Developing a Framework for the Design and Deployment of Virtual Reality (VR) in Clinical Education.

The emerging cost-effective and powerful standalone VR hardware is an increasingly viable supplement to traditional clinical educational modalities. These traditional approaches are effective but can be limited by the cost of simulation infrastructure, the requirement to attend at fixed times and locations and instructor availability present challenges in meeting the needs of clinicians. One barrier facing educators looking to develop bespoke VR-based solutions is the lack of guidelines around their design, development, deployment, and evaluation. Our team has produced and deployed a number of VR-based educational applications. Through reflecting on findings from surveys, interviews, observation, we summarise a range of insights into the complexity and nuances of the clinical VR design and deployment in a framework that can inform and guide educators, clinicians and developers looking to create their own VR applications for use in healthcare.

Predictive Radiation Oncology - A New NCI-DOE Scientific Space and Community.

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Café" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, and 27 universities. Here we summarize the workshops by first describing the background for the workshops. Participants identified twelve key questions-and collaborative parallel ideas-as the focus of work going forward to advance the field. These were then used to define short-term and longer-term "Blue Sky" goals. In addition, the group determined key success factors for predictive oncology in the context of radiation oncology, if not the future of all of medicine. These are: cross-discipline collaboration, targeted talent development, development of mechanistic mathematical and computational models and tools, and access to high-quality multiscale data that bridges mechanisms to phenotype. The workshop participants reported feeling energized and highly motivated to pursue next steps together to address the unmet needs in radiation oncology specifically and in cancer research generally and that NCI and DOE project goals align at the convergence of radiation therapy and advanced computing.

The management of the shoulder skin microbiome (Cutibacterium acnes) in the context of shoulder surgery: a review of the current literature.

BACKGROUND: This review aims to establish current knowledge of the shoulder skin microbiome and how to manage the bacteria that reside within it. METHODS: A review was undertaken of the current literature through OvidSP. All abstracts were reviewed by three independent researchers. RESULTS: Thirty-five studies met the inclusion criteria. With forward referencing an additional 14 were included. None commented on organisms specific to the shoulder microbiome other than Cutibacterium acnes. Therefore, this review is focussed on the current knowledge of C. acnes. DISCUSSION: C. acnes is a skin commensal within the pilo-sebaceous glands reported to be the primary pathogen in up to 86% of shoulder joint infections. Pre-operative culture of unprepared skin can be indicative of underlying joint infection in shoulder arthroplasty revision. Intra-articular biopsies may have a high false positive due to skin contamination. Correlating the number of positive samples and certain associated signs can give a greater than 90% probability of a true infection. Standard surgical skin preparation, peri-surgical intravenous antibiotics and oral pre-operative antibiotics do not reduce bacterial load within the skin. However, topical benzoyl peroxide and clindamycin have both demonstrated significantly reduced bacteria load. Phylogenetically there are six main types. Patients may have more than one phenotype present during infection.

Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells.

Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4+ and CD8+ effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.

Financial Implications of Early Hospital Discharge After AML-Like Induction Chemotherapy: A 4-Year Retrospective Analysis.

BACKGROUND: Early hospital discharge (EHD) after intensive acute myeloid leukemia (AML) induction chemotherapy has become routine at the University of Washington/Seattle Cancer Care Alliance over the past several years. We assessed the financial implications of EHD over the first 4 years after its broad adoption for patients with AML and other high-grade myeloid neoplasms undergoing AML-like induction chemotherapy. PATIENTS AND METHODS: We retrospectively compared charges between 189 patients with EHD who received all postinduction inpatient/outpatient care within our care system between August 2014 and July 2018 and 139 medically matched control patients who remained hospitalized for logistical reasons. Charges from the day of initial discharge (patients with EHD) or end of chemotherapy (control patients) until blood count recovery, additional chemotherapy or care transition, hospital discharge (for control patients only), an elapse of 42 days, or death were extracted from financial databases and separated into categories: facility/provider, emergency department, transfusions, laboratory, imaging, pharmacy, and miscellaneous. RESULTS: Combined charges averaged $4,157/day (range, $905-$13,119/day) for patients with EHD versus $9,248/day (range, $4,363-$48,522/day) for control patients (P<.001). The EHD cohort had lower mean facility/provider, transfusion, laboratory, and pharmacy charges but not imaging or miscellaneous charges. During readmissions, there was no statistically significant difference in daily inpatient charges between the EHD and control cohorts. After multivariable adjustment, average charges were $3,837/day lower for patients with EHD (P<.001). CONCLUSIONS: Together with previous data from our center showing that EHD is safe and associated with reduced healthcare resource utilization, this study further supports this care approach for AML and other high-grade myeloid neoplasms if infrastructure is available to enable close outpatient follow-up.

Using electronic health records and claims data to identify high-risk patients likely to benefit from palliative care.

OBJECTIVES: Palliative care has been demonstrated to have positive effects for patients, families, health care providers, and health systems. Early identification of patients who are likely to benefit from palliative care would increase opportunities to provide these services to those most in need. This study predicted all-cause mortality of patients as a surrogate for patients who could benefit from palliative care. STUDY DESIGN: Claims and electronic health record (EHR) data for 59,639 patients from a large integrated health care system were utilized. METHODS: A deep learning algorithm-a long short-term memory (LSTM) model-was compared with other machine learning models: deep neural networks, random forest, and logistic regression. We conducted prediction analyses using combined claims data and EHR data, only claims data, and only EHR data, respectively. In each case, the data were randomly split into training (80%), validation (10%), and testing (10%) data sets. The models with different hyperparameters were trained using the training data, and the model with the best performance on the validation data was selected as the final model. The testing data were used to provide an unbiased performance evaluation of the final model. RESULTS: In all modeling scenarios, LSTM models outperformed the other 3 models, and using combined claims and EHR data yielded the best performance. CONCLUSIONS: LSTM models can effectively predict mortality by using a combination of EHR data and administrative claims data. The model could be used as a promising clinical tool to aid clinicians in early identification of appropriate patients for palliative care consultations.

A highly effective reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay for the rapid detection of SARS-CoV-2 infection.

The COVID-19 pandemic has illustrated the importance of simple, rapid and accurate diagnostic testing. This study describes the validation of a new rapid SARS-CoV-2 RT-LAMP assay for use on extracted RNA or directly from swab offering an alternative diagnostic pathway that does not rely on traditional reagents that are often in short supply during a pandemic. Analytical specificity (ASp) of this new RT-LAMP assay was 100% and analytical sensitivity (ASe) was between 1 × 101 and 1 × 102 copies per reaction when using a synthetic DNA target. The overall diagnostic sensitivity (DSe) and specificity (DSp) of RNA RT-LAMP was 97% and 99% respectively, relative to the standard of care rRT-PCR. When a CT cut-off of 33 was employed, above which increasingly evidence suggests there is a low risk of patients shedding infectious virus, the diagnostic sensitivity was 100%. The DSe and DSp of Direct RT-LAMP (that does not require RNA extraction) was 67% and 97%, respectively. When setting CT cut-offs of ≤33 and ≤25, the DSe increased to 75% and 100%, respectively, time from swab-to-result, CT < 25, was < 15 min. We propose that RNA RT-LAMP could replace rRT-PCR where there is a need for increased sample throughput and Direct RT-LAMP as a near-patient screening tool to rapidly identify highly contagious individuals within emergency departments and care homes during times of increased disease prevalence ensuring negative results still get laboratory confirmation.

Modeling Immune Checkpoint Inhibitor Efficacy in Syngeneic Mouse Tumors in an Ex Vivo Immuno-Oncology Dynamic Environment.

The immune checkpoint blockade represents a revolution in cancer therapy, with the potential to increase survival for many patients for whom current treatments are not effective. However, response rates to current immune checkpoint inhibitors vary widely between patients and different types of cancer, and the mechanisms underlying these varied responses are poorly understood. Insights into the antitumor activities of checkpoint inhibitors are often obtained using syngeneic mouse models, which provide an in vivo preclinical basis for predicting efficacy in human clinical trials. Efforts to establish in vitro syngeneic mouse equivalents, which could increase throughput and permit real-time evaluation of lymphocyte infiltration and tumor killing, have been hampered by difficulties in recapitulating the tumor microenvironment in laboratory systems. Here, we describe a multiplex in vitro system that overcomes many of the deficiencies seen in current static histocultures, which we applied to the evaluation of checkpoint blockade in tumors derived from syngeneic mouse models. Our system enables both precision-controlled perfusion across biopsied tumor fragments and the introduction of checkpoint-inhibited tumor-infiltrating lymphocytes in a single experiment. Through real-time high-resolution confocal imaging and analytics, we demonstrated excellent correlations between in vivo syngeneic mouse and in vitro tumor biopsy responses to checkpoint inhibitors, suggesting the use of this platform for higher throughput evaluation of checkpoint efficacy as a tool for drug development.

A Microfluidic Device to Enhance Viral Transduction Efficiency During Manufacture of Engineered Cellular Therapies.

The development and approval of engineered cellular therapies are revolutionizing approaches to treatment of diseases. However, these life-saving therapies require extensive use of inefficient bioprocessing equipment and specialized reagents that can drive up the price of treatment. Integration of new genetic material into the target cells, such as viral transduction, is one of the most costly and labor-intensive steps in the production of cellular therapies. Approaches to reducing the costs associated with gene delivery have been developed using microfluidic devices to increase overall efficiency. However, these microfluidic approaches either require large quantities of virus or pre-concentration of cells with high-titer viral particles. Here, we describe the development of a microfluidic transduction device (MTD) that combines microfluidic spatial confinement with advective flow through a membrane to efficiently colocalize target cells and virus particles. We demonstrate that the MTD can improve the efficiency of lentiviral transduction for both T-cell and hematopoietic stem-cell (HSC) targets by greater than two fold relative to static controls. Furthermore, transduction saturation in the MTD is reached with only half the virus required to reach saturation under static conditions. Moreover, we show that MTD transduction does not adversely affect cell viability or expansion potential.

Reducing Unnecessary Head Computed Tomography in Mild Traumatic Brain Injury.

There is growing concern about the frequency of computed tomographic (CT) scans performed for evaluation of adults with suspected mild traumatic brain injury. The Canadian CT Head Rule and the New Orleans Criteria are the most studied head CT decision tools that aid providers in determining which patients do not require a CT scan. This article examines recent research to determine which of these tools has proven to be the most effective at safely reducing the use of head CT scans. The reviewed studies concluded that both the Canadian CT Head Rule and the New Orleans Criteria had similar sensitivities, but the Canadian CT Head Rule showed superior specificity in predicting the presence of a clinically significant brain injury. The authors of this article recommend that the Canadian CT Head Rule be used in the evaluation of minor head injury to reduce unnecessary CT scans.

Selective Inhibitors of Histone Deacetylases 1 and 2 Synergize with Azacitidine in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have potential beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, primary leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.

Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma.

Mutations in the ALK tyrosine kinase receptor gene represent important therapeutic targets in neuroblastoma, yet their clinical translation has been challenging. The ALK(F1174L) mutation is sensitive to the ALK inhibitor crizotinib only at high doses and mediates acquired resistance to crizotinib in ALK-translocated cancers. We have shown that the combination of crizotinib and an inhibitor of downstream signaling induces a favorable response in transgenic mice bearing ALK(F1174L)/MYCN-positive neuroblastoma. Here, we investigated the molecular basis of this effect and assessed whether a similar strategy would be effective in ALK-mutated tumors lacking MYCN overexpression. We show that in ALK-mutated, MYCN-amplified neuroblastoma cells, crizotinib alone does not affect mTORC1 activity as indicated by persistent RPS6 phosphorylation. Combined treatment with crizotinib and an ATP-competitive mTOR inhibitor abrogated RPS6 phosphorylation, leading to reduced tumor growth and prolonged survival in ALK(F1174L)/MYCN-positive models compared to single agent treatment. By contrast, this combination, while inducing mTORC1 downregulation, caused reciprocal upregulation of PI3K activity in ALK-mutated cells expressing wild-type MYCN. Here, an inhibitor with potency against both mTOR and PI3K was more effective in promoting cytotoxicity when combined with crizotinib. Our findings should enable a more precise selection of molecularly targeted agents for patients with ALK-mutated tumors.

Slow-cycling therapy-resistant cancer cells.

Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be secondary to small subsets of cancer cells that are better able to survive traditional forms of chemotherapy and thus drive tumor regrowth. The ability to isolate and better characterize these therapy-resistant cells is critical for the future development of targeted therapies aimed at achieving more robust and long-lasting responses. Using a novel application for the proliferation marker carboxyfluorescein diacetate, succinimidyl ester (CFSE), we have identified a population of slow-cycling, label-retaining tumor cells in both in vitro sphere cultures and in vivo xenograft models. Strikingly, label-retaining cells exhibit a multifold increase in ability to survive traditional forms of chemotherapy and reenter the cell cycle. Further, we demonstrate the innovative application of CFSE to live sort slow-cycling tumor cells and validate their chemoresistance and tumorigenic potential.

Complications of hand-assisted laparoscopic renal surgery: single-center ten-year experience.

OBJECTIVES: To review our perioperative complications during the first decade of using hand-assisted laparoscopic nephrectomy using a sleeve (HALN). HALN is a minimally invasive procedure first reported by our group in 1997. METHODS: After institutional review board approval, the charts of the patients who had undergone HALN, hand-assisted laparoscopic partial nephrectomy, or hand-assisted laparoscopic nephroureterectomy from 1997 to 2007, at our institution, were retrospectively reviewed. Standard laparoscopic procedures were not included. The relevant patient characteristics, operative details, American Society of Anesthesiologists score, body mass index, comorbidities, medications, and complications were recorded. RESULTS: A total of 227 consecutive patients had undergone Hand-assisted laparoscopic renal surgery, and all their charts were reviewed. Of these 227, 134 were radical HALN, 37 were nonradical HALN, 42 were hand-assisted laparoscopic partial nephrectomy, and 15 were hand-assisted laparoscopic nephroureterectomy. Complications developed in 59 patients (26%): 8% major and 18% minor. The procedure-specific complication rate was 29% for radical HALN, 27% for nonradical HALN, 33% for hand-assisted laparoscopic nephroureterectomy, and 17% for hand-assisted laparoscopic partial nephrectomy. Complications included blood transfusion in 6%, urinary retention in 4%, ileus in 4%, and wound infection in 4%. From 2003 through 2007 (n = 163), our overall complication rate was 22% (8% major and 13% minor). From 1997 to 2002 (n = 65), the overall complication rate was 38% (P = .02). The American Society of Anesthesiologists score and the use of systemic steroids were associated with the occurrence of perioperative complications. CONCLUSIONS: Our results have shown that hand assistance provides a safe, minimally invasive laparoscopic procedure. Our complications rates were comparable to those with other standard and hand-assist series, although the spectrum of complications varied. Hand-assisted laparoscopic renal surgery could be a method by which to improve patient access to minimally invasive nephron-sparing surgery.

Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance.

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.

Mutations in bone marrow-derived stromal stem cells unmask latent malignancy.

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, Apc(Min/+) and Apc(Min/+) Rag2(-/-) mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the Apc(Min/+) mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-alpha-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-alpha or by transfer of CD4(+) regulatory T cells from immune competent donors, demonstrating that immune competency to regulate inflammation was sufficient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The significant synergy between host immunity and mesenchymal cells identified here may restructure treatments to restore an anticancer microenvironment.

Sonographically documented stable seminoma: a case report.

Seminoma of the testis has a diverse natural history. We report a unique case of histologically confirmed classic seminoma in a 32-year-old patient documented by ultrasound on two occasions one year apart. The tumor size did not change during that time. We explore the possibility of a dichotomy in growth within seminoma and the need to identify molecular methods to predict the subset of tumors that behave biologically less aggressive.