor gene rearrangement by BIOMED-2 assay.

The cellular lineage of extranodal NK/T-cell lymphoma, nasal-type (ENKTL), is determined by expression of T-cell receptor (TR) or TR gene rearrangement. In ENKTL, from TR immunohistochemistry, it may often be difficult to decide whether TR-positive cells are tumor cells or not, especially when TR is expressed in a subset of tumor cells. To analyze TR expression pattern and TR rearrangement in T-lineage ENKTL, we performed double immunofluorescence staining for Epstein-Barr virus-encoded small RNAs (EBER)/T-cell receptor (TCR) ßF1 and CD56/TCR ßF1 in 12 cases of ENKTL that showed TCR ßF1 expression in immunohistochemistry. TR gene rearrangement was analyzed using a commercial BIOMED-2 multiplex polymerase chain reaction system. Immunohistochemistry showed that all 12 cases expressed TCR ßF1 in a wide range of infiltrating cells from 100% to <1%. Two of them expressed both TCR ßF1 and TCR cγM1. EBER/TCR-ßF1-positivity was confirmed in 10 cases by double staining. One case failed to show EBER/TCR-ßF1-positive cells but showed a CD56/TCR ßF1-positive result. Among 12 cases, 5 had poor-quality DNA, 3 of them showed no polymerase chain reaction product, and 2 cases showed nonspecific peak of low height. Five of 7 cases with good DNA quality demonstrated monoclonal TR gene rearrangement. Based on TR expression and TR gene rearrangement, 10 of 12 cases of ENKTL were decided as a T-lineage tumor. In conclusion, because of common TR silence and poor DNA quality, consideration of both immunohistochemistry and TR gene rearrangement is necessary to determine the lineage of ENKTL.

Erratum: Figure Correction.

[This corrects the article on p. 506 in vol. 59, PMID: 27896253.].

Erratum to: Raloxifene Administration in Women Treated with Long Term Gonadotropin-releasing Hormone Agonist for Severe Endometriosis: Effects on Bone Mineral Density.

[This corrects the article on p. 174 in vol. 22, PMID: 28119898.].

A Study on Laparoscopic Sacral Colpopexy for Uterine Prolapse.

OBJECTIVES: We sought to describe the perioperative and postoperative adverse events associated with sacral colpopexy and evaluate the surgical outcome, complications, and benefits of laparoscopic sacral fixation for patients with pelvic prolapse. METHODS: Ninety-two women with uterine prolapse underwent sacral colpopexy between January 2011 and September 2016 at Chosun University Hospital. Patients' electronic medical records were investigated for demographic, intraoperative, and postoperative data. Strict definitions were used for all clinically relevant adverse events. Patients' outcomes were documented with 1 self-administered quality of life questionnaires: the Pelvic Floor Distress Inventory-20 focused on symptom distress. The primary analysis looking at perioperative and postoperative adverse events was descriptive and statistics were reported for all groups as n/N (%) with 95% confidence intervals for categorical variables and as mean ± standard deviation and mean (range) for all continuous variables. RESULTS: Their mean age was 69 ± 8.1 years, mean follow-up duration was 12 months, and mean operating time was 61 minutes. There were seven conversions due to anesthetic or surgical difficulties. Follow-up was performed using a telephone questionnaire and physical examination at 12 months. There were three cases of sacral pain with strong analgesics, one of vaginal erosion, two of transient urinary retentions, one of spondylitis, and two of mesh infection. Of the patients, 98.9% were satisfied with the surgical results, while none complained of sexual dysfunction or problems performing her usual activities. CONCLUSIONS: Laparoscopic sacral colpopexy is a feasible and highly effective technique that offers good long-term results with complication rates similar to those of open surgery with the added benefit of being minimally invasive.

Study of dienogest for dysmenorrhea and pelvic pain associated with endometriosis.

OBJECTIVE: To evaluate the effect of orally administered dienogest (DNG) for dysmenorrhea and pelvic pain associated with endometriosis. METHODS: For this study we recruited 89 patients with dysmenorrhea and pelvic pain associated with endometriosis diagnosed by laparoscopy. All patients complained of persistent dysmenorrhea and pelvic pain despite surgical treatment 6 months previously. After 6 months of DNG treatment, we used a 0 to 3 point verbal rating scale to measure the severity of disability in daily life due to dysmenorrhea and pelvic pain, and the use of analgesics. Weight gain, serum lipid and liver enzyme tests were performed before treatment and after 6 months of DNG treatment. RESULTS: Total dysmenorrhea scores assessed by the verbal rating scale significantly decreased by the end of treatment (P<0.001). The mean (±standard deviation) pain score for dysmenorrhea before and after treatment were 1.42±1.1 and 0.1±0.3, respectively. The mean non-menstrual pelvic pain scores before and after treatment were 0.52±0.6 and 0.18±0.3, respectively, showing a significant difference (P<0.001). The use of analgesics significantly decreased by the end of the treatment (P<0.001). The associated adverse effects were weight gains (in 56 of 89 patients, 63%) and uterine bleeding (in 28 of 89 patients, 31.5%). The weight gain (before treatment, 57.9±9.7; after treatment, 61.1±12.6) was statistically significant (P<0.040). CONCLUSION: This study demonstrated that orally administered DNG could be used to effectively treat dysmenorrhea and pelvic pain associated with endometriosis although the side effects of weight gain and uterine bleeding should be considered.

Nasal-type NK/T-cell lymphomas are more frequently T rather than NK lineage based on T-cell receptor gene, RNA, and protein studies: lineage does not predict clinical behavior.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type, comprises NK or cytotoxic T cells. We evaluated the clinical impact of cell type and the usefulness of T-cell receptor (TCR) gene transcripts in distinguishing cell lineage. One hundred and eight cases of ENKTL were analyzed for TCR gene rearrangements using the BIOMED-2 protocol and for TCR gene expression using immunohistochemistry for TCR-ßF1 and TCR-cγM1, and RNA in situ hybridization for TCR gene transcripts. Prognostic factors were analyzed. Among the 108 cases, 44 were monoclonal for a TCR rearrangement (40%) while 64 (60%) were undefinable. The monoclonal cases expressed TCR-ßF1 in 14 out of 40 cases (35%) and TCR-cγM1 in 1 out of 44 cases (2%). The 64 undetermined cases expressed TCR-ßF1 in 15 cases (23%) and TCR-cγM1 in 1 (2%). Thirteen of 40 TCR-ß constant gene transcript-positive cases (33%) expressed TCR-ßF1 and one of nine TCR-γ constant gene transcript-positive cases (11%) expressed TCR-cγM1. TCR gene transcripts were not useful in the distinction of cell lineages. TCR gene transcripts were positive in ENKTLs as well as in normal B cells and aggressive NK-cell leukemia. Based on gene rearrangements and immunohistochemistry for TCR, there were 60 T-cell type cases (56%), 32 NK-cell type cases (30%), and 16 cases with an undetermined cell type (14%). TCR protein was expressed in 30/60 T-ENKTLs (50%) in a variable fraction of tumor cells. There were no significant differences in clinical findings or overall patient survival between T- or NK-cell types of ENKTL, although those with a T-cell type tended to show a better prognosis for those with localized nasal lymphomas. Univariate and multivariate analysis showed that a non-nasal ENKTL, age >60 years, high level of lactate dehydrogenase, bone marrow involvement, and the absence of radiotherapy were independent prognostic factors.

Raloxifene Administration in Women Treated with Long Term Gonadotropin-releasing Hormone Agonist for Severe Endometriosis: Effects on Bone Mineral Density.

OBJECTIVES: To evaluate the efficacy of raloxifene in preventing bone loss associated with long term gonadotropin-releasing hormone agonist (GnRH-a) administration. METHODS: Twenty-two premenopausal women with severe endometriosis were treated with leuprolide acetate depot at a dosage of 3.75 mg/4 weeks, for 48 weeks. Bone mineral density (BMD) was evaluated at admission, and after 12 treatment cycles. RESULTS: At cycle 12 of GnRH-a plus raloxifene treatment, lumbar spine, trochanter femoral neck, and Ward's BMD differed from before the treatment. A year after treatment, the lumbar spine and trochanter decreased slightly, but were not significantly different. CONCLUSIONS: Our study shows that the administration of GnRH-a plus raloxifene in pre-menopausal women with severe endometriosis, is an effective long-term treatment to prevent bone loss.

Antigen Expression Patterns of Plasma Cell Myeloma: An Association of Cytogenetic Abnormality and International Staging System (ISS) for Myeloma.

BACKGROUND: Immunophenotyping of plasma cell has become an important diagnostic tool for plasma cell myeloma. There have been a few studies for association of antigen expression and cytogenetic abnormality of plasma cell myeloma. METHODS: A total of 68 symptomatic/smoldering plasma cell myeloma case were analyzed by multicolor flow cytometry using CD38 and CD138 for primary gating of plasma cells. A conventional cytogenetics and fluorescence in situ hybridization (FISH) studies for detection of del(13q) or aneuploidy, del(17p), and IGH/FGFR translocation were done. We statistically analyzed the association of antigen expression and cytogenetic abnormality/myeloma stage (international staging system for multiple myeloma). RESULTS: Positive expression of CD19, CD28, CD45, CD56, CD117, and CD274 was detected in 8.8%, 50.0%, 50.0%, 75.0%, 39.7%, and 2.9% of cases, respectively. CD117-negative cases were associated with hypodiploidy (P = 0.017). CD45-negative cases were associated with deletion 13 or aneuploidy (P < 0.001) and del(17p)(P = 0.011) by FISH. CD45-negativity or CD117-negativity was associated with advanced stage (P = 0.012 and P = 0.016, respectively). CONCLUSION: The antigen expression patterns of myeloma plasma cell were associated with cytogenetic abnormality and stage.

Comparison of Laparoscopic Radiofrequency Myolysis (LRFM) and Ultrasonographic Radiofrequency Myolysis (URFM) in Treatment of Midline Dysmenorrhea.

OBJECTIVES: To access the effectiveness of radiofrequency myolysis (RFM) in women with midline dysmenorrhea. METHODS: We designed RFM in two ways laparoscopic RFM (LRFM), vaginal ultrasound-guided RFM (URFM). One hundred and thirty-two patients were in the LRFM group and, 140 patients were in the URFM group. RESULTS: Upon receipt of surgery, both the LRFM and the URFM groups demonstrated a significant decrease (P < 0.001) in the mean pain score when compared to those before and after surgery. CONCLUSION: The RF uterine myolysis procedure provides an alternative for those patients who suffer from intractable midline dysmenorrhea. LRFM is an alternative choice because it is relatively safe and, simple to perform and moreover, it is satisfactory. LRFM appears to increasingly succeed in the treatment of midline dysmenorrhea.

CD79B and MYD88 mutations in diffuse large B-cell lymphoma.

Mutations in 2 upstream components of the nuclear factor κB (NF-κB) pathway, CD79B and MYD88, are important information for new target therapy in malignant lymphoma. We examined the prevalence and clinicopathologic characteristics of CD79B and MYD88 mutation in a cohort of Asian diffuse large B cell lymphoma (DLBCL) patients. CD79B and MYD88 mutations were analyzed by Sanger sequencing in 187 DLBCL tissue samples. CD79B immunoreceptor tyrosine-based activation motif spanning exon 5 and 6 and MYD88 TIR domain spanning exons 3, 4 and 5 were amplified and sequenced. The cell-of-origin was determined based on immunohistochemical stains for CD10, BCL-6 and MUM-1 by Hans' algorithm. CD79B was mutated in 16 cases (8.5%), mostly involving the first tyrosine (Y196) of immunoreceptor tyrosine-based activation motif. For MYD88, L265P mutation was found in 31 cases (out of 161, 19.3%). In 11 of these, a CD79B mutation coexisted, which constituted 69% of CD79B mutants and 36% of MYD88 L265P cases. Clinicopathologic comparison between the mutant and the wild-type group showed that the mean age was older for both CD79B (66 versus 58 years) and MYD88 L265P mutant groups (64 versus 58 years). Survival analyses showed that neither CD79B mutation nor MYD88 L265P was a significant prognostic indicator. In conclusion, CD79B and MYD88 mutations are associated with an older age at onset in DLBCL with a significant overlap, which did not affect the outcome of the disease.

The role of 18F-FDG PET/CT for initial staging of nasal type natural killer/T-cell lymphoma: a comparison with conventional staging methods.

UNLABELLED: The utility of (18)F-FDG PET/CT in patients with nasal-type natural killer (NK)/T-cell lymphoma has not been established. Therefore, we evaluated the role of (18)F-FDG PET/CT for determining cancer staging by comparing its results to those of conventional staging methods (CSMs) (physical examination, CT with intravenous contrast, biopsies from primary sites, and bone marrow examinations) in patients with nasal-type NK/T-cell lymphoma. METHODS: In this study, 52 consecutive patients (34 men, 18 women; mean age, 49.4 y) with newly diagnosed nasal-type NK/T-cell lymphoma were studied. Anatomic regions (n = 1,300; 16 nodal and 9 extranodal regions per patient) were assessed with an (18)F-FDG PET/CT scan and with CSMs, and each anatomic region was classified as positive or negative for malignancy. Biopsy and clinical follow-up, including additional imaging studies, were used as the gold standard for diagnosis. RESULTS: Of the 59 nodal and 71 extranodal anatomic regions that were truly positive for malignancy, (18)F-FDG PET/CT detected 58 nodal and 69 extranodal. CSMs, however, detected only 44 of the nodal and 61 of the extranodal anatomic regions that were positive for malignancy (nodal comparison of PET/CT vs. CSMs, P < 0.001; extranodal comparison of PET/CT vs. CSMs, P = 0.008). PET/CT scans exhibited a significantly better sensitivity (97.7% vs. 80.7%, P < 0.001) than CSMs for the detection of malignant lesions. PET/CT findings altered the original staging category for 12 patients (21.2%) and affected treatment planning in 23 cases (44.2%). CONCLUSION: Our study demonstrated that (18)F-FDG PET/CT scanning is a valuable modality for staging and treatment planning in patients with nasal-type NK/T-cell lymphoma.

Primary central nervous system ALK positive anaplastic large cell lymphoma with predominantly leptomeningeal involvement in an adult.

A 31-year-old Korean male presented with altered consciousness and severe headache. Brain MRI delineated focal leptomeningeal enhancement without any intracerebral lesions. Diagnosis was made based on a brain biopsy showing anaplastic large cell lymphoma (ALCL), immunohistochemical stains revealing positivity for anaplastic lymphoma kinase (ALK) and an absence of involvement in any other organs; specifically, the primary central nervous system ALK+ALCL. Complete remission was achieved following 5 cycles of systemic chemotherapy with a high dose of Methotrexate and a simultaneous 7 cycles of intrathecal triple chemotherapy. Diagnosis of primary leptomeningeal ALK+ALCL is challenging given its rarity and non-specific symptoms along with non-pathognomonic radiologic findings. We present the first case of primary leptomeningeal ALK-positive ALCL where the clinical course, pathologic characteristics and treatment modality are described as well as a review of literature.

Association of polymorphisms in C2, CFB and C3 with exudative age-related macular degeneration in a Korean population.

This study was to investigate the association of genetic polymorphisms in complement component 2 (C2), complement factor B (CFB) and complement component 3 (C3) with exudative age-related macular degeneration (AMD) in a Korean population and the gene-gene and gene-environment interactions in the development of AMD. A total of six SNPs that are located in the C2 (rs547154, rs9332739), CFB (rs4151667, rs641153) and C3 (rs1047286, rs2230199) genes were genotyped in 350 samples comprised of 153 cases, 197 controls. The risk allele frequencies for rs547154 in C2 were 6.54% and 8.12% in AMD patients and controls. Those for rs641153 in CFB were 6.54% and 8.63% in AMD patients and controls. The risk allele frequency for rs9332739 in C2 (AMD, 0.65%, control, 2.03%) and rs4151667 in CFB (AMD, 0.65%, control, 1.78%) was very low. The protective allele of four SNPs was not significantly associated with decreased risk for AMD (P = 0.427, P = 0.199, P = 0.312, P = 0.303, respectively). The homozygotes for the protective allele of four SNPs were not significantly associated with decreased risk for AMD (P = 0.324, P = 0.474, P = 0.309, P = 0.411, respectively). The genetic effect of two SNPs in C3 could not be investigated because the variants were not observed. There was no evidence to support an interaction of these SNPs with LOC387715/HTRA1 variants or with environmental exposure like smoking. In conclusion, the genetic effect of C2, CFB and C3 polymorphisms, which are known to be important for AMD in Caucasian, were not significant in the Korean population. The low minor allele frequency of these SNPs in Koreans might have affected the results of this study. Ethnic differences in the roles of C2, CFB and C3 in conferring a risk of AMD should be further investigated.

Insufficient bilateral femoral subtrochanteric fractures in a patient receiving imatinib mesylate.

We present a case of insufficient bilateral femoral subtrochanteric fractures in a patient who was treated with imatinib mesylate, an anticancer drug, for 1 year after a diagnosis of chronic myelogenous leukemia (CML). A 60-year-old woman presented with bilateral thigh pain for 6 months. A plain radiograph revealed bilateral progressive insufficient fractures on the subtrochanteric areas of the femurs. MRI of the femurs revealed incomplete stress fractures and no evidence of bone metastasis on either femur. Bone densitometry showed normal T-scores around the hip joint and spine. The patient had normal serum levels of calcium, vitamin D derivatives, and thyroid hormones. Serum phosphate levels were decreased, and parathyroid hormone levels were increased. Serum osteocalcin and urinary N-telopeptide of collagen cross-links (NTx) were both decreased. A bone biopsy demonstrated normocellular marrow without leukemic cells. A histomorphometric evaluation of her bones revealed reduced bone turnover despite secondary hyperparathyroidism. The serum markers for bone metabolism and histomorphometric evaluations in this patient suggest that the drug may have an effect on bone metabolism. These effects could be seen for both bone formation and resorption: this could result in impaired bone mineralization, a severely suppressed bone turnover rate, insufficient fractures, and bone necrosis, which are sometimes seen with long-term use of bisphosphonates. To our knowledge, this is the first case of an insufficient bilateral femoral shaft fracture that is potentially related to the use of imatinib mesylate in a patient with CML. Careful examination of bone metabolism should be performed in patients with CML because imatinib mesylate treatment is a lifelong process.