A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia.

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia (CLL) developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count >32.0x103/microliter, 1 point. Low-, intermediate- and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144 / 395 / 540 / 322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage CLL, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 CLL being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemofree era.

Axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma.

INTRODUCTION: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was recently approved for relapsed or refractory follicular lymphoma following progression on two or more lines of therapy including an anti-CD20 monoclonal antibody with an alkylating agent, providing a therapeutic breakthrough in a subset of indolent non-Hodgkin lymphoma associated with poor clinical outcomes. AREAS COVERED: In this article, we outline the drug profile of axicabtagene ciloleucel in comparison to currently approved agents and other CAR T-cell and T-cell redirecting therapies under investigation for the treatment of relapsed or refractory follicular lymphoma. We also review the efficacy, safety, and pharmacokinetic data from the ZUMA-5 phase II trial, which forms the basis of the recent approval of axicabtagene ciloleucel. EXPERT OPINION: Axicabtagene ciloleucel is the first cellular therapy approved for relapsed or refractory follicular lymphoma, demonstrating high rates of durable responses and a manageable toxicity profile in heavily pre-treated patients.

TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia.

PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. EXPERIMENTAL DESIGN: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. RESULTS: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. CONCLUSIONS: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

Gastric Outlet Obstruction due to Gastrointestinal Amyloidosis.

A 64- year-old man with smoldering myeloma presented to the hospital for nausea, vomiting, and PO intolerance. Abdominal CT demonstrated massive gastric distention and collapsed proximal duodenum consistent with gastric outlet obstruction (GOO). Esophagogastroduodenoscopy demonstrated pyloric edema. Duodenal biopsies were consistent with AL amyloidosis. Given the concerns for bleeding risk and immediate need to start chemotherapy, surgery was deferred. Chemotherapy was initiated with a good clinical response. Our non-operative approach is novel, eliminates perioperative adverse events, allows for early initiation of chemotherapy, and can serve as a model for patients with GOO resulting from AL amyloidosis who are not surgical candidates.

Stable Meniscal Tears Left In Situ at the Time of Arthroscopic Anterior Cruciate Ligament Reconstruction: A Systematic Review.

Meniscal tears can be incidentally encountered at the time of anterior cruciate ligament (ACL) reconstruction. In these cases, the surgeon has several treatment options that include benign neglect, debridement, trephination, and repair. The authors performed a systematic review of the literature studying the various treatment options for meniscal tears discovered at the time of ACL reconstruction. This systematic review included eight articles that had relevant data regarding benign neglect compared with debridement, trephination, or repair of incidentally encountered meniscal tears. Combined data from these studies resulted in a total of 646 meniscal tears treated with benign neglect with follow-up information available. Importantly, there were differences in reoperation rates between medial and lateral meniscal tears left in situ. However, stable medial and lateral meniscal tears treated with benign neglect did not have different subjective or objective outcomes than those treated with surgical intervention. This systematic review concludes that when stable meniscal tears are encountered at the time of arthroscopic ACL reconstruction, benign neglect can be used for a successful outcome.

Herpes simplex virus seroprevalence and seroconversion among active duty US air force members with HIV infection.

BACKGROUND: Herpes simplex virus (HSV) infection is associated with an increased risk of both HIV transmission and acquisition. We evaluated longitudinal HSV serology and sexually transmitted infections (STIs) among active duty US Air Force (USAF) members with HIV infection. METHODS: USAF members diagnosed with HIV between 1996 and 2012 were included and divided into 2 groups: 1996-2004 (n=131) and 2005-2012 (n=266). HSV-1 and -2 serology was evaluated at HIV diagnosis. Longitudinal HSV-1 and -2 serology and ICD-9 codes for HSV and non-HSV STIs were also examined for those with ≥ 1 year of follow-up. RESULTS: Patients were most commonly Caucasian (44.2%) or African American (43.4%) men with a median age of 28 years at HIV diagnosis. HSV-2 seroprevalence at HIV diagnosis decreased from the period of 1996-2004 (48.8%) to 2005-2012 (30.1%; P<0.01). Odds of HSV-2 seropositivity was significantly greater for non-Caucasians (OR 2.19, 95% CI 1.33-3.60) and for HIV diagnosis between 1996 and 2004 (OR 2.06, 95% CI 1.29-3.27), with a trend observed for those age >30 years at HIV diagnosis (OR 1.73, 95% CI 0.94-3.18). A total of 81 (20.4%) patients developed STIs by ICD-9 codes, including 24 (6.1%) new genital herpes diagnoses, during a median follow-up of 4.6 years. HSV-2 seroconversion occurred in 33 of 253 (13.0%) with an incidence rate of 5.07 per 100 person-years (95% CI 4.76-5.37). CONCLUSION: Although HSV-2 seroprevalence at HIV diagnosis decreased over time, high-risk sexual behaviors were ongoing as evidenced by the high proportion of new STI diagnoses and HSV-2 seroconversions. Continued education to reduce risk behaviors is warranted to prevent acquisition and transmission of STIs in HIV-infected persons.

Aortic dissection associated with an obstructive aortic chondrosarcoma in a dog.

A 6-year-old, 35-kg, female spayed German wirehaired pointer was referred for evaluation of collapse/seizure-like activity and a suspected mediastinal mass. Echocardiographic examination revealed an obstructive, intraluminal aortic mass with aortic dissection. Gross and histopathological findings confirmed the aortic dissection with right pulmonary artery compression and an aortopulmonary fistula. The mass was histologically consistent with an intraluminal chondrosarcoma. To the authors knowledge this case represents only the second case of aortic chondrosarcoma in a dog, and interestingly the first case in either a dog or human to have aortic dissection associated with aortic obstruction by an intraluminal aortic tumor.

Time-of-day affects expression of hippocampal markers for ischemic damage induced by global ischemia.

Time-of-day-dependent variation in neuronal ischemia is well documented. Whether this results from changes in time-of-day variation in susceptibility or from other causative factors remains unclear. We hypothesize that hippocampal cells exhibit variation in activation of cell death predictive markers in response to ischemia induced at different times-of-day. Changes in hippocampal circadian clock gene rhythmicity may also be associated with ischemia. Transient global ischemia was induced in rats at three times of day and animals were sacrificed 24 h later. Hippocampal caspase-3, -8 and -9 transcripts and active proteins and calbindin protein were measured in the CA1 region of the hippocampus. In a second study, 24-h rhythms of circadian regulatory transcripts were determined in hippocampus after global ischemia. Caspase-3, -8 and -9 transcripts and active protein levels were increased substantially when ischemia occurred in early night (ZT14); smaller changes were observed in late night (ZT20, or day ZT6). Calbindin levels decreased following ischemia, especially at ZT14. Ischemia shifted the rhythm of the Per1 transcript; peak expression occurred 6 h earlier following ischemia. Rhythms of Cry1 and Bmal1 were not altered. Greater induction of caspases and decline of calbindin when ischemia was performed at ZT14 than at ZT20 or ZT6 support the concept of increased hippocampal susceptibility to ischemia at ZT14. Alteration of the Per1 transcript suggests a potential role for the circadian clock in this process. Notably, ZT14 represents the beginning of the rats' nocturnal period of activity, corresponding to the time when humans experience the greatest neuronal ischemic damage from stroke.