Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas

Homozygous deletion of p16/CDKN2A is the most common genetic abnormality in malignant mesotheliomas. The aim of this study was to determine prognostic significance of p16/CDKN2A loss in malignant pleural mesotheliomas (MPM) as defined by immunohistochemistry and fluorescence in situ hybridization (FISH). High-density tissue microarrays were constructed from archival formalin-fixed paraffin-embedded samples of 48 MPM. Long survival (LS) was defined as survival greater than 3 years from the time of diagnosis, and short survival was defined as less than 3 years from the time of diagnosis. Both loss of p16 protein expression by immunohistochemistry and homozygous deletion of p16 by FISH were associated with adverse prognosis. Female gender, positive p16 immunoexpression, and lack of p16/CDKN2A deletion significantly predicted the survival for the LS group. Statistical analysis showed a very strong correlation of immunohistochemistry and FISH data. Cases positive for p16 immunoexpression and negative for 9p21 deletion showed the best survival time. Our study is the first to demonstrate decreased frequency of homozygous deletion of 9p21 and loss of p16 immunoreactivity in pleural mesotheliomas from patients with long-term survival of greater than 3 years in contrast to patients with rapidly fatal mesotheliomas. A possible implementation of these tests into preoperative prognostication of MPM and therapeutic decisions should be considered.     

A possible link between subtype 2 and asymptomatic infections of Blastocystis hominis

Blastocystis hominis is one of the most common eukaryotic organisms in the intestinal tract of humans, while its pathogenic potential is still controversial. A total of 286 stool samples obtained from adult and pediatric patients with or without gastrointestinal symptoms in two hospitals in Manisa, Turkey, were cultured to detect B. hominis infection. Forty-one and 51 isolates were obtained from the adults and children, respectively, and these isolates were subjected to subtyping by polymerase chain reaction (PCR) with the known sequence-tagged site primers. The correlation between the genotype and the symptoms was evaluated. PCR subtyping indicated that subtype 3 was the most common genotype in both symptomatic and asymptomatic groups, and the second common genotype was subtypes 1 and 2 in symptomatic and asymptomatic groups, respectively. A significant correlation between subtype 2 and the asymptomatic groups was found among both in pediatric and adult patients (chi(2) (cal) = 4.38, df = 1, p = 0.044). However, there were no significant differences between the other genotypes and the symptomatic or asymptomatic groups, as well as both the age and sex of the patients. The present study suggests that subtype 2 is a non-pathogenic genotype of B. hominis.     

Single-Center Study of 72 Patients with Severe Combined Immunodeficiency: Clinical and Laboratory Features and Outcomes

Journal of Clinical Immunology - Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various...     

Immunohistochemical detection of pS2 protein and heat shock protein-70 in pancreatic adenocarcinomas. Relationship with disease extent and patient survival

We investigated pS2 and HSP-70 protein expression in 36 pancreatic adenocarcinomas for their effect on disease extent and patient outcome. The cases were reviewed, histologically diagnosed, typed, graded, and staged. Lymphatic vessel, blood vessel and perineural invasion as well as lymph node, resection margin and adjacent organ involvements were re-evaluated. The standard streptavidin biotin immunperoxidase method was used for immunostaining with pS2 and HSP-70 antibodies. Cytoplasmic staining with both antibodies was scored semiquantitatively. The scores were compared with histopathological prognostic parameters using statistical methods. Standard prognostic parameters and staining scores were tested by survival analysis in terms of their effect on survival. All the tumors showed a positive cytoplasmic reaction with HSP-70 antibody. Seventy-seven percent of the tumors showed positive cytoplasmic staining with pS2 antibody (22.2% +, 13.9% ++ and 41.7% +++). There was a statistically significant difference between HSP-70 staining scores with N status and final stages of the tumors (Chi-square, p = 0.03 and p = 0.026, respectively), while neither direct nor inverse correlation was detected for both parameters. PS2 staining scores showed no statistically significant relationship with tumor grade T, M status, perineural invasion, lymph and blood vessel invasion. In tumors with extensive staining with pS2, tumor stage tended to be low (Chi square, p = 0.024, Kendall Tau-b, r: -0.336, p = 0.036). There was a statistically significant difference and inverse correlation between tumors with extensive pS2 staining and tumors with less intense staining in terms of lymph node metastasis (Chi-square, p = 0.041, Kendall Tau: p = 0.024, r = -0,373). In the R0 resection group, in univariate analysis, we found that with higher scores of HSP-70 staining, the prognosis of the patient tended to improve. (Cox regression, p = 0.013). In multivariate analysis, HSP-70 expression was found to be an independent prognostic factor. We found no relationship between pS2 staining and patient survival.     

The significance of coasting duration during ovarian stimulation for conception in assisted fertilization cycles

BACKGROUND: Withholding gonadotrophin administration and postponing HCG injection, termed coasting, has been suggested as a treatment modality in cases of impending ovarian hyperstimulation syndrome (OHSS). It presents an opportunity to reduce the risk of OHSS and salvage the treatment, without apparent compromise to outcome. However, the duration of the coasting period, which would maintain the advantage without reducing conception rate, has not been fully established. In this retrospective study, we attempted to define the optimal interval of coasting in patients at risk of developing OHSS. METHODS: Patients were grouped according to the number of days elapsed between cessation of gonadotrophins and administration of HCG. Overall, out of 207 patients (mean age 30.76 +/- 0.33 years) coasting lasted 1 day in 39 cycles (18.8%), 2 days in 61 cycles (29.4%), 3 days in 49 cycles (23.6%) and > or = 4 days in the remaining 58 cycles (28.5%). RESULTS: There was no difference between the groups in patients' age, serum estradiol concentrations at the time of HCG administration, oocyte maturity, fertilization and embryo cleavage rates. However, patients in whom coasting lasted > or = 4 days had significantly reduced implantation (10.5%) and pregnancy (26.7%) rates compared with patients with a shorter coasting interval (ranges 18.4-27.9 and 41-55.7% respectively; P < 0.05). CONCLUSION: Coasting for >3 days appears to reduce implantation and pregnancy rates while in-vitro oocyte and embryo quality do not appear to be affected. We suggest that in patients who need coasting for >3 days, cryopreservation of embryos should be considered.     

Molecular Characterization of a Full Genome Turkish Hepatitis C Virus 1b Isolate (HCV-TR1): A Predominant Viral Form in Turkey

Based on direct sequencing information from 5UTR and NS5B regions, we identified subtype 1b as a predominant hepatitis C virus genome in Turkey, which affected more than 91% of 79 patients studied. Next, the full genome sequence of a Turkish 1b isolate was obtained by the cloning of polypeptide-encoding region into 7 overlapping fragments. Turkish 1b isolate, which was named HCV-TR1, comprises 9361 nucleotides, including 306 nucleotides of 5UTR, a single long open reading frame of 9033 nucleotides, and 22 nucleotides of 3UTR. When compared to HCV 1b polypeptide sequences available at GenBank, the predicted polypeptide displayed a total of 36 amino acid substitutions, of which 16 was specific for HCV-TR1 isolate. Despite these changes, major structural and functional motifs of HCV proteins were maintained in HCV-TR1. In contrast, HCV-TR1 displayed amino acid substitutions in 6 out of 9 major cytotoxic T-cell epitopes. These data suggest that HCV-TR1 encodes functionally intact viral proteins, but it also encodes altered viral epitopes, which may affect host immune-response.     

Novel Mutation in <Emphasis Type="Italic">CECR1</Emphasis> Leads to Deficiency of ADA2 with Associated Neutropenia

Purpose

Adenosine deaminase 2 (ADA2) have been reported to cause vasculitic diseases and immunodeficiency recently. Patients present with stroke episodes and rashes mimicking polyarteritis nodosa (PAN). We report a patient who has been followed up with severe neutropenia and found an unexpectedly revealed novel mutation in CECR1 affecting ADA2.

Methods

We reviewed medical records and clinical history of the patient. No mutations in other known neutropenia genes such as ELA, G6PC3, HAX1, AP3B1, LAMTOR2, VPS13B, VPS45, GFI1, JAGN1, or WAS could be detected. Sanger sequencing was used to confirm the genetic variants in the patient and relatives.

Results

Genetic analysis by exome sequencing revealed a novel mutation in the gene CECR1 (c.G962A; p.G321E) which segregated perfectly in the relatives.

Conclusion

This is the first DADA2 patient presenting with severe neutropenia. We suggest that in patients with unexplained cytopenias combined with immunodeficiency, fevers of unknown origin and high inflammation markers, DADA2 should be considered.

     

Patients with Primary Immunodeficiencies in Pediatric Intensive Care Unit: Outcomes and Mortality-Related Risk Factors

Purposes

The aims of this study were to review the frequency, characteristics, and the clinical course of primary immunodeficiency (PID) patients admitted to pediatric intensive care unit (PICU) and attempt to identify factors related with mortality that might predict a poor outcome.

Methods

We performed a retrospective review of children with PID aged 1 month to 18 years and admitted to PICU from January 2002 to January 2012 in our tertiary teaching children’s hospital.

Results

There were a total of 51 patients accounting for 71 admissions to the PICU. The most common diagnosis was severe combined immunodeficiency. Respiratory problems were the leading cause for admission. A total of 20 patients received hematopoietic stem cell transplantation. Immune reconstitution was achieved in 9 (45 %) patients and eight of them did survive. In all 56 % of all admission episodes resulted in survival. Risk factors for mortality included requirement of mechanical ventilation (P?<?.001), number of organ system failure (P?=?.013), need for renal replacement therapy (P?<?.001), use of inotropes (P?<?.001), higher Pediatric Logistic Organ Dysfunction (PELOD) score (P?=?.005), and length of PICU stay (P?<?.001).

Conclusions

This is the first study regarding the outcome and mortality-related risk factors for PID patients requiring PICU admission. We suggest that PICU management is as important as early diagnosis and treatment for these patients. Prediction of those at risk for poorer outcome might be beneficial for accurate intensive care management and survival.     

Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.

Nonmyeloablative allogeneic stem cell transplantation has recently been explored as a safer alternative to conventional high-dose transplant regimens. Although a high incidence of mixed chimerism after nonmyeloablative procedures has been reported, the exact kinetics of engrafting donor cells in specific cellular lineages has yet to be defined. We investigated lineage-specific chimerism in 15 patients receiving an allogeneic peripheral blood stem cell (PBSC) transplant from an HLA-identical (n = 14) or a 5/6 antigen-matched sibling donor after a preparative regimen of cyclophosphamide and fludarabine. Donor chimerism was assessed weekly in T lymphocytes and myeloid cells by polymerase chain reaction (PCR) of minisatellite regions. Eight patients survived between 121 to 409 days after transplant. Ten of 14 patients surviving more than 30 days (71.4%) had delayed disease regression consistent with a graft-versus-malignancy (GVM) effect. One patient rejected the transplant with subsequent recovery of autologous hematopoiesis. Hematological recovery was rapid (median, 11 days to >/=500 neutrophils/microL) and was initially predominantly recipient in origin. Donor myeloid chimerism gradually supplanted recipient hematopoiesis and became fully donor in all survivors by 200 days after transplantation. In contrast, T-cell engraftment was more rapid, with full chimerism in 7 patients by day 30 and in 6 further patients by day 200 after cyclosporine withdrawal and donor lymphocyte infusion. Full donor T-cell engraftment preceded donor myeloid engraftment, acute graft-versus-host disease, and disease regression, consistent with a requirement for 100% donor T-cell chimerism for full expression of the alloresponse. These results emphasize the importance of lineage-specific chimerism analysis to successfully manipulate engraftment after nonmyeloablative allogeneic PBSC transplantation.     

Which factors affect the likelihood of miscarriage after single euploid blastocyst transfer?

Research questionWhich parameters affect the likelihood of miscarriage after single euploid frozen–thawed blastocyst transfer (FBT)?DesignIn this retrospective study, clinical and laboratory data from 1051 single euploid FBTs were evaluated. Exclusion criteria were endocrine or systemic pathologies, uterine anomalies or pathologies, unilateral or bilateral hydrosalpinx, karyotypic abnormalities (either maternal or paternal) or thrombophilia. Patients were divided into two groups according to pregnancy outcome: live birth and miscarriage.ResultsBody mass index (BMI) (25.98 ± 0.5 versus 24.36 ± 0.21, P = 0.019), duration of infertility (6.62 ± 0.54 versus 4.92 ± 0.18, P = 0.006) and number of previous miscarriages (1.36 ± 0.13 versus 0.79 ± 0.05, P < 0.001) were significantly higher in the miscarriage group (n = 100) than in the live birth group (n = 589). Although the trophectoderm and inner cell mass (ICM) percentage scores were not statistically different among the miscarriage and live birth groups, the percentage of day-6 biopsied embryos was significantly higher in the miscarriage group. Binary logistic regression analysis revealed that BMI (OR 1.083, 95% CI 1.013 to 1.158, P = 0.02) and number of previous miscarriages (OR 1.279, 95% CI 1.013 to 1.158, P = 0.038) were independent factors for miscarriage. Patients with elevated BMI and a higher number of miscarriages were at increased risk of miscarriage.ConclusionAfter a single euploid FBT, BMI and number of previous miscarriages are predictors of miscarriage. Lifestyle interventions before FBT may decrease miscarriage rates.