Surface Localization of Glucosylceramide during Cryptococcus neoformans Infection Allows Targeting as a Potential Antifungal

Cryptococcus neoformans (Cn) is a significant human pathogen that, despite current treatments, continues to have a high morbidity rate especially in sub-Saharan Africa. The need for more tolerable and specific therapies has been clearly shown. In the search for novel drug targets, the gene for glucosylceramide synthase (GCS1) was deleted in Cn, resulting in a strain (Δgcs1) that does not produce glucosylceramide (GlcCer) and is avirulent in mouse models of infection. To understand the biology behind the connection between virulence and GlcCer, the production and localization of GlcCer must be characterized in conditions that are prohibitive to the growth of Δgcs1 (neutral pH and high CO2). These prohibitive conditions are physiologically similar to those found in the extracellular spaces of the lung during infection. Here, using immunofluorescence, we have shown that GlcCer localization to the cell surface is significantly increased during growth in these conditions and during infection. We further seek to exploit this localization by treatment with Cerezyme (Cz), a recombinant enzyme that metabolizes GlcCer, as a potential treatment for Cn. Cz treatment was found to reduce the amount of GlcCer in vitro, in cultures, and in Cn cells inhabiting the mouse lung. Treatment with Cz induced a membrane integrity defect in wild type Cn cells similar to Δgcs1. Cz treatment also reduced the in vitro growth of Cn in a dose and condition dependent manner. Finally, Cz treatment was shown to have a protective effect on survival in mice infected with Cn. Taken together, these studies have established the legitimacy of targeting the GlcCer and other related sphingolipid systems in the development of novel therapeutics

Analysis of Virtual Versus In-Person Prospective Peer Review Workflow in a Multisite Academic Radiation Oncology Department

Purpose In radiation oncology, peer review is a process where subjective treatment planning decisions are assessed by those independent of the prescribing physician. Before March 2020, all peer review sessions occurred in person; however due to the COVID-19 pandemic, the peer-review workflow was transitioned from in-person to virtual. We sought to assess any differences between virtual versus in-person prospective peer review. Methods and Materials Patients scheduled to receive nonemergent nonprocedural radiation therapy (RT) were presented daily at prospective peer-review before the start of RT administration. Planning software was used, with critical evaluation of several variables including treatment intent, contour definition, treatment target coverage, and risk to critical structures. A deviation was defined as any suggested plan revision. Results In the study, 274 treatment plans evaluated in-person in 2017 to 2018 were compared with 195 plans evaluated virtually in 2021. There were significant differences in palliative intent (36% vs 22%; P = .002), but not in total time between simulation and the start of treatment (9.2 vs 10.0 days; P = .10). Overall deviations (8.0% in-person vs 2.6% virtual; P = .015) were significantly reduced in virtual peer review. Conclusions Prospective daily peer review of radiation oncology treatment plans can be performed virtually with similar timeliness of patient care compared with in-person peer review. A decrease in deviation rate in the virtual peer review setting will need to be further investigated to determine whether virtual workflow can be considered a standard of care

Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction

<p>Abstract</p> <p>Background</p> <p>To define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement.</p> <p>Methods and Materials</p> <p>Twenty-three patients were identified who had undergone postmastectomy radiotherapy with tangent only fields. All patients had pre-radiation tissue expander placement and expansion. Thirteen patients had bilateral expander reconstruction. The level I/II axillary volumes were contoured using the RTOG contouring atlas. The patient-specific variables of expander volume, superior-to-inferior location of expander, distance between expanders, expander angle and axillary volume were analyzed to determine their relationship to the axillary volume and lung volume dose.</p> <p>Results</p> <p>The mean coverage of the level I/II axillary volume by the 95% isodose line (V_D95%) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung V_D50%was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary V_D95%in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung V_D50%correlated with angle of the expander from midline (p = 0.05).</p> <p>Conclusions</p> <p>In patients undergoing PMRT with tissue expanders, incidental doses delivered by tangents to the axilla, as defined by the RTOG contouring atlas, do not provide adequate coverage. The posterior-superior region of level I and II is the region most commonly underdosed. Axillary volume coverage increased with increasing expander volumes in patients with bilateral reconstruction. Lung dose increased with increasing expander angle from midline. This information should be considered both when placing expanders and when designing PMRT tangent only treatment plans by contouring and targeting the axilla volume when axillary treatment is indicated.</p

Patients of Asian descent with gastric cancer treated in the United States: Comparative characteristics and survival outcomes.

10 Background: Asian gastric cancer trials often show better outcomes than similar Western trials suggesting a possible difference in disease characteristics or biology. Large databases can be used to assess whether ethnic differences persist in the United States. Methods: The National Cancer Database was queried to examine disease characteristics, treatment utilization, and outcomes for gastric cancer from 2004-2013 for Asian vs. non-Asian patients. Patients were excluded with inadequate follow-up, unknown staging or race. Cox proportional hazards model was used to assess hazard ratio (HR) of death. Results: 101,426 patients were analyzed (6,994 Asians, 94,432 non-Asians). Asian patients were more likely to be female, younger, treated at academic centers, early stage, lower co-morbidity score, and high grade vs. non-Asian (Chi-square, all p&lt;0.001). Asian patients were less likely to receive chemotherapy or radiation or have a positive margin. HRs of death (adjusted for age, sex, facility, histology, insurance, co-morbidity score, margin, grade, surgery, radiation, and chemotherapy) for Asian patients are shown in the table. Further dividing by most represented Asian sub-groups showed differences between countries of origin. Conclusions: Imbalances exist in clinical features and treatment utilization in Asian patients compared to non-Asians. After adjustment, Asian race is associated with higher overall survival. Adjusted sub-group analyses show survival differences by country of origin, suggesting biological variability. [Table: see text] </jats:p

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ‘‘one size fits all’’ paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.</jats:p

Long-term outcomes of acromegaly treated with fractionated stereotactic radiation: case series and literature review

Abstract Background Growth hormone (GH)-secreting pituitary adenomas represent an uncommon subset of pituitary neoplasms. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) have been used as primary or adjuvant treatment. The purpose of this study is to report the long-term tumor control and toxicity from our institution and to perform a systematic literature review of acromegaly patients treated with FSRT. Methods We retrospectively reviewed all patients treated with FSRT (median dose 50.4 Gray [Gy], range 50.4–54 Gy) between 2005 and 2012 who had: 1) GH-secreting adenoma with persistently elevated insulin growth factor-1 (IGF-1) despite medical therapy and 2) clinical follow up &gt;3 years after FSRT. Patients were treated with modern FSRT planning techniques. Biochemical control was defined as IGF-1 normalization. Systematic review of the literature was performed for FSRT in acromegaly. Results With a median follow-up of 80 months, radiographic control was achieved in all 11 patients and overall survival was 100%. Long-term biochemical control was achieved in 10 patients (90.9%) with either FSRT alone (36.4%) or FSRT with continued medical management (45.5%). No patient experienced new hypopituitarism, cranial nerve dysfunctions, or visual deficits. Our systematic review found published rates of biochemical control and hypopituitarism vary, with uniformly good radiographic control and low incidence of visual changes. Conclusions Adjuvant FSRT offered effective long-term biochemical control and radiographic control, and there was a lower rate of complications in this current series. Review of the literature shows variations in published rates of biochemical control after FSRT for acromegaly, but low incidence of serious toxicities. </jats:sec