Physiologic and biochemical rationale for treating COVID-19 patients with hyperbaric oxygen.

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world's population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemia and tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.

Hyperbaric oxygen is still needed in the management and prevention of mandibular necrosis: a response to Mr. Richard Clarke.

Mr. Richard Clarke presents in this Journal his arguments against continued application of hyperbaric oxygen (HBO2) therapy to the pre-extraction neoadjuvant treatment or the treatment of frank mandibular ORN. In the same article he advocates a promising renewed interest in HBO2 as a radiosensitizer. Arguments against HBO2 prior to extractions are based on several papers which consistently include low-risk patients. The just-released HOPON trial reports a negative pre-extraction outcome for HBO2, but patients were enrolled with radiation doses as low as 50Gy. For advanced mandibular necrosis (Marx Stage III) requiring resection, fibular free flap reconstruction is advocated. A high complication rate with free flaps is acknowledged but the magnitude of these complications is not discussed. A cost savings for this procedure is suggested, but no mention is made of the typical cost of the procedure ($90,000) or the requirement of a typical one-week hospital stay, including an initial one or two days in the ICU. Nor is mention made of the very low rate of subsequent dental rehabilitation. The success reported by Delainian, et al. employing pentoxifylline, Vitamin E and sometimes a bisphosphonate is equated to the four decades of HBO2 success with the Marx protocol for Stage I and II ORN. In the phase II trial by Delainian (not randomized) six of her 54 patients died secondary to sepsis, and she graded patients as complete responders if 5mm or less bone was exposed. Even at entry patients had an average of only 1.7 cm exposed bone and treatment was prolonged (16 + or -9 months). Any cost comparison studies will have to account for the indirect expenses of this prolonged treatment including lost productivity.

Primary CNS lymphoplasmacytic lymphoma: a case report and review of literature.

Lymphoplasmacytic lymphoma is a chronic lymphoproliferative disorder characterized by a proliferation of plasma cells, small lymphocytes, plasmacytoid lymphocytes and the production of monoclonal IgM. Primary central nervous system lymphomas (PCNSL) are rare non-Hodgkin lymphomas (NHL) that can be found in the brain, leptomeninges, eyes or spinal cord, and are mostly intracerebral. PCNSLs constitute 3-4% of primary brain tumors, and in most cases are diffuse large B-cell lymphomas (DLBCL).(1) Low grade lymphomas as primary central nervous system (CNS) lymphoma are very rare. We present here a case report of a woman who presented with headache and was found to have primary intracranial lymphoplasmacytic lymphoma (LPL).

Hyperbaric oxygen therapy and delayed radiation injuries (soft tissue and bony necrosis): 2012 update.

Informal surveys at CME meetings have shown that approximately one-third of patients in the United States receive hyperbaric oxygen (HBO2) for delayed radiation injury. More than 600,000 patients receive radiation for malignancy in our country annually, and about one-half will be long-term survivors. Serious radiation complications occur in 5-10% of survivors. A large population of patients is therefore at risk for radiation injury. HBO2 has been applied to treat patients with radiation injury since the mid-1970s. Published results are consistently positive, but the level of evidence for individual publications is usually not high level, consisting mostly of case series and case reports. Only a rare randomized controlled trial has been accomplished. Radiation injury is one of the UHMS "approved" indications, and third-party payors will usually reimburse for this application. This updated review summarizes the publications available reporting results in treating radiation-injured patients. Mechanisms of HBO2 in radiation injury are discussed briefly. Outcome is reported on a mostly anatomic basis though due to the nature of the injury a positive outcome at one anatomic site is supportive of HBO2 at other sites. The potential benefit of prophylactic HBO2 before frank damage is also discussed in high-risk patients. The concerns of HBO2 enhancing growth of or precipitating recurrence of malignancy is discussed and largely refuted.

A quantitative three-dimensional dose attenuation analysis around Fletcher-Suit-Delclos due to stainless steel tube for high-dose-rate brachytherapy by Monte Carlo calculations.

PURPOSE: The commercially available brachytherapy treatment-planning systems today, usually neglects the attenuation effect from stainless steel (SS) tube when Fletcher-Suit-Delclos (FSD) is used in treatment of cervical and endometrial cancers. This could lead to potential inaccuracies in computing dwell times and dose distribution. A more accurate analysis quantifying the level of attenuation for high-dose-rate (HDR) iridium 192 radionuclide ((192)Ir) source is presented through Monte Carlo simulation verified by measurement. METHODS AND MATERIALS: In this investigation a general Monte Carlo N-Particles (MCNP) transport code was used to construct a typical geometry of FSD through simulation and compare the doses delivered to point A in Manchester System with and without the SS tubing. A quantitative assessment of inaccuracies in delivered dose vs. the computed dose is presented. In addition, this investigation expanded to examine the attenuation-corrected radial and anisotropy dose functions in a form parallel to the updated AAPM Task Group No. 43 Report (AAPM TG-43) formalism. This will delineate quantitatively the inaccuracies in dose distributions in three-dimensional space. The changes in dose deposition and distribution caused by increased attenuation coefficient resulted from presence of SS are quantified using MCNP Monte Carlo simulations in coupled photon/electron transport. The source geometry was that of the Vari Source wire model VS2000. The FSD was that of the Varian medical system. In this model, the bending angles of tandem and colpostats are 15 degrees and 120 degrees , respectively. We assigned 10 dwell positions to the tandem and 4 dwell positions to right and left colpostats or ovoids to represent a typical treatment case. Typical dose delivered to point A was determined according to Manchester dosimetry system. RESULTS AND CONCLUSIONS: Based on our computations, the reduction of dose to point A was shown to be at least 3%. So this effect presented by SS-FSD systems on patient dose is of concern.

Surface and build-up region dose analysis for clinical radiotherapy photon beams.

The standard clinical approach of dose measurement using a Farmer type fixed plane parallel cylindrical ionization chamber produces erroneous results in the build-up region. We studied dose distribution in this region using a Monte Carlo simulation technique and compared our results with data measured using extrapolation, parallel plate, and cylindrical farmer type ionization chambers for 6 and 10 MV photon beams from two different accelerators. The extrapolation chamber data agreed favorably with the Monte Carlo results, suggesting that dose at the skin surface and a few mm beneath is significantly lower than conventionally accepted values.

Three-dimensional quantitative dose reduction analysis in MammoSite balloon by Monte Carlo calculations.

Current treatment planning systems (TPSs) for partial breast irradiation using the MammoSite brachytherapy applicator (Cytyc Corporation, Marlborough, MA) often neglect the effect of inhomogeneity, leading to potential inaccuracies in dose distributions. Previous publications either have studied only a planar dose perturbation along the bisector of the source or have paid little attention to the anisotropy effect of the system. In the present study, we investigated the attenuation-corrected radial dose and anisotropy functions in a form parallel to the updated American Association of Physicists in Medicine TG-43 formalism. This work quantitatively delineates the inaccuracies in dose distributions in three-dimensional space. Monte Carlo N-particle transport code simulations in coupled photon-electron transport were used to quantify the changes in dose deposition and distribution caused by the increased attenuation coefficient of iodine-based contrast solution. The source geometry was that of the VariSource wire model VS2000 (Varian Medical Systems, Palo Alto, CA). The concentration of the iodine-based solution was varied from 5% to 25% by volume, a range recommended by the balloon's manufacturer. Balloon diameters of 4, 5, and 6 cm were simulated. Dose rates at the typical prescription line (1 cm away from the balloon surface) were determined for various polar angles. The computations showed that the dose rate reduction throughout the entire region of interest ranged from 0.64% for the smallest balloon diameter and contrast concentration to 6.17% for the largest balloon diameter and contrast concentration. The corrected radial dose function has a predominant influence on dose reduction, but the corrected anisotropy functions explain only the effect at the MammoSite system poles. By applying the corrected radial dose and anisotropy functions to TPSs, the attenuation effect can be reduced to the minimum.

Cost-effectiveness analysis of the treatment for intermediate risk endometrial cancer: postoperative brachytherapy vs. observation.

OBJECTIVE: To compare the survival, morbidity, and cost of treating women with intermediate risk endometrial cancer with postoperative vaginal cuff brachytherapy versus observation followed by treatment for vaginal recurrence. METHODS: A cost-effectiveness analysis was performed comparing two treatment strategies for intermediate risk endometrial cancer (Stage IC, IG3, II-tumors limited to the uterus with greater than 50% myometrial invasion or poor differentiation or cervical metastasis). All patients undergo hysterectomy, oophorectomy, and lymphadenectomy: strategy 1-postoperative vaginal cuff brachytherapy, strategy 2-observation. Strategy 2 patients who develop vaginal recurrence undergo diagnostic work-up followed by teletherapy and brachytherapy. All six principles of cost-effectiveness analysis were employed. Importantly, actual payer costs were evaluated, not charges. RESULTS: Although the treatment for vaginal cuff recurrence is expensive, since only 8% of patients develop a vaginal recurrence, there was a 31% decreased cost by not treating patients with postoperative low-dose rate brachytherapy (strategy 2). Also, although the complication rate for teletherapy is greater than brachytherapy, since only 8% of patients develop a vaginal recurrence and require teletherapy, projected complication rates for the two strategies are similar. Survival would be decreased 3% by withholding postoperative brachytherapy (strategy 2). With postoperative high-dose rate brachytherapy (strategy 1), the cost per life saved would be 38,764 US dollars. CONCLUSION: Using a cost-effectiveness analysis, we have shown that withholding postoperative brachytherapy for patients with intermediate risk endometrial cancer results in a 31% decrease in cost, has a similar radiation complication rate, and results in a 3% decrease in survival.

Dosimetric characteristics of a linear array of gamma or beta-emitting seeds in intravascular irradiation: Monte Carlo studies for the AAPM TG-43/60 formalism.

In principle, the AAPM TG-43/60 formalism for intravascular brachytherapy (IVBT) dosimetry of catheter-based sources is fully valid with a single seed of cylindrical symmetry and in the region comparable to or larger than the mean-free path of emitting radiation. However, for the geometry of a linear array of seeds within the few millimeter range of interest in IVBT, the suitability of the AAPM TG-43/60 formalism has not been fully addressed yet. We have meticulously investigated the dosimetric characteristics of catheter-based gamma (192Ir) and beta (90Sr/Y) sources using Monte Carlo methods before applying the AAPM TG-43/60 formalism. The dosimetric perturbation due to radiation interactions with neighboring seeds is at most 2% over the entire region of interest for the 192Ir source, while it increases to about 5% for the 90Sr/Y source. As the transaxial distance (y) increases beyond 3 mm, the sum of the dose contributions from neighboring seeds exceeds the dose contribution from the center seed for both sources. However, it continues to increase with the increasing y for 192Ir but is saturated beyond y = 5 mm for 9Sr/Y. Even within a few millimeters from the seeds, the dose from the low-energy betas of 192Ir is still less than 1% of the total dose. The radial dose and anisotropy functions are reformulated in reduced cylindrical coordinate with the reference point at y = 2 mm. The dose rate constant of 192Ir and the dose rate of 90Sr/Y at the reference point showed a fairly good agreement (within +/- 2%) with earlier studies and the NIST-traceable value, respectively. We conclude that the dosimetric perturbation caused by close proximity of neighboring seeds is nearly negligible so that the AAPM TG-43/60 formalism can be applied to a linear array of seeds.

Prophylactic hyperbaric oxygen treatment and rat spinal cord re-irradiation.

Normal tissue injury may lead to severe, life threatening, late side effects after therapeutic use of irradiation. Neurological complications caused by radiation of the spinal cord are ascribed to progressive, irreversible damage to the vasculature. Hyperbaric oxygen (HBO) is known to induce angiogenesis in irradiated tissue and has been proven to reduce late radiation injury in several normal tissues when applied during the latent period before complications become manifest. In the present study: (1). the prophylactic potential of HBO; (2). optimal timing of HBO therapy after spinal cord irradiation, i.e. during the latent period; and (3). effect of HBO on the re-irradiation tolerance of the spinal cord were investigated. The rat cervical spinal cord was locally X-ray irradiated with ten fractions of 6.5 Gy in 11 days. Five treatment groups (n=10) included: irradiation alone and irradiation followed by 30 HBO treatments (100% oxygen at 240 kPa for 90 min) during latency, with HBO starting either immediately, 5, 10 or 15 weeks after the primary irradiation course. One year after the primary treatment, the same spinal cord volume was re-irradiated with 20 Gy single dose. During life span, the animals were observed on the incidence of myelitis and the duration of the latent period. The actuarial analysis revealed no significant difference in neurological complications free survival between the irradiation alone and the irradiation+HBO treatment groups. A tendency towards radiosensitization was found in the group in which the primary irradiation course was immediately followed by the HBO treatment course. The data show that HBO applied during the latent period of progressively developing irradiation damage to the spinal cord does not increase the re-irradiation tolerance of this tissue.