Blood derivative therapy

There are three main components manufactured from whole blood: red blood cells (RBCs), plasma, and platelets. Plasma contains a multitude of different proteins, peptides, and biologic substances. Approximately 53 million liters of plasma was collected in the United States in 2019. Following collection, plasma is frozen and manufactured into plasma-derived medicinal products (PDMPs). During the manufacture process, several thousand plasma units are pooled for Cohn fractionation, which is based upon cold ethanol precipitation of proteins. The PDMPs are further prepared using ion exchange or affinity chromatography and additional steps to inactivate and remove infectious diseases such as viruses. Almost 20 different therapeutic plasma proteins are purified from plasma via these multi-step manufacturing processes. Interestingly, the demand for pharmaceutical plasma products, particularly intravenous immunoglobulin (IVIG) products, has been increasing. The manufacture and therapeutic role of blood derivatives particularly immunoglobulin therapy, Rh immunoglobulin (RhIG), COVID-19 convalescent plasma (CCP) and hyperimmune globulins, albumin, clotting factors, fibrin sealants, and platelet rich plasma will be described.Copyright © 2022 AME Publishing Company. All Rights Reserved.

Luteolin Isolated from Juncus acutus L., a Potential Remedy for Human Coronavirus 229E.

The COVID-19 pandemic, caused by SARS-CoV-2, addressed the lack of specific antiviral drugs against coronaviruses. In this study, bioguided fractionation performed on both ethyl acetate and aqueous sub-extracts of Juncus acutus stems led to identifying luteolin as a highly active antiviral molecule against human coronavirus HCoV-229E. The apolar sub-extract (CH2Cl2) containing phenanthrene derivatives did not show antiviral activity against this coronavirus. Infection tests on Huh-7 cells, expressing or not the cellular protease TMPRSS2, using luciferase reporter virus HCoV-229E-Luc showed that luteolin exhibited a dose-dependent inhibition of infection. Respective IC50 values of 1.77 µM and 1.95 µM were determined. Under its glycosylated form (luteolin-7-O-glucoside), luteolin was inactive against HCoV-229E. Time of addition assay showed that utmost anti-HCoV-229E activity of luteolin was achieved when added at the post-inoculation step, indicating that luteolin acts as an inhibitor of the replication step of HCoV-229E. Unfortunately, no obvious antiviral activity for luteolin was found against SARS-CoV-2 and MERS-CoV in this study. In conclusion, luteolin isolated from Juncus acutus is a new inhibitor of alphacoronavirus HCoV-229E.

Cardioneuroablation in a Woman with Ictal-Induced Cardiac Asystole

Background: Ictal-induced cardiac bradyarrhythmia and asystole is a rare phenomenon. The exact mechanism of ictal-induced cardiac bradyarrhythmia and asystole remains unclear. It was postulated that stimulation of central autonomic network during ictal episode may trigger an abrupt burst of hypervagotonia. Prolonged episode of cardiac bradyarrhythmia and asystole may result in syncope or death due to impairment of cerebral perfusion. The role of cardioneuroablation (CNA) in this condition has not been well-described in the literature. Objective(s): To describe a case of successful CNA in a patient with ictal-induced bradyarrhythmia and asystole. Method(s): n/a Results: A 47-year-old female has a 1.5-year history of intractable focal epilepsy and COVID-19 infection. She started having multiple episodes of seizures following a mild COVID-19 infection. Electroencephalogram (EEG) and brain MRI revealed right temporal onset seizures without structural lesions. Due to ongoing uncontrolled seizures with multiple semiologies despite multiple anti-epileptic drugs, she was admitted to Epilepsy Monitoring Unit for seizure classification. Her ictal EEGs (Figure 1) showed onset of ictal rhythm in the right temporal region with episodes of severe sinus bradycardia (15-30 bpm) and sinus pauses (15-16 seconds). Telemetry tracings demonstrated PP interval slowing with PR interval prolongation prior to the pauses consistent with a vagally-mediated mechanism. Cardiac electrophysiology team recommended CNA for treating the episodes of ictal-induced bradyarrhythmia and asystole. 3D anatomic maps of the right atrium (RA) and left atrium (LA) were created using CARTO system (Biosense Webster). Right superior ganglionated plexus (RSGP) was localized with fractionation mapping and intracardiac echocardiography guidance. RSGP was targeted from the RA using an irrigated radiofrequency catheter with power limit of 25 W. Post-ablations of RSGP, her heart rate increased from 60 - 99 bpm. Additional lesions were delivered from the LA site but no additional heart rate increase was not seen. An implantable loop recorder was implanted post-ablation procedure. During follow-up of 8 months, she had recurrent focal epilepsy, but no bradyarrhythmias or asystole was noted on her loop recorder. Resting heart rates at long-term follow up were between 70 - 100 bpm. Conclusion(s): This case highlights the utility of CNA in patient with ictal-induced cardiac bradyarrhythmia and asystole. CNA may be an approach to avoid permanent pacemakers in this population. [Formula presented]Copyright © 2023

Prospects of accelerated fractionation chemoradiotherapy for locally advanced oropharyngeal cancer during the COVID-19 pandemic.

Objective. To comparatively assess the early toxicity of treatment, its tolerability, 1-, 2-, 3-year overall survival, and local regional control rates in a group of patients receiving a radical cycle of accelerated or conventional fractionation chemoradiotherapy. Subjects and methods. The paper presents the interim results of a prospective study that included 115 patients with locally advanced cancer of the oropharynx, tongue root, and larynx who received a radical cycle of conformal chemoradiotherapy using accelerated (the single focal dose (SFD) was 2.4 Gy for 25-26 fractions) or conventional (SFD was 2.0 Gy for 32-33 fractions) fractionation in the period from 2015 to 2020. Results. An analysis comparing the study group with the control one revealed no statistically significant differences in the level of early toxicity of treatment (p=0.41). Complete tumor reversal was achieved in 57 (86.3%) patients in the study group and in 39 (79.5%) in the comparison group (p=0.23). The 1-, 2-, and 3-year local regional control rates in the accelerated fractionation group was 78.3+/-5.3%;65.9+/-6.8%, and 54.5+/-9.2%, respectively. The 3-year overall survival rate was 80.4+/-7.4%. These rates did not differ statistically from those in the conventional radiotherapy group (p=0.12-0.82);53 (80.3%) patients in the study group and 37 (75.5%) in the standard fractionation group received a radiation cycle without a forced interval. The treatment interval in the patients of both groups reduced the 2-year local regional control rates by 30.2% compared to that in the continuous cycle group (p=0.02). Conclusion. Accelerated fractionation chemoradiotherapy (SFD was 2.4 Gy for 25-26 fractions, the daily focal dose was 60.0- 62.4 Gy) is a procedure comparable with conventional radiation in its direct efficiency and safety. During the COVID-19 pandemic, this regimen can be considered to be a mainstay for patients with locally advanced oropharyngeal cancer in order to preserve the previous volumes of specialized healthcare.Copyright © A.V. SEMENOV I.A. GULIDOV O.G. LEPILINA M.U. RADZHAPOVA F.E. SEVRYUKOV K.B. GORDON.

CD27-IgD- B cells might portray an exhausted B cell phenotype resulting in lack of response to checkpoint inhibitor treatment in NSCLC

Background Checkpoint inhibitor (CI) therapy has revolutionized the therapy landscape of NSCLC. However, why some patients do not respond to CI therapy remains unknown. The correlation between intra-tumoral B cell follicles and response to CI therapy has been established. B cell follicles within the lymph node become more dispersed with age and CD27-IgD- B cells (DNBc) are described to be age-associated. Moreover, DNBc are abundant in chronic infection, elderly, long COVID and auto-immunity and are described to be anergic and exhausted and often lack expression of CD21. DNBc are expanded in NSCLC tumors compared to healthy lung tissue and inversely correlate to switched memory B cells in the tumor. In this study we explored if there is a correlation between this B cell subtype in peripheral blood of NSCLC patients and response to CI therapy. Methods Patients treated with CIs within the Erasmus Medical Center were included in a prospective observational immunomonitoring study. Nineteen NSCLC patients treated with either Pembrolizumab (Pem) or Nivolumab and 5 healthy controls (HC) were selected. Pem was given in 6/11 responding patients (R) and 5/8 non-responding patients (NR). Peripheral blood mononuclear cells (PBMC) were collected before start of treatment and characterized by multicolor flow cytometry. Results HC and R showed a similar pattern in most B cell subsets. NR had significantly lower proportion of B cells within the PBMC fraction than Rand HC (R: 7.14%, NR: 2.91%, HC: 10.60%). In addition, NR had a significantly higher frequency of DNBc than R and HC (R: 9.43%, NR: 23.78%, HC: 7.19%) and there was no correlation between age and DNBc. The frequency of DNBc correlated positively with lack of CD21 expression (r2: 0.83) and expression of Ki67 (r2: 0.54) both in NR, Rand HC. The frequency of Ki67+CD21-DNBc within the B cell fraction was higher in NR than in R and HC (NR: 18.34%, R: 3.51%, HC: 0.67%). Conclusions We are the first to describe that frequencies of DNBc are higher in NR compared to R and HC. Specifically, Ki67+CD21-DNBc are increased in NR and might reflect an anergic, exhausted B cell phenotype. The absence of a correlation between age and DNBc could suggest that the increase in DNBc is induced by the tumor. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure D. Dumoulin: Financial Interests, Personal, Other: Roche, BMS, MSD, AstraZeneca, Novartis. J.G. Aerts: Financial Interests, Personal, Research Grant: Amphera, Roche, Eli Lilly;Financial Interests, Personal, Advisory Board: Amphera, Bristol-Myers Squibb, Eli Lilly, MSD, Roche;Financial Interests, Personal, Ownership Interest: Amphera;Financial Interests, Personal, Other: Takeda. All other authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Comparing dosimetry of locally advanced cervical cancer patients treated with 3 versus 4 fractions of MRI-guided brachytherapy.

PURPOSE: To demonstrate the feasibility of treating cervical cancer patients with MRI-guided brachytherapy (MRgBT) using 24 Gy in 3 fractions (F) versus a standard, more resource-intensive regimen of 28 Gy in 4F, and its ability to meet EMBRACE II planning aims. METHODS AND MATERIALS: A retrospective review of 224 patients with FIGO Stage IB-IVA cervical cancer treated with 28 Gy/4F (n = 91) and 24 Gy/3F (n = 133) MRgBT between 2016-2021 was conducted. Multivariable linear regression models were fitted to compare dosimetric parameters between the two groups, adjusting for CTVHR and T stage. RESULTS: Most patients had squamous cell carcinoma, T2b disease, and were treated with intracavitary applicator plus interstitial needles (96%). The 28 Gy/4F group had higher CTVHR (median 28 vs. 26 cm3, p = 0.04), CTVIR D98% (mean 65.5 vs. 64.5 Gy, p = 0.03), rectum D2cm3 (mean 61.7 vs. 59.2 Gy, p = 0.04) and bladder D2cm3 (81.3 vs. 77.9 Gy, p = 0.03). There were no significant differences in the proportion of patients meeting the EMBRACE II OAR dose constraints and planning aims, except fewer patients treated with 28 Gy/4F met rectum D2cm3 < 65 Gy (73 vs. 85%, p = 0.027) and ICRU rectovaginal point < 65 Gy (65 vs. 84%, p = 0.005). CONCLUSIONS: Cervical cancer patients treated with 24 Gy/3F MRgBT had comparable target doses and lower OAR doses compared to those treated with 28 Gy/4F. A less-resource intense fractionation schedule of 24 Gy/3F is an alternative to 28 Gy/4F in cervix MRgBT.

Cost effectiveness of fractional doses of COVID-19 vaccine boosters in India.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major global public health crisis that exacts significant human and economic costs. Booster vaccination of individuals can improve waning immunity and reduce the impact of community epidemics. METHODS: Using an epidemiological model that incorporates population-level severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and waning of vaccine-derived immunity, we identify the hypothetical potential of mass vaccination with fractionated vaccine doses specific to ChAdOx1 nCoV-19 (AZD1222 [Covishield]; AstraZeneca) as an optimal and cost-effective strategy in India's Omicron outbreak. FINDINGS: We find that the optimal strategy is 1/8 fractional dosing under mild (Re ∼ 1.2) and rapid (Re ∼ 5) transmission scenarios, leading to an estimated $6 (95% confidence interval [CI]: -13, 26) billion and $2 (95% CI: -26, 30) billion in health-related net monetary benefit over 200 days, respectively. Rapid and broad use of fractional dosing for boosters, together with delivery costs divided by fractionation, could substantially gain more net monetary benefit by $11 (95% CI: -10, 33) and $2 (95% CI: -23, 28) billion, respectively, under the mild and rapid transmission scenarios. CONCLUSIONS: Mass vaccination with fractional doses of COVID-19 vaccines to boost immunity in a vaccinated population could be a cost-effective strategy for mitigating the public health costs of resurgences caused by vaccine-evasive variants, and fractional dosing deserves further clinical and regulatory evaluation. FUNDING: Financial support was provided by the AIR@InnoHK Program from Innovation and Technology Commission of the Government of the Hong Kong Special Administrative Region.

Radiotherapy Management of Locally Advanced Cervical Cancer during the COVID-19 Era: A Single Centre Report on Treatment Approach, Brachytherapy Fractionation and Timing

Background: The COVID-19 pandemic had a catastrophic impact on healthcare. Keeping an optimal cancer care routine has been challenging. For cervical cancer (CC) patients external beam radiotherapy (EBRT) and brachytherapy (BT) are key elements for radical treatment. Oncological treatment delays have represented a major issue during the pandemic. Overall treatment time (OTT) is a well-known prognostic factor for CC. Thus, we decided to evaluate radiotherapy timing and modalities, and OTT trends for locally advanced cervical cancer (LACC) patients treated at our center during the Pandemic. Method(s): We retrospectively collected and analyzed data of patients treated for LACC at our Center, (Department of Oncology, Radiation Oncology, S.Anna Hospital, Turin, Italy), during the COVID-19 pandemic. Result(s): Between March 2020 and March 2022, 36 patients were treated. All patients underwent EBRT (median pelvic dose 48 Gray (Gy)). Concurrent chemotherapy (ChT) was administered in 31/36 patients. High Dose Rate (HDR) BT boost was delivered to 32/36 patients. BT schedules adopted were: 28 Gy in 4 fractions (18 cases, 56.2%), 26 Gy in 4 fractions (5 cases, 15.6%), 21 Gy in 3 fractions (4 cases, 12.5%), 18 Gy in 3 fractions (3 cases, 9.3%), 24 Gy in 4 fractions (one case, 3.2%), 12 Gy in 2 fractions plus 11 Gy in 2 fractions (one case, 3.2%). Most of the patients (25/32, 78.1%) received one fraction per week;6 patients (18.1%) 2 fractions per week and one patient 3 fractions per week. Median OTT was 74 days (57-99). The median interval from EBRT to HDR-BT was 14 days (6-54). Four patients tested positive for COVID-19 between EBRT and BT. At a median follow-up of 10.7 months (range 1.8-20.3), a complete response was obtained in 25 patients (69.5%), a partial response in 8 cases (22.2%), and a disease progression in two patients (5.5%). Conclusion(s): in terms of radiotherapy management of LACC, brachytherapy resulted as the most affected by the restrictions due to the pandemic. We adopted different schedules and fractionations to optimize the resources available and to keep providing an optimal care. A be-weekly fractionation emerged as a promising option for LACC during the pandemic, with a good toxicity profile. Copyright: © 2022 The Author(s).

Prospects of accelerated fractionation chemoradiotherapy for locally advanced oropharyngeal cancer during the COVID-19 pandemic

Objective. To comparatively assess the early toxicity of treatment, its tolerability, 1-, 2-, 3-year overall survival, and local regional control rates in a group of patients receiving a radical cycle of accelerated or conventional fractionation chemoradiotherapy. Subjects and methods. The paper presents the interim results of a prospective study that included 115 patients with locally advanced cancer of the oropharynx, tongue root, and larynx who received a radical cycle of conformal chemoradiotherapy using accelerated (the single focal dose (SFD) was 2.4 Gy for 25—26 fractions) or conventional (SFD was 2.0 Gy for 32—33 fractions) fractionation in the period from 2015 to 2020. Results. An analysis comparing the study group with the control one revealed no statistically significant differences in the level of early toxicity of treatment (p=0.41). Complete tumor reversal was achieved in 57 (86.3%) patients in the study group and in 39 (79.5%) in the comparison group (p=0.23). The 1-, 2-, and 3-year local regional control rates in the accelerated fractionation group was 78.3±5.3%;65.9±6.8%, and 54.5±9.2%, respectively. The 3-year overall survival rate was 80.4±7.4%. These rates did not differ statistically from those in the conventional radiotherapy group (p=0.12—0.82);53 (80.3%) patients in the study group and 37 (75.5%) in the standard fractionation group received a radiation cycle without a forced interval. The treatment interval in the patients of both groups reduced the 2-year local regional control rates by 30.2% compared to that in the continuous cycle group (p=0.02). Conclusion. Accelerated fractionation chemoradiotherapy (SFD was 2.4 Gy for 25—26 fractions, the daily focal dose was 60.0— 62.4 Gy) is a procedure comparable with conventional radiation in its direct efficiency and safety. During the COVID-19 pandemic, this regimen can be considered to be a mainstay for patients with locally advanced oropharyngeal cancer in order to preserve the previous volumes of specialized healthcare. © A.V. SEMENOV I.A. GULIDOV O.G. LEPILINA M.U. RADZHAPOVA F.E. SEVRYUKOV K.B. GORDON.

Immunogenicity, efficacy, and safety of SARS-CoV-2 vaccine dose fractionation: a systematic review and meta-analysis.

BACKGROUND: Dose fractionation of a coronavirus disease 2019 (COVID-19) vaccine could effectively accelerate global vaccine coverage, while supporting evidence of efficacy, immunogenicity, and safety are unavailable, especially with emerging variants. METHODS: We systematically reviewed clinical trials that reported dose-finding results and estimated the dose-response relationship of neutralizing antibodies (nAbs) of COVID-19 vaccines using a generalized additive model. We predicted the vaccine efficacy against both ancestral and variants, using previously reported correlates of protection and cross-reactivity. We also reviewed and compared seroconversion to nAbs, T cell responses, and safety profiles between fractional and standard dose groups. RESULTS: We found that dose fractionation of mRNA and protein subunit vaccines could induce SARS-CoV-2-specific nAbs and T cells that confer a reasonable level of protection (i.e., vaccine efficacy > 50%) against ancestral strains and variants up to Omicron. Safety profiles of fractional doses were non-inferior to the standard dose. CONCLUSIONS: Dose fractionation of mRNA and protein subunit vaccines may be safe and effective, which would also vary depending on the characteristics of emerging variants and updated vaccine formulations.

Stereotactic Ablative Radiotherapy Before Resection to AvoId Delay for Early-Stage LunG Cancer or OligomEts

Introduction: The COVID-19 pandemic led to worldwide barriers to access to operating rooms;some multidisciplinary thoracic oncology teams pivoted to a paradigm of stereotactic ablative radiotherapy (SABR) as a bridge to provide radical-intent treatment combining immediate SABR followed by planned surgery when surgical resource constraints ameliorated. This pragmatic approach, termed SABR-BRIDGE, was instituted with prospective data collection at four institutions (3 Canada, 1 USA);herein we present the surgical and pathological results from this approach. Methods: Eligible participants had early-stage presumed or biopsy-proven lung malignancy that would otherwise be surgically-resected. SABR was delivered using standard institutional guidelines with one of three fractionation regimens: 30-34 Gy /1 fraction, 45-55 Gy/3-5 fractions, or 60 Gy/8 fractions. Surgery was recommended at a minimum of 3 months following SABR with standardized pathologic assessment of resected tissue. A pathological complete response (pCR) was defined as absence of viable cancer, and a major pathologic response (MPR) was defined as ≤10% viable tissue. Results: Seventy-five participants were enrolled, of which 72 received SABR. Following SABR, 26 patients underwent resection, while 46 did not;reasons for not undergoing surgery included metastasis (n=2), non-cancer death (n=1), awaiting lung surgery (n=13) and patient choice given favorable post-SABR imaging response (n=30). Of 26 patients who underwent resection, 62% had a pre-treatment biopsy. The most common SABR regimens were 34 Gy /1 fraction (31%) and 48 Gy in 3-4 fractions (31%). SABR was well-tolerated, with two grade 1 toxicities (pain, 7.7%), and one grade 3 pneumonitis (3.8%). Median time-to-surgery was 4.5 months from SABR completion (range:2-17.5 months). Most had minimally-invasive surgery (n=19, 73%) with 4 patients (15%) requiring conversion to thoracotomy, and 3 (12%) had planned open operation. Surgery was reported as being more difficult because of SABR in 38% (n=10). There were two intraoperative complications (7.7%, pulmonary artery injury), and 8 patients with post-operative complications (31%, all grade 2, most commonly air leaks [n=5]). The amount of residual primary tumor ranged from 0% to 90%. Thirteen (50%) had pCR while 19 (73%) had MPR. Rates of pCR were higher in patients operated upon at earlier time points (75% if within 3 months, 50% if 3-6 months, and 33% if ≥6 months). Rates of pCR were higher in patients without pre-treatment tissue diagnosis (91% versus 20% in those without and with tissue diagnosis, respectively). In 31% (n=8) of patients, nodal disease was discovered on resection, with half being N2 (4/26=15%). Conclusions: The SABR-BRIDGE approach allowed for delivery of treatment with minimal upstaging during a period of operating room closure & high risk for patients. Surgery was well-tolerated. However, most patients who received SABR did not proceed to surgery, limiting precise estimates of pCR rates. However, the reported pCR rate is consistent with previous phase II trial data. Keywords: lung surgery, SBRT, Multi-modal therapy

Trends in low-value oncology care during the COVID-19 pandemic

Background: Low-value services, which provide minimal patient benefit while entailing costs and risks, are prevalent in cancer care. Shifts in cancer care delivery during the COVID-19 pandemic to minimize exposure provided opportunities for health systems and clinicians to prioritize higher-value over lowvalue oncology services. Methods: In this retrospective cohort study, we investigated the association between the COVID-19 pandemic period and low-value cancer care practices using administrative claims from the HealthCore Integrated Research Environment, consisting of ∼65 million members managed by 14 health plans across the US. We identified commercial or Medicare Advantage members diagnosed with breast, colorectal, or lung cancer between January 2015 and March 2021. Low-value cancer care practices were identified from peer-reviewed medical literature, including ASCO and ASTRO Choosing Wisely campaigns and evidence-based pathways. Five low-value practices were studied: (1) conventional fractionation instead of hypofractionation for early-stage breast cancer;(2) off-pathway systemic therapy;(3) non-guideline-based antiemetic use for minimal-, low-, or moderate-to-high-risk chemotherapies;(4) Positron Emission Tomography/Computed Tomography (PET/CT) instead of conventional CT for staging;and (5) aggressive end-of-life care (chemotherapy ≤14 days, multiple emergency department visits ≤30 days, ICU utilization ≤30 days, hospice initiation ≤3 days, and/or no hospice before death). We used linear probability models to evaluate the association between the COVID- 19 period (March to December 2020) and the 5 outcomes, adjusting for patient, facility, geographic and temporal characteristics. Results: Among 204,581 members (mean age 63.1, 139,488 [68.1%] female), 83,593 (40.8%) had breast cancer, 56,373 (27.5%) had colon cancer, and 64,615 (31.5%) had lung cancer. Rates of low-value care were similar in pre-COVID vs. COVID periods: conventional radiotherapy: 22.1% vs. 9.4%;off-pathway systemic therapy: 36.7% vs. 43.2%;non-guideline-based antiemetics: 61.2% vs. 58.1%;PET/CT imaging: 39.9% vs. 41.3%;aggressive end-of-life care: 75.8% vs. 73.3%. In adjusted analyses, the COVID-19 period was associated with no changes in off-pathway therapy (adjusted percentage point difference [aPPD] 0.82, SD 0.08, p = 0.33), PET/CT imaging (aPPD 0.10, SD 0.005, p = 0.83), and aggressive end-of-life care (aPPD 2.71, SD 0.02, p = 0.16). Small changes in conventional radiotherapy (aPPD 3.93, SD 0.01, p < 0.01) and non-guideline-based antiemetics (aPPD -3.62, SD 0.006, p < 0.01), were noted. Conclusions: The shock of the COVID-19 pandemic did not meaningfully change several metrics of low-value cancer care. Broader changes to payment and incentive design should be considered to turn the tide toward higher-value cancer care.

How may shorter fractionation schedules affect patient care?

Hypofractionation has shown to be beneficial in the management of a wide range of cancers1,2 including other advantages such as cost savings3. Trials over the last decade4,5,6 have demonstrated the advantages of hypofractionation compared with a standard radiotherapy regimen3. Covid-19 significantly impacted the way in which cancer patients7 are managed and even though the use of hypofractionation is well established in some cancer types;the application thereof during the pandemic has been widely expanded to minimise treatment time8. Even though the treatment outcomes have been well defined, there is limited evidence to suggest changes in patient care. Some oncology centres advocated for a reduced contact time between patient and staff9. Hypofractionation in an ageing population is particularly advantageous in allowing people to receive treatment in a shorter time demonstrating treatment outcomes similar to younger age groups10 however;greater consideration should be given to performance status and comorbidities associated with these treatment outcomes11. Fractionation schedules which allow delivery in less fractions, can be highly effective with limited treatment-related toxicity. Studies have shown that the late consequences of radiotherapy in these patient groups are seldom an issue even with larger fraction s12. However more recent studies suggest that a reduction in treatment time should not be the only reason for selecting this approach. Moderate hypofractionation should therefore be considered for those patient who are younger and who might experience long terms effects13. More studies are now investigating the tolerability of ultra-hypofractionated radiotherapy in an attempt to improve the therapeutic gain, suggesting that these approaches are well-tolerated and showed no statistical difference in toxicity14. Hypofractionation in radiotherapy may be a good alternative to conventional fractionation however patience care remains paramount in the management of all toxicities related the radiotherapy delivery. There is no evidence to suggest the patient care of these patients have changed, however the tolerability and outcomes of this method of delivery requires constant review. Patient care needs to consider the site of treatment, age of the patient, performance status, and tolerability. A model of shared decision making in managing care is advocated with greater emphasis on selfcare.

Moderate hypofractionated radiotherapy after prostatectomy in the context of the COVID19

Purpose or Objective We designed a hypofractionated radiotherapy protocol for adjuvant or salvage treatment after radical prostatectomy. In this first report we present the implementation of this protocol in the context of a COVID-19 pandemic. Materials and Methods Patients meeting the inclusion criteria (high-risk features on histopathology or biochemical recurrence) received radiotherapy to the prostate bed 51 Gy in 17 fractions, elective treatment of the pelvis at a dose of 36 Gy in 12 fractions was permited. Acute gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events versión 4.03. The disease-related quality of life, urinary, gastrointestinal, sexual and hormonal function were evaluated with the Expanded Prostate Cancer Index Composite (EPIC), QLQc30 and PR25 questionnaires at baseline before the start of radiotherapy and at one month after radiotherapy, then every six monts for two years. In addition, the incidence of COVID-19 cases was reported in the patients recruited in the trial and in those who underwent standard fractionation treatment (1.8-2.0 Gy per fraction), and in health personnel involved in the treatment of patients in study period. Results From August 2020 to March 2021, 22 patients have been registered. Fourteen patients have completed treatment and are included in this report. The median age was 64 years and most had a Gleason 3 + 4 (50%), with a pT3a (35.7%) and negative surgical margins (71.4%). Three patients (21.4%) were staged as pN1. Most patients were treated for salvage (57.1%), with an median PSA prior to the start of RT of 0,29 ng/ml. Most patients report minimal or low acute radiation effects in terms of GI and GU toxicity, with an acute toxicity grade 2 GI and GU of 50% and 14.3%, respectively. Without Grade 3 or higher GI / GU toxicity. Of the 14 patients who received the trial protocol, none had a clinical of COVID-19 infection, while one patient who received treatment with conventional fractionation development a COVID-19 infection. Conclusion We present the implementation of an protocol of hypofractionated schedule of postoperative prostate radiotherapy in an academic center in a developing country in the context of a COVID-19 pandemic. Preliminary results show the absence of COVID infection in the included patients, and low GU and GI toxicity.

Radiotherapy Quality Assurance;is volume review all that matters?

Purpose or Objective RTQA practice is known to have significant variation amongst institutions worldwide. It is critical to maintaining patient safety, treatment effectiveness and accuracy. However there is no standard practice, with often only target volume delineation reviewed alone and performed retrospectively. Previous studies have highlighted higher rates of changes made in more complex techniques and subsites. This study aims at evaluating our prospective structured peer review process in a proton beam therapy (PBT) centre. Materials and Methods We reviewed the RTQA cases of all patients treated at The Christie Proton Beam Centre since its opening in November 2018 until February 2021. The RTQA process is carried out weekly, is subsite specific and every case has their target volumes and plans reviewed in detail in the presence of consultants, fellows, physicists and dosimetrists. Since the COVID-19 pandemic, the peer review meetings are now virtual. Every peer review has a standardised RTQA form filled. We classified the peer reviews as having major/minor or no change. A major change was one where the target volumes (GTV and/or CTV) were too small or big;dose fractionation was incorrect to that of the prescription treated and any plan that was changed. A minor change was one where there were minor modifications to the target volumes, OARs or non-essential suggestions in relation to the plan that didn’t result in the plan being altered eg. addition of an OAR. Results There was a total of 1,209 peer reviews for 462 patients. 100% of cases had both volumes and plans peer reviewed prospectively. 591 were reviews of target volumes and 618 were plan reviews. In total there were 208 (17%) major changes, 194 (16%) minor and 807 (67%) with no changes. Of the major changes 137 (66%) were target volumes and 71 (34%) plans. Of the minor changes 174 (90%) were target volumes and 20 (10%) plans. There were more major and minor changes in the brain and head & neck subsites possibly due to their complexity. When diagnoses in the brain were categorised (Table 1) and reviewed against changes using a chi-squared test the resulting p-value = 0.027 suggests a significant relationship between type of diagnoses and likely need for change following peer review.(Table Presented) Conclusion Target volume delineation and radiotherapy plans particularly in brain, head & neck as well as other complex subsites require mandatory prospective review as highlighted above. We have shown this to be practically achievable and successful despite challenging times

Our Experience in Palliative Radiotherapy During the COVID-19 Pandemic

Background/aims: Radiotherapy is an effective palliative treatment for metastatic disease. The current COVID-19 pandemic has led us to consider shorter courses, new guidelines and prioritize cases clinically urgent. The purpose of this study is to analyze our practice in palliative treatment, new potential strategies and hypofractionation. Methods: 252 patients who receive palliative radiation treatment from March 2020 to March 2021 were reviewed. We analyze how the treatment line has been modified throughout the 1 year of the pandemic and other items related to the different therapeutic options as mortality, reirradiation, primary localization and intention. Results: Median age was 68 years (range 33-95y), 66% males, 34% females. Main primary tumors were 30% lung, 12% prostate and 10% breast. 65% patients had painful bone metastases, 15% brain metastases, 14% cord compression, 4% bleeding and 2% superior vena cava obstruction. Advanced disease was detected in 12% as debut. Half of patients were treated in the two first months of the pandemic than later. Treatment provided was: 8 patients required reirradiation. Currently, 66% died. Conclusions: Radiotherapy plays a critical role improving quality of life in patients with advanced disease, even in the midst of the COVID-19 pandemic. During the first months of confinement, short radiation therapy cycles prevailed over the long ones, as the normal schemes of fractionation coinciding with a greater number of sessions gained importance as time went on. (Table Presented).

'WHO Action Framework to advance universal access to safe, effective and quality assured blood products: how far are we?'

In response to the recommendations of WHA63.12 (2010) resolution on availability, safety and quality of blood products, the World Health Organization has steadily implemented numerous initiatives over the years to assist countries in building and strengthening their national blood systems, although with uneven success. In February 2020, WHO has developed the WHO Action Framework to Advance Universal Access to Safe, Effective and Quality-Assured Blood Products 2020-2023, which proposes a renewed effort to scale up programme implementation and improve access to blood products. The Framework aims to provide strategic direction to global efforts to address barriers to safety and availability of blood products and focuses on six strategic objectives: (1) an appropriately structured, well-coordinated and sustainably resourced national blood system;(2) an appropriate national framework of regulatory controls;(3) functioning and efficiently managed blood services;(4) effective implementation of patient blood management to optimize clinical practice of transfusion;(5) effective surveillance, haemovigilance and pharmacovigilance;and (6) partnerships, collaboration and information exchange to achieve key priorities and jointly address challenges and emerging threats at global, regional and national levels. During 2020-2021, to achieve these strategic objectives, some activities have been conducted, in the form of development written guidance as well as country assistance. Guidance on Centralization of blood donation testing and processing, and guidance on Increasing supply of plasma-derived medicinal products (PDMPs) in LMICs through fractionation of domestic plasma;Education Module on Update clinical use of blood and Policy Brief on the urgent need to implement Patient Blood Management have been published and disseminated through webinars. To assist country in implementation of WHO guidance, webinars on strengthening blood system through effective blood regulation, online training on haemovigilance system and on self-assessment using the Global Benchmarking Tools plus Blood have already been conducted. Assistance has also been given to Egypt in developing a plan for plasma fractionation. Some challenges to implement the action framework at country level still exist, for example, weak government support and commitment to the blood program, limited resources, and the Covid-19 pandemic, which hinders holding face to face meetings which are still effective for some activities. Currently some guidance is under development, and the Achilles Project, which is a WHO project to assist country in improving quality of their plasma for fractionation, will be run in Senegal, in collaboration with the International Coalition led by ISBT. As soon as the Covid-19 pandemic situation allows for face-to-face meetings, country assistance in the form of training, country visit for assessment and twinning program will be increased, to accelerate implementation of the action framework at country level.

GUNNERA PERPENSA ELLAGITANNINS SYNERGISTICALLY INHIBIT MULTIPLE SARS-CoV-2 VARIANTS

Background: Antivirals are urgently needed to supplement SARS-CoV-2 vaccines and target SARS-CoV-2 variants of concern, particularly in resource-limited regions. Active derivatives from the medicinal plant Gunnera perpensa, already in use as a general antiviral in humans by traditional health practitioners in the Eastern Cape Province of South Africa, warrant further evaluation against SARS-CoV-2. Methods: Active constituents of Gunnera perpensa were identified using hyphenated analytical techniques and for ability to inhibit binding of recombinant SARS-CoV-2 spike with host ACE2 protein as assessed by AlphaScreen. Inhibition was tested against parental (USA-WA1/2020), beta (B.1.351), and delta (B.1.617.2) spike proteins using AlphaScreen and spike-expressing VSVΔG-GFP pseudoviruses. Infection of Vero cells was monitored by high-content imaging of GFP or nucleocapsid-positive Vero-E6 cells in pseudovirus and virus assays, respectively, at 2 days post-infection (dpi). Viral cytopathic effect (CPE) ± GC-376 or remdesivir was also monitored using resazurin viability dye at 4 dpi. All assays were described previously (PMID: 34543092). Synergism was assessed by the Bliss Independence model, and group differences were analyzed by two-sided, paired t-test. Results: Crude extracts from the leaves of Gunnera perpensa were confirmed to inhibit parental spike/ACE2 interactions with an IC50 of 37 ± 23 ng/mL. Bioassay-guided fractionation identified two ellagitannins, punicalin and punicalagin, which inhibited parental, beta, and delta spike/ACE2 binding with IC50s of 2.7 ± 0.6-5.8 ± 4.8 and 6.0 ± 4.5-19 ± 23 nM, respectively. Both compounds inhibited all spike variants in pseudovirus at low to mid micromolar concentrations (see Table). Notably, in CPE-based viral assays, a 1:1 molar mixture of punicalin and punicalagin significantly enhanced antiviral activity (EC50 = 2.9 μM vs. 11.6 and 46.8 μM for single compounds, p < 0.05), on par with activities of preclinical candidate GC-376 (1.3 μM) and remdesivir (2.8 μM;see Table). When combined in a 1:1 molar mixture, punicalin further significantly enhanced activity of GC-376 (EC50 = 0.6 μM, p < 0.05) and remdesivir (EC50 = 1.1 μM, p < 0.05). Conclusion: Punicalin and punicalagin inhibit entry and replication of SARS-CoV-2 variants in vitro and synergize when applied in combination and/or with GC-376 or remdesivir. Ellagitannins and medicinal plant extracts are promising new leads for SARS-CoV-2 antivirals in resource-limited regions.

Elimination of cervical cancer as a public health problem—how shorter brachytherapy could make a difference during COVID-19

The World Health Organization has called for elimination of cervical cancer as a public health problem and has adopted strategies in this regard. However, the estimates for achieving the goals depend on the ability to provide timely treatment in a certain proportion of cases. The coronavirus disease 2019 pandemic has had a serious impact on healthcare delivery in many low and middle income countries (LMICs) with the highest burden of cervical cancer;funds and infrastructure are being reallocated to deal with the emergency, and cancer care has been seriously affected. In the absence of clear and reliable estimates, the exact extent of disruption remains unclear. It is, therefore, essential that pragmatic approaches are adopted to save lives. There has been considerable debate regarding the use of the 9 Gy × 2 fractions high dose rate brachytherapy schedule for the treatment of locally advanced cervical carcinoma. However, in LMICs with the highest global burden of locally advanced cervical cancer cases, radiation facilities have been using this fractionation schedule in many cases to deal with the overwhelming number of patients, who would have otherwise been denied timely treatment. In view of the current pandemic, and the difficulties in accessing and delivering timely healthcare, mortality owing to delayed treatment cannot be denied in LMICs, which already have underequipped healthcare facilities. Use of the shortest available fractionation schedule to provide timely treatment would serve to save more lives in regions with high incidence and mortality from the disease.