Disease evolution and outcomes in familial AML with germline CEBPA mutations

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model.

The updated Vienna Prediction Model for estimating recurrence risk after an unprovoked venous thromboembolism (VTE) has been developed to identify individuals at low risk for VTE recurrence in whom anticoagulation (AC) therapy may be stopped after 3 months. We externally validated the accuracy of the model to predict recurrent VTE in a prospective multicenter cohort of 156 patients aged ≥65 years with acute symptomatic unprovoked VTE who had received 3 to 12 months of AC. Patients with a predicted 12-month risk within the lowest quartile based on the updated Vienna Prediction Model were classified as low risk. The risk of recurrent VTE did not differ between low- vs higher-risk patients at 12 months (13% vs 10%; P = .77) and 24 months (15% vs 17%; P = 1.0). The area under the receiver operating characteristic curve for predicting VTE recurrence was 0.39 (95% confidence interval [CI], 0.25-0.52) at 12 months and 0.43 (95% CI, 0.31-0.54) at 24 months. In conclusion, in elderly patients with unprovoked VTE who have stopped AC, the updated Vienna Prediction Model does not discriminate between patients who develop recurrent VTE and those who do not. This study was registered at www.clinicaltrials.gov as #NCT00973596.

The physiological roles of ICAM-1 and ICAM-2 in neutrophil migration into tissues

PURPOSE OF REVIEW Neutrophil extravasation from the blood into tissues is initiated by tethering and rolling of neutrophils on endothelial cells, followed by neutrophil integrin activation and shear resistant arrest, crawling, diapedesis and breaching the endothelial basement membrane harbouring pericytes. Endothelial intercellular cell adhesion molecule (ICAM)-1 and ICAM-2, in conjunction with ICAM-1 on pericytes, critically contribute to each step. In addition, epithelial ICAM-1 is involved in neutrophil migration to peri-epithelial sites. The most recent findings on the role of ICAM-1 and ICAM-2 for neutrophil migration into tissues will be reviewed here. RECENT FINDINGS Signalling via endothelial ICAM-1 and ICAM-2 contributes to stiffness of the endothelial cells at sites of chronic inflammation and junctional maturation, respectively. Endothelial ICAM-2 contributes to neutrophil crawling and initiation of paracellular diapedesis, which then proceeds independent of ICAM-2. Substantial transcellular neutrophil diapedesis across the blood-brain barrier is strictly dependent on endothelial ICAM-1 and ICAM-2. Endothelial ICAM-1 or ICAM-2 is involved in neutrophil-mediated plasma leakage. ICAM-1 on pericytes assists the final step of neutrophil extravasation. Epithelial ICAM-1 rather indirectly promotes neutrophil migration to peri-epithelial sites. SUMMARY ICAM-1 and ICAM-2 are involved in each step of neutrophil extravasation, and have redundant but also distinct functions. Analysis of the role of endothelial ICAM-1 requires simultaneous consideration of ICAM-2.

Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis.

Immunoassays are essential in the workup of patients with suspected heparin-induced thrombocytopenia. However, the diagnostic accuracy is uncertain with regard to different classes of assays, antibody specificities, thresholds, test variations, and manufacturers. We aimed to assess diagnostic accuracy measures of available immunoassays and to explore sources of heterogeneity. We performed comprehensive literature searches and applied strict inclusion criteria. Finally, 49 publications comprising 128 test evaluations in 15 199 patients were included in the analysis. Methodological quality according to the revised tool for quality assessment of diagnostic accuracy studies was moderate. Diagnostic accuracy measures were calculated with the unified model (comprising a bivariate random-effects model and a hierarchical summary receiver operating characteristics model). Important differences were observed between classes of immunoassays, type of antibody specificity, thresholds, application of confirmation step, and manufacturers. Combination of high sensitivity (>95%) and high specificity (>90%) was found in 5 tests only: polyspecific enzyme-linked immunosorbent assay (ELISA) with intermediate threshold (Genetic Testing Institute, Asserachrom), particle gel immunoassay, lateral flow immunoassay, polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and immunoglobulin G (IgG)-specific CLIA with low threshold. Borderline results (sensitivity, 99.6%; specificity, 89.9%) were observed for IgG-specific Genetic Testing Institute-ELISA with low threshold. Diagnostic accuracy appears to be inadequate in tests with high thresholds (ELISA; IgG-specific CLIA), combination of IgG specificity and intermediate thresholds (ELISA, CLIA), high-dose heparin confirmation step (ELISA), and particle immunofiltration assay. When making treatment decisions, clinicians should be a aware of diagnostic characteristics of the tests used and it is recommended they estimate posttest probabilities according to likelihood ratios as well as pretest probabilities using clinical scoring tools.

Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874.

Targeted therapies for small cell lung cancer: Where do we stand?

Small cell lung cancer (SCLC) accounts for 15% of lung cancer cases and is associated with a dismal prognosis. Standard therapeutic regimens have been improved over the past decades, but without a major impact on patient survival. The development of targeted therapies based on a better understanding of the molecular basis of the disease is urgently needed. At the genetic level, SCLC appears very heterogenous, although somatic mutations targeting classical oncogenes and tumor suppressors have been reported. SCLC also possesses somatic mutations in many other cancer genes, including transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components. Several avenues have been explored to develop targeted therapies for SCLC. So far, however, there has been limited success with these targeted approaches in clinical trials. Further progress in the optimization of targeted therapies for SCLC will require the development of more personalized approaches for the patients.

Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency.

The congenital form of thrombotic thrombocytopenic purpura (TTP) is caused by genetic mutations in ADAMTS13. Some, but not all, congenital TTP patients manifest renal insufficiency in addition to microangiopathic hemolysis and thrombocytopenia. We included 32 congenital TTP patients in the present study, which was designed to assess whether congenital TTP patients with renal insufficiency have predisposing mutations in complement regulatory genes, as found in many patients with atypical hemolytic uremic syndrome (aHUS). In 13 patients with severe renal insufficiency, six candidate complement or complement regulatory genes were sequenced and 11 missense mutations were identified. One of these missense mutations, C3:p.K155Q mutation, is a rare mutation located in the macroglobulin-like 2 domain of C3, where other mutations predisposing for aHUS cluster. Several of the common missense mutations identified in our study have been reported to increase disease-risk for aHUS, but were not more common in patients with as compared to those without renal insufficiency. Taken together, our results show that the majority of the congenital TTP patients with renal insufficiency studied do not carry rare genetic mutations in complement or complement regulatory genes.

MS 073 Guide to the William C. Moloney MD papers; 1952-1954

William C. Moloney MD kept a personal journal, with photographs, for much of his two years in Japan with the Atomic Bomb Casualty Commission. In January of 1986, Dr.Moloney donated his journal, correspondence and diary pages to the Harris County Medical Archive. He died in 1998 at the age of 91. His first contribution was a set of ten reprints representing his work with the ABCC from 1952 to 1954. Dr.Moloney's journal is a fine document, one which will be of great use to historians. It is an important record of personal impressions, thoughts and details of events. The journal gives new insights into the work of the ABCC and into the people who participated in that work. Dr. Moloney wrote in his journal from April 1952 to February 1954. The Korean War was on and there was a great deal of military activity in southern Japan. The collection is open for research. The collection consists of a handwritten journal, loose calendar or notebook pages and some reprints. The journal is in generally fair condition. The paper is slightly acidic and the binding is loose. There are numerous photos glued onto the pages. The collection encompasses the years 1952-1954 and is 0.25 cubic feet (1 box).

MS#73 William C. Moloney, M.D., papers; 1952-1954

Dr. Moloney kept a personal journal, with photographs, for much of his two years with the Atomic Bomb Casualty Commission in Japan. Along with other scientists, he studied the biological and medical effects of ionized radiation on the survivors of the Hiroshima and Nagasaki atomic bombings. In January of 1986, Dr. Moloney donated his journal, correspondence and diary pages to the Harris County Medical Archive, whose collections were later incorporated into the Texas Medical Center Library. Dr. Moloney's journal is in relatively good shape containing a mix of handwritten notes and comments, news-clippings, photos, and ephemera. The journal is an important record of personal impressions, thoughts and details of events during a pivotal time in Japan. This 192-pagee journal gives new insights into the work of the ABCC and into the people who participated in that work. The journal covers the period from April 1952 to February 1954. In these documents, Moloney records his struggles with understanding the Japanese culture, his frustration at not being allowed to treat the survivors he studied, and his concerns, fears, hopes and revelations as he dealt with the bombing survivors and their children. The original papers are open for research at the John P. McGovern Historical Collections and Research Center in the TMC Library in Houston.

Africa en tres tiempos. El impacto de la experiencia oriental en la obra de Roberto Arlt

En 1935, Carlos Muzio Saénz Peña, el director de El Mundo, envía a Roberto Arlt como corresponsal a Europa desde donde remite casi a diario y por avión sus impresiones de viajero. Entre julio y agosto de 1935 se publican en el diario las aguafuertes que documentan y describen su recorrido por el norte de Africa. Es relevante destacar que la intervención de Arlt en el diario no sólo se llevó a cabo a partir de sus crónicas, sino también a partir de su labor como fotógrafo. Estas notas de viaje fueron publicadas, en su gran mayoría, junto a dos o tres fotografías tomadas por el mismo autor. Posteriormente, en 1938, Arlt retoma el escenario africano y sus personajes los relatos que componen El criador de gorilas.1 La siguiente ponencia se propone indagar, a este respecto, el modo en que la experiencia oriental es plasmada por el autor a través de tres manifestaciones artísticas diferentes- fotografía, discurso periodístico, cuento fantástico- que al mismo tiempo que demuestran el impacto de la cultura africana en el pensamiento del autor, también postulan un recorrido que se inicia con la instantaneidad de la imagen fotográfica y desemboca, años más tarde, en la relaboración fantástica de los relatos de El criador de gorilas

Africa en tres tiempos. El impacto de la experiencia oriental en la obra de Roberto Arlt

En 1935, Carlos Muzio Saénz Peña, el director de El Mundo, envía a Roberto Arlt como corresponsal a Europa desde donde remite casi a diario y por avión sus impresiones de viajero. Entre julio y agosto de 1935 se publican en el diario las aguafuertes que documentan y describen su recorrido por el norte de Africa. Es relevante destacar que la intervención de Arlt en el diario no sólo se llevó a cabo a partir de sus crónicas, sino también a partir de su labor como fotógrafo. Estas notas de viaje fueron publicadas, en su gran mayoría, junto a dos o tres fotografías tomadas por el mismo autor. Posteriormente, en 1938, Arlt retoma el escenario africano y sus personajes los relatos que componen El criador de gorilas.1 La siguiente ponencia se propone indagar, a este respecto, el modo en que la experiencia oriental es plasmada por el autor a través de tres manifestaciones artísticas diferentes- fotografía, discurso periodístico, cuento fantástico- que al mismo tiempo que demuestran el impacto de la cultura africana en el pensamiento del autor, también postulan un recorrido que se inicia con la instantaneidad de la imagen fotográfica y desemboca, años más tarde, en la relaboración fantástica de los relatos de El criador de gorilas

Africa en tres tiempos. El impacto de la experiencia oriental en la obra de Roberto Arlt

En 1935, Carlos Muzio Saénz Peña, el director de El Mundo, envía a Roberto Arlt como corresponsal a Europa desde donde remite casi a diario y por avión sus impresiones de viajero. Entre julio y agosto de 1935 se publican en el diario las aguafuertes que documentan y describen su recorrido por el norte de Africa. Es relevante destacar que la intervención de Arlt en el diario no sólo se llevó a cabo a partir de sus crónicas, sino también a partir de su labor como fotógrafo. Estas notas de viaje fueron publicadas, en su gran mayoría, junto a dos o tres fotografías tomadas por el mismo autor. Posteriormente, en 1938, Arlt retoma el escenario africano y sus personajes los relatos que componen El criador de gorilas.1 La siguiente ponencia se propone indagar, a este respecto, el modo en que la experiencia oriental es plasmada por el autor a través de tres manifestaciones artísticas diferentes- fotografía, discurso periodístico, cuento fantástico- que al mismo tiempo que demuestran el impacto de la cultura africana en el pensamiento del autor, también postulan un recorrido que se inicia con la instantaneidad de la imagen fotográfica y desemboca, años más tarde, en la relaboración fantástica de los relatos de El criador de gorilas