Large-pore connexin hemichannels function like molecule transporters independent of ion conduction.

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.

Multidisciplinary, articular surface-preserving treatment strategy for locally aggressive epithelioid hemangioma of the acetabulum employing serial bland transarterial embolization.

Epithelioid hemangioma is a rare, histologically benign but locally aggressive primary vascular neoplasm that can rarely arise in bone. Mainstay treatment is surgical resection or curettage with bone grafting. We report a novel multidisciplinary, joint-sparing treatment approach for an epithelioid hemangioma of bone arising in the acetabulum causing severe thinning of the subchondral bone plate. After 4 sessions of transarterial bland particle and ethanol embolization, the resultant increased ossification of the tumor allowed preservation of the articular surface during surgical resection. Imaging follow-up 14 months after surgical resection showed no evidence of recurrence and continued ossification of the portions of the lesion treated only with embolization.

Multidisciplinary approach for repeat musculoskeletal lesion biopsy after nondiagnostic initial sampling: A 10-year single-center experience.

BACKGROUND AND OBJECTIVES: Success rates for initial image-guided biopsy of musculoskeletal (MSK) lesions have been well documented; evidence regarding success rates for repeat biopsy following initially nondiagnostic (ND) image-guided biopsy of MSK lesions is more limited. This study evaluates the outcomes of repeat computerized tomography-guided MSK biopsies following ND biopsies using a multidisciplinary approach. MATERIALS AND METHODS: Electronic medical record search covering a 10-year period identified patients that received two or more biopsies for an MSK tumor or tumor-like process. The decision for initial and repeat image-guided biopsy of each lesion was made following multidisciplinary MSK tumor board review. Lesion location, histopathology results, size of biopsy needle when available, and change in technique between biopsy attempts was documented. RESULTS: Repeat biopsy rate was 1.6%. 23 patients with repeat MSK biopsy were identified. A total of 17 of 23 (74%) repeat biopsy attempts were diagnostic. A total of 22 of 23 (96%) repeat biopsy attempts were clinically useful. Diagnostic repeat biopsies were described as employing one or more of five technical differences compared to the first biopsy attempt, the most common being improved targeting of the lesion itself. CONCLUSIONS: A multidisciplinary approach may yield improved repeat-biopsy rates and clinical utility of repeat MSK biopsies compared to prior reports.

Platinum-based regimens versus cetuximab in definitive chemoradiation for human papillomavirus-unrelated head and neck cancer.

For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT.

Plasma-based biomaterials for the treatment of cutaneous radiation injury.

Cutaneous wounds caused by an exposure to high doses of ionizing radiation remain a therapeutic challenge. While new experimental strategies for treatment are being developed, there are currently no off-the-shelf therapies for the treatment of cutaneous radiation injury that have been proven to promote repair of the damaged tissues. Plasma-based biomaterials are biologically active biomaterials made from platelet enriched plasma, which can be made into both solid and semi-solid forms, are inexpensive, and are available as off-the-shelf, nonrefrigerated products. In this study, the use of plasma-based biomaterials for the mitigation of acute and late toxicity for cutaneous radiation injury was investigated using a mouse model. A 2-cm diameter circle of the dorsal skin was irradiated with a single dose of 35 Gy followed by topical treatment with plasma-based biomaterial or vehicle once daily for 5 weeks postirradiation. Weekly imaging demonstrated more complete wound resolution in the plasma-based biomaterial vs. vehicle group which became statistically significant (p < 0.05) at weeks 12, 13, and 14 postmaximum wound area. Despite more complete wound healing, at 9 and 17 weeks postirradiation, there was no statistically significant difference in collagen deposition or skin thickness between the plasma-based biomaterial and vehicle groups based on Masson trichrome staining nor was there a statistically significant difference in inflammatory or fibrosis-related gene expression between the groups. Although significant improvement was not observed for late toxicity, plasma-based biomaterials were effective at promoting wound closure, thus helping to mitigate acute toxicity.

An Analysis of Cancer Center-Provided Rideshare Utilization for Radiation Therapy.

OBJECTIVES: The potential of rideshare services to facilitate timely radiation therapy (RT), especially for resource-limited patients, is understudied. METHODS: Patients (n = 63) who received 73 courses of RT (1,513 fractions) and utilized free hospital-provided rideshare service (537 rides) were included in this retrospective study. A multidimensional analysis was conducted including a comparison of demographic, disease characteristics, and treatment completion data; a revenue analysis to evaluate the financial impact of rideshare services; and a geospatial analysis to evaluate community-level characteristics of patients. RESULTS: Median age was 59; most were female (56%) and self-identified as Black or African American (56%), not working (91%), not partnered (83%), high school educated or less (78%), and insured with Medicaid (51%). Geospatial analysis revealed that patients lived in communities with significantly higher rates of resource deprivation. Median rideshare distance was 6.4 miles (interquartile range 3.4-11.2) with a median cost of $13.04 per rideshare (interquartile range 9-19). Of the rideshare-facilitated treatments, 100% were completed, with an overall course completion rate of 97.3% compared with 85.4% for those who did not use rideshare (P = .001); two patients discontinued RT for reasons unrelated to transportation. High rideshare utilization (n = 32), defined as utilization ≥ 45% of the treatment course, was associated with significantly shorter treatment courses and lower radiation doses compared with low rideshare utilization (P = .04). Total rideshare cost for high utilizers and whole cohort was $11,589 and $16,895, facilitating an estimated revenue of $401,952 and $1,175,119, respectively. CONCLUSIONS: Free hospital-provided rideshare service is economically feasible and associated with high RT completion rates. It may help enhance quality radiation care for those who come from resource-limited communities.

Understanding the role of R266K mutation in cystathionine ß-synthase (CBS) enzyme: an in silico study.

Human cystathionine ß-synthase (hCBS) is a Heme-containing, unique pyridoxal 5'-phosphate (PLP) dependent enzyme. CBS catalyzes the bio-chemical condensation reactions in the transsulfuration pathway. The role of Heme in the catalytic activities of the hCBS enzyme is still unknown, even though various experimental studies indicated its participation in the bi-directional electronic communication with the PLP center. The hypothesis is, Heme acts as an electron density reservoir for the catalytic reaction center rather than a redox electron source. In this work, we have investigated In Silico dynamical aspects of the bi-directional communications by performing classical molecular dynamics (MD) simulations upon developing the necessary force field parameters for the cysteine and histidine bound hexa-coordinated Heme. The comparative aspects, of electron density overlap across the communicating pathways, were investigated adopting the Density Functional Theory (DFT) in conjunction with the hybrid exchange-correlation functional for the CBSWT (wild-type) and CBSR266K (mutated) enzymes. The molecular dynamics simulations and subsequent explorations of the electronic structures confirm the reported observations. It also provides an in-depth mechanistic understanding of how the non-covalent hydrogen bonding interactions with Cys52 control such long-distance communication. Our study also provides a convincing answer to the reduced enzymatic activities in the R266K mutated hCBS compared to the wild-type enzymes. The difference in hydrogen-bonding patterns and salt-bridge interactions play the pivotal roles in such long distant bi-directional communications.Communicated by Ramaswamy H. Sarma.

α-Helix in Cystathionine ß-Synthase Enzyme Acts as an Electron Reservoir.

The modulation of electron density at the Pyridoxal 5'-phosphate (PLP) catalytic center, because of charge transfer across the α-helix/PLP interface, is the determining factor for the enzymatic activities in the human Cystathionine ß-Synthase (hCBS) enzyme. Applying density functional theory calculations, in conjunction with the real space density analysis, we investigated the charge density delocalization across the entire heme-α-helix-PLP electron communication channels. The electron delocalization due to hydrogen bonds at the heme/α-helix and α-helix/PLP interfaces are found to be extended over a very long range, as a result of redistribution of electron densities of the cofactors. Moreover, the internal hydrogen bonds of α-helix that are crucial for its secondary structure also participate in the electron redistribution through the structured hydrogen-bond network. α-Helix is found to accumulate the electron density at the ground state from both of the cofactors and behaves as an electron reservoir for catalytic reaction at the electrophilic center of PLP.

Telemedicine Use and Satisfaction Among Radiation Oncologists During the COVID-19 Pandemic: Evaluation of Current Trends and Future Opportunities.

PURPOSE: During the COVID-19 pandemic, telemedicine became an attractive alternative to in-person appointments. The role of telemedicine in patients who undergo frequent on-site treatment, such as radiation therapy, is unclear. The purpose of this study was to examine telemedicine use, physician satisfaction, and barriers to continued use in radiation oncology. METHODS AND MATERIALS: An anonymous, electronic survey was distributed to radiation oncologists internationally between June and October 2020. Respondents described demographic and practice characteristics, and a 5-point Likert scale assessed provider satisfaction, ease of use, and overall utility of telemedicine. Analyses include descriptive statistics and subgroup comparisons using the χ2 test and Fisher's exact test. RESULTS: The response rate was 4.3%. Two hundred thirty-two respondents completed the survey, 63.8% of whom were male, 52.6% aged 50 or younger, and 78.0% from the United States. Only 14.2% used telemedicine previously, which increased to 93.1% during COVID-19. Among all telemedicine users, usage rates were 77.9% for initial consultations, 97.2% for follow-up visits, and 35.9% for on-treatment visits. Of the respondents, 69.8% reported that <25% of patients requiring treatment experienced delays due to COVID-19. Most conducted appointments from the workplace, with 40.1% also doing so from home. Satisfaction was high at 73.8%, perceived usefulness was 76.9%, and 81.5% hope to continue using telemedicine after the pandemic. However, 82.4% had concerns with the inability to examine patients and 63.0% had concerns about poor patient access to the required technology. In addition, 49.5% had concerns regarding continued billing/reimbursement, less commonly at government centers (18.8%) compared with academic/satellite facilities (52.7%) and free-standing centers/community hospitals (50.7%, P = .039 for both comparisons). These concerns were also significantly higher among US physicians (53.2% vs 34.9%, P = .048). CONCLUSIONS: Widespread adoption of telemedicine by radiation oncologists occurred during COVID-19 with high rates of satisfaction and interest in continued use. Sustained reimbursement for telemedicine services is a significant concern, particularly in the United States and outside of government facilities.

Design, characterization and structure-function analysis of novel antimicrobial peptides based on the N-terminal CATH-2 fragment.

The emergence of multidrug resistance coupled with shrinking antibiotic pipelines has increased the demand of antimicrobials with novel mechanisms of action. Therefore, researchers across the globe are striving to develop new antimicrobial substances to alleviate the pressure on conventional antibiotic therapies. Host-Defence Peptides (HDPs) and their derivatives are emerging as effective therapeutic agents against microbial resistance. In this study, five analogs (DP1-5) of the N-terminal (N-15) fragment of CATH-2 were designed based on the delicate balance between various physicochemical properties such as charge, aliphatic character, amphipathicity and hydrophobicity. By means of in-silico and in-vitro studies a novel peptide (DP1) with the sequence "RFGRFLRKILRFLKK" was found to be more effective and less toxic than the N-terminal CATH-2 peptide. Circular dichroism spectroscopy and differential scanning calorimetry were applied for structural insights. Antimicrobial, haemolytic, and cytotoxic activities were also assessed. The resulting peptide was characterized by low cytotoxicity, low haemolytic activity, and efficient anti-microbial activity. Structurally, it displayed strong helical properties irrespective of the solvent environment and was stable in membrane-mimicking environments. Taken together, the data suggests that DP1 can be explored as a promising therapeutic agent with possible clinical applications.

Proton Beam Therapy for Locally Advanced Head and Neck Tumors: An Analysis of Dosimetric and Clinical Outcomes.

OBJECTIVE: Locally advanced tumors of the head and neck region often lie in close proximity to critical organs at risk (OARs). Providing effective treatment coverage to these malignancies while minimizing radiation dose to surrounding OARs is advantageous. Our aim is to compare dosimetric data of OARs from proton beam therapy (PBT) plans to volumetric modulated arc therapy (VMAT) treatment plans, and to evaluate clinical outcomes in patients treated with PBT. METHODS: We identified patients with locally advanced head and neck tumors treated with PBT at our institution from 2016 to 2019. Study endpoints included mean and maximum doses for the OAR structures for each treatment plan, overall survival, time to local-regional or distant progression, and presence of acute and late toxicities. Mean and maximum doses to OAR structures were compared between treatment modalities using a paired Wilcoxon signed-rank test. P-values <0.05 were considered significant. RESULTS: A total of 42 patients were identified. Clinical target volume coverage was >95% for both PBT and VMAT plans. PBT plans showed a significant reduction to the mean doses to all OARs, and max doses to most OARs (P<0.05). The largest reduction mean dose was seen in the contralateral cochlea and parotid glands at 71% and 75%, respectively. Median follow-up was 27 months. Overall survival at 4 years was 44.75%. Freedom from local-regional progression was 73.28% at 2 years. The majority of patients developed Common Terminology Criteria for Adverse Events (CTCAE) grade I dermatitis, mucositis, or both. CONCLUSIONS: PBT resulted in meaningful dose reductions to OARs while maintaining comparable target coverage when compared with VMAT plans. Further refinements to proton therapy may have the potential to further minimize dose to critical structures.

Thyroid-optimized and thyroid-sparing radiotherapy in oral cavity and oropharyngeal carcinoma: A dosimetric study.

BACKGROUND: Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT. METHODS: We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV. RESULTS: Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p < 0.0001). In model II, average mean dose was reduced to 3154 cGy (p < 0.0001). For PTV low and PTV int, all had acceptable target coverage. CONCLUSION: In patients with oral-cavity and oropharyngeal cancers, mean dose could be significantly reduced using a thyroid-optimized or thyroid-sparing IMRT technique with adequate coverage.

Proton Beam Therapy in the Treatment of Periorbital Malignancies.

PURPOSE: Periorbital tumor location presents a significant challenge with 3-dimensional conformal radiation therapy or intensity modulated radiation therapy due to high tumor dose needed in the setting of close proximity to orbital structures with lower tolerance. Proton beam therapy (PBT) is felt to be an effective modality in such cases due to its sharp dose gradient. MATERIALS AND METHODS: We reviewed our institutional PBT registry and identified 17 patients with tumor epicenters within 2 cm of the eye and optic apparatus treated with passive scatter PBT with comparison volumetric arc therapy plans available. Maximum and mean doses to organs at risk of interest, including optic nerves, optic chiasm, lens, eye ball, pituitary, cochlea, lacrimal gland, and surrounding brain, were compared using the paired Wilcoxon signed rank test. Overall survival was determined using the Kaplan-Meier method. RESULTS: Median age was 67. Median follow-up was 19.7 months. Fourteen patients underwent upfront resection and received postoperative radiation and 3 received definitive radiation. One patient received elective neck radiation, 2 underwent reirradiation, and 3 had concurrent chemotherapy. There was a statistically significant reduction in mean dose to the optic nerves and chiasm, brain, pituitary gland, lacrimal glands, and cochlea as well as in the maximum dose to the optic nerves and chiasm, pituitary gland, lacrimal glands, and cochlea with PBT. The 18-month cumulative incidence of local failure was 19.1% and 1-year overall survival was 80.9%. CONCLUSION: Proton beam therapy resulted in significant dose reductions to several periorbital and optic structures compared with volumetric arc therapy. Proton beam therapy appears to be the optimal radiation modality in such cases to minimize risk of toxicity to periorbital organs at risk.

Erratum: Clinical Outcomes and Multidisciplinary Patterns of Failure for Olfactory Neuroblastoma: The Ohio State Experience.

[This corrects the article DOI: 10.1055/s-0039-1692479.].

A series of typical and atypical cases of Bazex syndrome: Identifying the red herring to avoid delaying cancer treatment.

Bazex syndrome is a rare paraneoplastic dermatosis that precedes diagnosis of cancer. Awareness of this syndrome is important, as it allows early detection of underlying malignancy and may prevent misdiagnosis and delays in cancer treatment.

Reirradiation for Recurrent Scalp Angiosarcoma: Dosimetric Advantage of PBT over VMAT and EBT.

PURPOSE: Reirradiation in the scalp area can be challenging given the proximity to organs at risk (OARs), such as the eye and brain. Our aim is to evaluate the dosimetric differences of volumetric modulated arc therapy (VMAT) and electron beam therapy (EBT) compared with 3-dimensional proton beam therapy (PBT). PATIENTS AND METHODS: We evaluated a patient with recurrent angiosarcoma of the left temporal scalp after prior surgical resections and radiation therapy to 60 Gy in 30 fractions who needed reirradiation. We generated VMAT, EBT, and PBT plans using the Pinnacle Treatment Planning System (TPS). Both VMAT and EBT plans used a skin bolus, whereas no bolus was used for the proton plan. Doses to the OARs, including cochlea, eyes, lens, lacrimal glands, optic nerves, optic chiasm, pituitary gland, and underlying brain, were compared. RESULTS: The reirradiation treatment dose was 60 Gy(RBE). Target volume coverage was comparable in all plans. Compared with VMAT and EBT, the PBT plan showed reductions in mean and maximum doses to all OARs. Without the use of protons, several OARs would have exceeded dose tolerance utilizing VMAT or electrons. Dose reduction of up to 100% was achieved for central and contralateral OARs. CONCLUSION: Compared with VMAT and EBT, PBT resulted in dose reductions to all OARs, while maintaining excellent target coverage. PBT showed a significant advantage in treating superficially located skin cancers, such as angiosarcoma, without the need for a bolus. PBT can be considered in the upfront treatment and certainly in the reirradiation setting.

Clinical Outcomes and Multidisciplinary Patterns of Failure for Olfactory Neuroblastoma: The Ohio State Experience.

Purpose Olfactory neuroblastoma (ONB) is a rare head and neck cancer believed to be originated from neural crest cells of the olfactory membrane located in the roof of the nasal fossa. This study evaluates clinical outcomes and failure patterns in ONB patients of those patients treated with surgical resection at a high-volume tertiary cancer center. Methods and Materials Thirty-nine ONB patients who underwent surgical resection at our institution from 1996 to 2017 were retrospectively identified. Univariate, multivariate, and survival analysis were calculated using Cox regression analysis and Kaplan-Meier log-rank. Results Median follow-up time was 59 months (range: 5.2-236 months). The median overall survival (OS) and disease-free survival (DFS) for the entire cohort were 15 and 7.6 years, respectively. The 5-year cumulative OS and DFS were 83 and 72%, respectively. The 5-year OS for low Hyams grade (LHG) versus high Hyams grade (HHG) was 95 versus 61% ( p = 0.041). LHG was found in 66% of the early Kadish stage patients compared with 28% in the advanced Kadish stage patients ( p = 0.057). On multivariate analysis, HHG and positive node status predicted for worse OS and only HHG predicted for worse DFS. Of note, five patients (all Kadish stage A) who received surgical resection alone had no observed deaths or recurrences with a median follow-up of 44 months (range: 5-235 months). Conclusion In this retrospective cohort, patients with positive nodes or HHG have significantly worse clinical outcomes. Future studies should explore treatment intensification for HHG or positive nodes.

Primary vs nodal site PET/CT response as a prognostic marker in oropharyngeal squamous cell carcinoma treated with intensity-modulated radiation therapy.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) in staging of advanced oropharyngeal squamous cell carcinoma (OPSCC) and at 3 months posttreatment (PETpost) is often utilized to assess response. The significance of lymph node vs primary site treatment response is incompletely understood. METHODS: We reviewed 230 patients treated with radiation therapy. PETpost response was graded at primary and nodal sites and correlated with survival. RESULTS: Median age was 58, and 83% were p16-positive. Median follow-up was 24.3 months. Nodal response at PETpost predicted improved 2-year local recurrence-free survival (LRFS) (93% vs 72%, P =.004), 2-year disease-free survival (DFS) (80% vs 61.3%, P =.021), and 2-year overall survival (OS) (89% vs 83%, P =.051), while primary response only predicted improved 2-year LRFS (91% vs 76% P = .035). CONCLUSION: In OPSCC patients, both nodal and primary response at 3 months on PET/CT predicted for improved LRFS, but only nodal response predicted DFS and OS.

Emerging Opportunities for Digital PET/CT to Advance Locoregional Therapy in Head and Neck Cancer.

The purpose of this article is to present the recent imaging advancements enabled by digital photon counting positron emission tomography detector technology and discuss its potential applications in the clinical management of head and neck cancer (HNC) and nodal metastases. 18F-fluorodeoxyglucose positron-emission tomography is a clinically useful biomarker for the detection, targeted biopsy, treatment planning, and therapeutic response assessment of HNC. This article highlights the current state of 18F-fluorodeoxyglucose positron-emission tomography imaging in HNC management as well as the emerging capabilities of the recently introduced digital photon counting positron emission tomography/computed tomography platform for more effective molecular and functional HNC imaging.