Circadian Rhythmicity as a Predictor of Quality of Life in Allogeneic Hematopoietic Cell Transplant Patients

Context

Quality of life (QoL) is increasingly recognized as an important outcome of cancer treatment. Previous studies have examined clinical predictors of QoL, but with the increasing prevalence of wearable sensors that monitor sleep and activity patterns, further investigation into whether these behaviors are predictive of post-treatment QoL is now feasible. Among patients receiving aggressive cancer treatment such as hematopoietic cell transplantation (HCT), analysis of circadian rhythms (24-hour patterns of sleep and activity) via wearable sensors is limited.

A rare case of invasive melanoma likely arising from passenger melanocytes of a basal cell carcinoma

Neoplasms consisting of different cell lineages within a single skin specimen are rare, yet well documented in the literature. However, to date, there appears to be no report of invasive melanoma arising directly from the passenger melanocytes of a basal cell carcinoma (BCC). We present a case of a 91-year-old male with a suspicious lesion on the ear. Histopathology and immunohistochemical staining revealed BCC closely intertwined with invasive melanoma that exhibited foci of chondroid differentiation. The melanoma appeared to arise from the benign-appearing passenger melanocytes of the BCC and lacked connection to the overlying epidermis or an in situ component. Multiple dermatopathologists reviewed the case and agreed that the most likely explanation for the histopathologic findings was that the invasive melanoma arose from the passenger melanocytes within the BCC.     

Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing’s sarcoma A673-xenograft growth and normalize tumor vascular architecture

Increasing experimental evidence suggests that IGF-1 may modulate tumor angiogenesis via activation of the expression of VEGF in Ewing sarcomas and rhabdomyosarcomas. This study investigates the effects of the PEGylated Adnectins? CT-322, a VEGFR2-inhibitor and AT580Peg40, an IGF-1R inhibitor, as monotherapy and in combination in a murine A673 xenograft tumor model. The combination of Adnectins CT-322 and AT580Peg40 revealed a 83?% reduction in tumor growth, a nearly 5 times lower vessel density, less necrotic areas and less appearance of intussusceptive angiogenesis. Monotherapy with IGF-1R or CT-322 revealed equally a significant inhibition of tumor and vessel growth. Combinatory inhibition of IGF-1R and VEGFR2 shows a downregulation of IGF-binding protein 2 and a compensatory upregulation of VEGF levels. Immunohistological analysis showed remodeling vascular effects of CT-322-treatment or combination therapy. The vascular architecture in Adnectin-treated tumors was characterized by a strong normalization of vasculature. 3D-evaluation in microvascular corrosion casts showed significantly higher intervascular and interbranching distances in Adnectin-treated tumors. CT-322-treatment and combinatory inhibition reveal a significant reduction of intussusceptive angiogenesis. These pronounced effects on tumor vasculature suggest potential therapeutic benefit of combinatorial IGF1- and VEGF- pathways inhibition in Ewing’s sarcoma.     

Qualitative research within the Deaf community in Northern Ireland: A multilingual approach

In this methodology article, the authors illustrate how they conducted multilingual qualitative research in an exploration of the barriers that Deaf people in Northern Ireland face when attempting to access the system of justice. The authors’ research practices are informed, to the extent possible, by the principles of community-based participatory research (CBPR). They explore the challenges of conducting research in American Sign Language (ASL), British Sign Language (BSL), and Irish Sign Language (ISL), and spoken English, facilitated by sign language interpreters fluent in BSL and ISL. Centering the research on the lived experiences of Deaf people who navigate the system of justice, the authors implemented CBPR-informed research methods, which ultimately led to sustained discussion and joint action by the authors and members of the Northern Ireland Deaf community aimed at the removal of barriers that Deaf people face when interacting with the justice system. By writing about their methodological approach in Northern Ireland, the authors wish to be transparent about their work in the hope that other researchers can replicate their successes and avoid the limitations of conducting this work in partnership with members of the Deaf community in other countries.     

How accurate is Invisalign in nonextraction cases? Are predicted tooth positions achieved?

Objective:To evaluate the accuracy of Invisalign technology in achieving predicted tooth positions with respect to tooth type and direction of tooth movement.Materials and Methods:The posttreatment models of 30 patients who had nonextraction Invisalign treatment were digitally superimposed on their corresponding virtual treatment plan models using best-fit surface-based registration. The differences between actual treatment outcome and predicted outcome were computed and tested for statistical significance for each tooth type in mesial-distal, facial-lingual, and occlusal-gingival directions, as well as for tip, torque, and rotation. Differences larger than 0.5 mm for linear measurements and 2° for angular measurements were considered clinically relevant.Results:Statistically significant differences (P < .05) between predicted and achieved tooth positions were found for all teeth except maxillary lateral incisors, canines, and first premolars. In general, anterior teeth were positioned more occlusally than predicted, rotation of rounded teeth was incomplete, and movement of posterior teeth in all dimensions was not fully achieved. However, except for excess posttreatment facial crown torque of maxillary second molars, these differences were not large enough to be clinically relevant.Conclusions:Although Invisalign is generally able to achieve predicted tooth positions with high accuracy in nonextraction cases, some of the actual outcomes may differ from the predicted outcomes. Knowledge of dimensions in which the final tooth position is less consistent with the predicted position enables clinicians to build necessary compensations into the virtual treatment plan.     

Chapter 12: Systematic Review of Prognostic Tests

A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted.     

Cytoplasmic TRADD Confers a Worse Prognosis in Glioblastoma

Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-κB. Recent studies have highlighted the importance of NF-κB activation as a key pathogenic mechanism in glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults.We examined the expression of TRADD by immunohistochemistry (IHC) and find that TRADD is commonly expressed at high levels in GBM and is detected in both cytoplasmic and nuclear distribution. Cytoplasmic IHC TRADD scoring is significantly associated with worse progression-free survival (PFS) both in univariate and multivariate analysis but is not associated with overall survival (n = 43 GBMs). PFS is a marker for responsiveness to treatment. We propose that TRADD-mediated NF-κB activation confers chemoresistance and thus a worse PFS in GBM. Consistent with the effect on PFS, silencing TRADD in glioma cells results in decreased NF-κB activity, decreased proliferation of cells, and increased sensitivity to temozolomide. TRADD expression is common in glioma-initiating cells. Importantly, silencing TRADD in GBM-initiating stem cell cultures results in decreased viability of stem cells, suggesting that TRADD may be required for maintenance of GBM stem cell populations. Thus, our study suggests that increased expression of cytoplasmic TRADD is both an important biomarker and a key driver of NF-κB activation in GBM and supports an oncogenic role for TRADD in GBM.