Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer

Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.     

The comparison of angular and curvilinear marginal mandibulectomy on force distribution with three dimensional finite element analysis

AimThe purpose of this study was to analyse and compare right angled and curved osteotomy design on stress distribution and to determine an osteotomy design which decreases the risk of pathologic fracture.Patients and methodsSolid mathematical model of the mandible was created by three dimensional finite element analysis and two different osteotomy, right angled and curvilinear osteotomy was performed on model. 150 N incisal force vertically and 250 N molar force to the angulus area oblically were applied. The effects of osteotomy types to the stress formation and risk of fracture between models were evaluated.ResultsRight angled osteotomy causes much more stress in the posteroinferior quadrant and mainly localized on the horizontal and vertical osteotomy intersection area. On the other hand, the distribution of the stress on curvilinear formed osteotomy shows posteroinferior localization and stress spreads wider area. Furthermore the amount of stress was less than right-angled one.ConclusionIn this study, curved osteotomy denominated less stress distribution. The shape of osteotomy might be a factor to decrease the risk of postoperative atrophic mandible fracture.     

Cross-correlation between stress, pain, physical activity, and temporalis muscle EMG in tension-type headache

Thirty-six tension-type headache subjects and 36 non-headache matched controls recorded their temporalis muscle electromyographic (EMG) activity and their pain intensity, stress and physical activity levels in a daily diary. Measurements were performed every 30 min for 6 days (EMG 3 days only). A time-lagged cross-correlational analysis between pain, stress, physical activity, and EMG shows that the highest correlation coefficient values occurred between pain and stress at the same ( r =0.33) and at the two preceding 0.5 h time points ( r =0.21 and r =0.26) in the headache group. Virtually no correlation was found between pain, stress, or physical activity with EMG for either group. These data show that temporalis muscle activity levels were not related to the rise and fall of the subjects' pain or stress levels. Conversely, elevated stress appeared to be highly related to pain; it occurs as both an antecedent and simultaneous event with elevated headache pain.     

Aggressive Kaposi's sarcoma in children: a case report

A three-year-old-boy with generalized Kaposi's sarcoma (KS) is presented. The child died of progressive pulmonary insufficiency on the eighteenth day of the course of his illness, the tenth hospital day. On postmortem examination diffuse KS infiltration was observed in the respiratory and gastrointestinal tracts, lymph nodes, liver, spleen and thymus. The patient was considered to be a case of KS unrelated to AIDS because of his negative HTLV-III antibody and epidemiologic characteristics, and therefore was believed to have primary aggressive KS.     

Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis [published erratum appears in Hum Mol Genet 1997 Jan;6(1):146]

Mutations in the gene encoding lysosomal protective protein/cathepsin A (PPCA) are the cause of the lysosomal disorder galactosialidosis (GS). Depending on age of onset and severity of the symptoms, patients present with either an early infantile (EI), a late infantile (LI), or a juvenile/adult (J/A) form of the disease. To study genotype-phenotype correlation in this disorder, we have analyzed the mutations in the PPCA gene of eight clinically different patients. In two EI and one J/A patient, we have identified four novel point mutations (Val104Met, Leu208Pro, Gly411Ser and Ser23Tyr), that prevent phosphorylation and, hence, lysosomal localization and maturation of the mutant precursors. Two amino acid substitutions (Phe412Val and Tyr221Asn) are shared by five LI patients. These mutations appear to be pathognomonic for this phenotype, and determine the clinical outcome depending on whether they are present together or in combination with other mutations. The latter include a single base deletion and a novel amino acid change (Met378Thr), which generates an additional glycosylation site. Within the LI group, patients carrying the Phe412Val mutation are clinically more severe than those with the Tyr221Asn substitution. This is in agreement with the biochemical behavior of the Asn221-mutant protein, that is, like the Phe412Val protein, phosphorylated, routed to lysosomes and proteolytically processed, but its intralysosomal stability is intermediate between that of wild-type PPCA and Val412- PPCA. Overall, these results may explain the clinical heterogeneity observed in GS patients and may help to correlate mutant allelic combinations with specific clinical phenotypes.      

Analysis of pediatric thrombotic patients in Turkey

This study analyzes the data of thrombotic children who were followed up in different pediatric referral centers of Turkey, to obtain more general data on the diagnosis, risk factors, management, and outcome of thrombosis in Turkish children. A simple two-page questionnaire was distributed among contact people from each center to standardize data collection. Thirteen pediatric referral centers responded to the invitation and the total number of cases was 271. All children were diagnosed with thromboembolic disease between January 1995 and October 2001. Median age at time of first thrombotic event was 7.0 years. Of the children 4% of the cases were neonates, 12% were infants less than 1 year old, and 17% were adolescents. Thromboembolic event was mostly located in the cerebral vascular system (32%), deep venous system of the limbs, femoral and iliac veins (24%), portal veins (10%), and intracardiac region (9%). Acquired risk factors were present in 86% of the children. Infection was the most common underlying risk factor. Inherited risk factors were present in 30% of the children. FVL was the most common inherited risk factor. Acquired and inherited risk factors were present simultaneously in 19% of the patients. Eleven children had a history of familial thrombosis. Due to the local treatment preferences, the treatment of the children varied greatly. Outcome of the 142 patients (52%) was reported: 88 (62%) patients had complete resolution, 47 (33%) had complications, 12 (9%) had recurrent thrombosis, and 34 (24%) died. Three children (2.1%) died as a direct consequence of their thromboembolic disease. The significant morbidity and mortality found in this study supports the need for multicentric prospective clinical trials to obtain more generalizable data on management and outcome of thrombosis in Turkish children.