ABSTRACT
Objectives: A 14-year-old female patient presents with marked haemorrhagic, adherent crusting of the upper and lower lip and enoral vesicles and erosions. Two weeks before, she had suffered from a respiratory tract infection. She did not take antibiotics but ibuprofen. One week later, she described a swelling and crusting of the upper and lower lips. Urogenital mucosa was also erosive. There was no ocular involvement. Another week later, cocard-like single lesions with partly central blister formation developed. A flaccid blister of 15 mm in diameter was detected in the left ear helix. In total, there was a limited cutaneous involvement of <10% BSA. The girl was admitted to the paediatric clinic. Method(s): Due to mucocutaneous eruptions, bullous lesions and multimucosal involvement, we assumed a Steven-Johnson syndrome or reactive infectious mucocutaneous eruption (RIME). Intravenous rehydration and prophylactic administration of cefotaxime and aciclovir were given. She was balanced and given analgesia with novalgin. The recent increased intake of ibuprofen was discontinued. Local therapy included mometasone cream and serasept dressings. During the inpatient stay, the general condition stabilised and the skin efflorescence's showed a clear regression. Result(s): The microbiological smears for COVID-19, HSV, VZV, mycoplasma, and chlamydia were negative. Discussion(s): As adult classifications for blistering severe cutaneous adverse reactions are limited applicable in children, Ramien et al. proposed revised paediatric-focused clinical criteria 2021. They leave traditional definitions of EEM, SJS and TEN. But they distinguish erythema multiforme (EM) for classic targets with/without mucosal involvement, RIME for cases with mucosal predominance and a respiratory infection trigger, and drug-induced epidermal necrolysis (DEN) for cases caused by medications. (Ramien BJD 2021) There are no current guidelines for RIME therapy. A reasonable management approach includes symptomatic therapy, treatment of identifiable infectious triggers (if possible), consulting urologists, ophthalmologists and gynaecologists (if necessary), immunosuppression, and psychological support. (Ramien ClinExpDermatol 2021).
ABSTRACT
Introduction/Aim: Rates of hospitalisation and death from COVID-19 in lung transplant (LTx) recipients vary internationally. We aimed to assess risk factors for this in an Australian cohort. Method(s): We performed a retrospective cohort study of all LTx recipients between January 2020 and September 2022. LTx recipients with COVID-19 were included. Baseline characteristics and treatments were recorded. Multivariate logistic regression was performed to identify risk factors associated with hospitalisation and death. Result(s): 128/387 (33%) recipients tested positive to SARS-CoV-2 during the study period, 97.6% during the Omicron waves with 40(31.3%) requiring hospitalisation and 10 (7.8%) died. The median (IQR) recipient age was 50.6 (22-77). The cohort was of Caucasian ethnicity 105 (82%), 48% were female with high vaccination rates (98.4%). Chronic lung allograft dysfunction (CLAD) was present in 48 (37.5%). 103 (80.5%) of patients received early SARS-CoV-2 treatment with either Sotrovimab 84(65%), Molnupirivir 50(39%) or combination 31(24%). 25 patients (19.5%) received no early treatment. All hospitalised patients received Remdesivir and Dexamethasone as per local treatment protocols. Regarding risk of hospitalisation, multivariate analysis showed that recipient age (1-unit change OR 1.04 95% CI 1.01-1.07 p = 0.019) was associated with an increased risk, whereas Molnupiravir was protective (OR 0.32 95% CI 0.13-0.80 p = 0.02). In univariable analysis, increasing age (1-unit change, OR 1.07 95% CI 1.02-1.129 p = 0.01) and severe disease (OR 9.95 95% CI 2.58-38.32 p =< 0.001) were associated with an increased risk of death. Male gender, non-Caucasian ethnicity, CLAD, CKD stage 3-5 were correlated with death with weak association. Conclusion(s): Recipient age is a significant risk factor for both hospitalisation and death, and older patients with COVID-19 should be monitored closely during COVID-19 illness. Molnupirivir is protective against hospitalisation, with Sotrovimab having a weak association. Further analysis of the protective effect of pre-exposure prophylaxis with emerging therapies such as Evusheld would be helpful to fully evaluate the currently available early disease therapies in Australia.
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The post-COVID-19 recovery period is characterized by persistence of some symptoms, with immunological alterations being of great importance. Development of preventive measures to normalize mucosal immunity after a coronavirus infection determines the relevance of the current study. The aim was to study dynamics of clinical symptoms and level of secretory immunoglobulin A in individuals after a novel coronavirus infection as well as evaluate effectiveness of using IFNalpha-2b. Materials and methods. A study was conducted with patients aged 18 to 60 years old (n = 130), surveyed 1 to 9 months after post-infection, as well as in apparently healthy individuals lacking COVID-19 (n = 15). Previous novel coronavirus infection and post-COVID manifestations were verified based on medical documentation, complaints, anamnesis data, physical examination and questionnaires. The concentration of salivatory and nasopharyngeal mucosal sIgA was measured dynamically prior to and after administration of local therapy with IFNalpha-2b (gel applied intranasally twice a day for 30 days). Results. The acute period of COVID-19 was characterized by fever, anosmia, severe asthenia (fatigue and weakness), muscle and joint pain. Among the post-COVID manifestations at early period (1-3 months), pain in the joints and muscles (75.0%) as well as elevated body temperature (21.2%) were reliably detected, whereas in the long period (6-9 months) there were revealed dominance with the same frequency of shortness of breath, muscle and joint pain (75.8%, respectively). Based on examination data in healthy subjects, there was determined an arbitrary normal range of secretory IgA in saliva - 6.45+/-1.81 mg/ml and nasal swabs - 13.43+/-3.24 mg/ml. In the group of patients 1-3 months post-infection, therapy with IFNalpha-2b one month later resulted in significantly increased level of secretory IgA in saliva (from 1.84+/-0.28 to 5.78+/-1.96 mg/ml) and in nasal swabs (from 28.61+/-3.0 to 39.83+/-3.85 mg/ml) by more than 3- and 1.5-fold, respectively. In the group of patients without therapy was featured with stably sustained decline in sIgA level up to 9 months after COVID-19. In particular, the level of saliva sIgA ranged from 2.36+/-0.56 down to 2.16+/-0.66 mg/ml, and in nasal smears - from 15.66+/-1.32 to 10.23+/-1.07 mg/ml that differed insignificantly compared to baseline level. The rate of respiratory diseases prevailed in this group (27.6% of cases), which fully lacked in the group of topically administered IFNalpha-2b. Conclusion. In the post-COVID period, multiple organ disorders persist and reduced sIgA level is registered. Intranasally applied IFNalpha-2b made possible to normalize sIgA level and prevent accumulation of respiratory infectious pathologies.Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.
ABSTRACT
Over the last decade we have witnessed rapid advances in the treatment of patients with metastatic breast cancer (MBC) with seminal discoveries in cancer biology, correlative biomarkers and clinical trials leading to multiple new drug approvals. While these milestones have improved survival, the science of survivorship in this population is just beginning. The diagnosis of MBC is life-changing and requires individualized and multidisciplinary support. The NCI defined the areas of epidemiology and surveillance, symptom management, psychosocial research, health-care delivery, and health behaviors as necessary fields to advance the state of the science in advanced cancer survivors. A multifaceted program addressing these domains is needed to assess MBC patients and their unique and ever-changing needs. With input from patients and providers, program components should include: therapeutic clinical trials, multidisciplinary specialty care, individualized patient navigation, peer support, continuing education, and patient reported outcome (PRO) collection to support patients living with MBC. Input for a program for MBC patients can be guided by a multidisciplinary steering committee in which patient advocates are a major voice. Patients can provide insight into what works for them, and what they are facing may be very different from the experience of an early-stage breast cancer patient. Clinical trials designed to advance the current scientific knowledge of breast cancer treatment are essential to patients living longer, more fulfilled lives with MBC. Clinical trials may include systemic therapy, local therapies such as surgery and radiation for MBC patients, side-effect management and quality of life (may put elsewhere). A comprehensive systemic therapy portfolio should include all biological subtypes as well as recommended treatment options (hormonal therapy, targeted therapy, chemotherapy, and immunotherapy). Multidisciplinary care is necessary to diagnose and treat any condition the MBC patient may encounter and is essential in providing quality care. Comorbidities and debilitating side effects arising from cancer treatment are known to be associated with inferior outcomes. MBC patients may experience lack of familiarity of some providers with novel MBC cancer treatment, side effects, and interactions of their cancer treatment with non-cancer conditions and treatment. With the increasing life expectancy of MBC patients, it is important to manage the medical comorbidities in coordination with the MBC patient's cancer treatment. Integrative Medicine helps support the quality of life of patients through providing clinical modalities such as stress management, yoga, meditation, acupuncture, massage and lifestyle counseling. Supportive care helps support cancer related fatigue and sleep challanges, geriatrics and hospice and palliative care for advanced cancer patients. The role of navigation for MBC patients is unique and should be designed to support the patient's many individual needs. Navigation requires assessment of individual knowledge deficit, coordination of care challenges, internal resource utilization, cultural requests, and emotional health. Navigation should also address the patient's financial and disability questions, medication assistance, symptom management, advanced care planning and goals of care discussions. Additional items to be discussed during navigation visits include primary care provider utilization, COVID-19 vaccination, illness and medication questions, and other patient questions as they arise. A comprehensive registry of MBC patient's medical records and histories will assist researchers in designing future therapeutic and quality of life clinical trials. The categories of patient demographics, clinical variables, pathological variables, treatment variables, outcomes of MBC, and PROs will create a robust registry. A comprehensive patient registry can create a rich database which can guide and inspire future innovative research. Peer support through support groups and peer-to-peer matching s pivotal to MBC patients finding and utilizing their patient voice, emotionally supporting each other and learning from other's similar experiences. Connection between patients and the creation of a community of survivors can empower patients to positively impact their care through self-advocacy and self-efficacy. Continuing patient education is also essential to providing quality cancer care. The format of a weekly virtual education webinars are helpful in creating an engaged patient community and a platform to disseminate educational resources in a reoccurring digestible format. Frequent educational webinars covering a wide variety of topics can positively influence patient interactions with their healthcare providers and influence how patients living with MBC view their own cancer experience. Educational webinars provide opportunities for patients to connect with subject matter experts, other patients like themselves, and share information with their family and friends. Informed patients can discuss and ask questions more confidently with their health care providers about information and services presented during the educational webinars. The symptom profile of patients living with MBC are impacted by numerous variables such as disease burden, treatment plan, comorbidities, supportive regimen etc. The collection of PROs has been shown to improve patient satisfaction with his/her care, improve quality of life, decrease emergency room visits and hospitalizations, and increased overall survival. The routine measurement and management of MBC patients' symptoms has been found to be integral in providing comprehensive cancer treatment. The collection of PROs improves patient and provider communication and elicits the outcome to symptoms that matter most to each patient. Patients diagnosed with MBC are living longer because of the recent advancements in therapeutic treatments. A multifaceted and comprehensive program consisting of therapeutic clinical trials, multidisciplinary specialty care, individualized patient navigation, peer support, continuing education, and PROs collection is integral to fully support patients living with MBC.
ABSTRACT
Over the course of a clinical trial, changes in the practice environment have the potential to reduce internal and external validity and impact change in patient outcomes. Such ''history effects''1 can take the form of changes in standard of care, clinical guidelines and recommendations, new drug/device availability in the marketplace, testing and screening procedures, and, as recently experienced, a global pandemic. Clinical trials conducted over many years are particularly susceptible to history effects. Such effects can impact foundational ability to continue a trial, including clinician equipoise and ability to implement trial interventions, necessitating awareness and action planning. For example, Curtis et al.2 acknowledged challenges with clinical guideline history effects and issued recommendations for addressing them such as consideration of participant wellbeing, stakeholder engagement, safety monitoring, review of guideline and policy changes, and development of rules for protocol changes. This session will explore how four multisite clinical trials conducted with VA Cooperative Studies Program sponsorship and coordination have weathered history effects during prolonged periods of enrollment. Topics to be covered include the implementation of pragmatic designs, monitoring of clinical guidelines, assessing control group treatment conditions, modifying protocols, adjusting quality assurance procedures, refining recruitment pathways, and training site investigators. The speakers, Study Chairs, will describe best practices and provide recommendations for navigating history effects in prolonged multisite clinical trials that can ensure outcomes remain relevant and compelling to inform public health at trial commencement. The CSP 2008/PTXRx study is a pragmatic, randomized, double-blind, placebo-controlled, multicenter clinical trial of Veteran patients with diabetic kidney disease (DKD) examining whether pentoxifylline (PTX), when added to usual care, can delay time to end-stage renal disease or death. Enrollment for the study began in 2019, and it is anticipated that 9 years of follow-up will be required to observe the required number of primary events. Given the long duration of the study, changes in clinical guidelines were anticipated and have occurred, including the approval of new DKD therapies and introduction of a new formula for estimated glomerular filtration rate (eGFR) calculation. In anticipation of these changes, the study design allows for whatever standard of care is extant at any time during the course of the study. PTXR's pragmatic trial design and protocol leverage the VA's research infrastructure and remote platforms allowing the study to be responsive to external changes and to safely continue during a global pandemic. The CSP 596/OPTION study is a randomized, double- blind, multicenter trial of Veteran patients with a first or second recurrent Clostridium difficile infection (CDI) comparing (1) fidaxomicin and (2) vancomycin, followed by a taper and pulse to (3) a standard vancomycin regimen. Since enrollment began in 2016, significant changes in CDI epidemiology and clinical management have impacted the study. The COVID-19 pandemic also resulted in an administrative hold on all trial activity followed by staggered reopening of sites due to variable COVID-19 activity and clinical priorities. Many clinical laboratories switched to algorithms that included free toxin assays in addition to polymerase chain reaction (PCR) tests out of concern for overdiagnosis based on PCR testing alone, reducing the number of potentially enrollable cases. There has been increased empirical vancomycin treatment for recurrent CDI without confirmation by stool testing, a requirement for enrollment, and a recruitment strategy for identifying potential cases. Finally, conflicting clinical guidelines for recurrent CDI has created potential equipoise when considering enrollment. Ongoing educational efforts have been made to clarify the protocol and emphasize the validity of the research question as well as protoco changes to allow safe enrollment and follow-up of participants in the face of the ongoing COVID-19 pandemic. The CSP 2005/VALOR is a phase III randomized, open label, multicenter clinical trial of Veteran patients with operable stage I non-small cell lung cancer that compares stereotactic radiotherapy and anatomic pulmonary resection with a primary outcome measure of overall survival. The study was activated in 2017 and recruitment to the trial has been affected by ongoing changes in public and clinician perceptions about stereotactic radiotherapy and surgery that have interfered with equipoise and willingness of participants to enroll. The study team perpetually addresses this challenge through group conversations with local site investigators, study coordinators, and other research personnel to preserve group equipoise across the study. Since the study's activation, new safety information about stereotactic radiotherapy has emerged necessitating protocol modifications while aiming to preserve internal and external validity. The includes modifying standard operating procedures for the study's centralized quality assurance program that has had to adapt its process to remain contemporary. STARPORT, funded by VA CSRD with CSP collaboration, is a randomized, open label, multicenter clinical trial of Veteran patients with oligorecurrent prostate cancer comparing the effects of standard systemic therapy (SST) alone or with PET-directed local therapy using surgery or radiation. Although enrollment was initiated in 2021, changes are already evident in clinical practice guidelines regarding the use of imaging in workup in this patient population. Shortly before the start of accrual, 18F-DCFPyL PSMA PET/CT received FDA-approval. Consequently, it is being rapidly adopted at the STARPORT VA medical centers and the use of conventional imaging using CT or bone scan prior to PET/CT imaging-part of the original eligibility criteria-quickly is falling out of favor. Furthermore, shortly after the start of enrollment, NCCN guidelines adopted the stance that conventional imaging was no longer required in the setting of PSMA PET/CT imaging, solidifying the transition away from conventional imaging. Thus, the protocol is being amended to remove the requirement for conventional imaging as part of workup for oligorecurrence. In addition, to be generalizable, the study is designed to integrate future PSMA radiotracers that are incorporated into practice as well as changes in SST regimens over the time of the study.
ABSTRACT
The post-COVID-19 recovery period is characterized by persistence of some symptoms, with immunological alterations being of great importance. Development of preventive measures to normalize mucosal immunity after a coronavirus infection determines the relevance of the current study. The aim was to study dynamics of clinical symptoms and level of secretory immunoglobulin A in individuals after a novel coronavirus infection as well as evaluate effectiveness of using IFNα-2b. Materials and methods. A study was conducted with patients aged 18 to 60 years old (n = 130), surveyed 1 to 9 months after post-infection, as well as in apparently healthy individuals lacking COVID-19 (n = 15). Previous novel coronavirus infection and post-COVID manifestations were verified based on medical documentation, complaints, anamnesis data, physical examination and questionnaires. The concentration of salivatory and nasopharyngeal mucosal sIgA was measured dynamically prior to and after administration of local therapy with IFNα-2b (gel applied intranasally twice a day for 30 days). Results. The acute period of COVID-19 was characterized by fever, anosmia, severe asthenia (fatigue and weakness), muscle and joint pain. Among the post-COVID manifestations at early period (1–3 months), pain in the joints and muscles (75.0%) as well as elevated body temperature (21.2%) were reliably detected, whereas in the long period (6–9 months) there were revealed dominance with the same frequency of shortness of breath, muscle and joint pain (75.8%, respectively). Based on examination data in healthy subjects, there was determined an arbitrary normal range of secretory IgA in saliva — 6.45±1.81 mg/ml and nasal swabs — 13.43±3.24 mg/ml. In the group of patients 1–3 months post-infection, therapy with IFNα-2b one month later resulted in significantly increased level of secretory IgA in saliva (from 1.84±0.28 to 5.78±1.96 mg/ml) and in nasal swabs (from 28.61±3.0 to 39.83±3.85 mg/ml) by more than 3- and 1.5-fold, respectively. In the group of patients without therapy was featured with stably sustained decline in sIgA level up to 9 months after COVID-19. In particular, the level of saliva sIgA ranged from 2.36±0.56 down to 2.16±0.66 mg/ml, and in nasal smears — from 15.66±1.32 to 10.23±1.07 mg/ml that differed insignificantly compared to baseline level. The rate of respiratory diseases prevailed in this group (27.6% of cases), which fully lacked in the group of topically administered IFNα-2b. Conclusion. In the post-COVID period, multiple organ disorders persist and reduced sIgA level is registered. Intranasally applied IFNα-2b made possible to normalize sIgA level and prevent accumulation of respiratory infectious pathologies.
ABSTRACT
The post-COVID-19 recovery period is characterized by persistence of some symptoms, with immunological alterations being of great importance. Development of preventive measures to normalize mucosal immunity after a coronavirus infection determines the relevance of the current study. The aim was to study dynamics of clinical symptoms and level of secretory immunoglobulin A in individuals after a novel coronavirus infection as well as evaluate effectiveness of using IFNalpha-2b. Materials and methods. A study was conducted with patients aged 18 to 60 years old (n = 130), surveyed 1 to 9 months after post-infection, as well as in apparently healthy individuals lacking COVID-19 (n = 15). Previous novel coronavirus infection and post-COVID manifestations were verified based on medical documentation, complaints, anamnesis data, physical examination and questionnaires. The concentration of salivatory and nasopharyngeal mucosal sIgA was measured dynamically prior to and after administration of local therapy with IFNalpha-2b (gel applied intranasally twice a day for 30 days). Results. The acute period of COVID-19 was characterized by fever, anosmia, severe asthenia (fatigue and weakness), muscle and joint pain. Among the post-COVID manifestations at early period (1-3 months), pain in the joints and muscles (75.0%) as well as elevated body temperature (21.2%) were reliably detected, whereas in the long period (6-9 months) there were revealed dominance with the same frequency of shortness of breath, muscle and joint pain (75.8%, respectively). Based on examination data in healthy subjects, there was determined an arbitrary normal range of secretory IgA in saliva - 6.45+/-1.81 mg/ml and nasal swabs - 13.43+/-3.24 mg/ml. In the group of patients 1-3 months post-infection, therapy with IFNalpha-2b one month later resulted in significantly increased level of secretory IgA in saliva (from 1.84+/-0.28 to 5.78+/-1.96 mg/ml) and in nasal swabs (from 28.61+/-3.0 to 39.83+/-3.85 mg/ml) by more than 3- and 1.5-fold, respectively. In the group of patients without therapy was featured with stably sustained decline in sIgA level up to 9 months after COVID-19. In particular, the level of saliva sIgA ranged from 2.36+/-0.56 down to 2.16+/-0.66 mg/ml, and in nasal smears - from 15.66+/-1.32 to 10.23+/-1.07 mg/ml that differed insignificantly compared to baseline level. The rate of respiratory diseases prevailed in this group (27.6% of cases), which fully lacked in the group of topically administered IFNalpha-2b. Conclusion. In the post-COVID period, multiple organ disorders persist and reduced sIgA level is registered. Intranasally applied IFNalpha-2b made possible to normalize sIgA level and prevent accumulation of respiratory infectious pathologies. Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.
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Objective. To evaluate the efficacy of a benzydamine-containing drug in children with COVID-19. Patients and methods. This observational randomized study included 88 children with confirmed mild or moderate COVID-19. The experimental group comprised 44 children who received drugs containing benzydamine, whereas the control group comprised 44 children who received other local treatments. The groups were matched for age, sex, disease severity, main manifestations, and systemic therapy received. Results. Children in the experimental group demonstrated faster recovery than those from the control group (after 6.20 ± 2.93 days vs 7.36 ± 3.17 days, respectively;р < 0.05). Virus elimination occurred earlier in children receiving benzydamine than in controls (3.93 ± 2.48 days vs 5.27 ± 3.64 days, respectively;р < 0.05. Benzydamine significantly reduced the duration of pharyngeal hyperemia (by 2.29%), sore throat (by 1.77 days;р < 0.05), and fever (by 0.93 days;р < 0.05) compared to other local treatments. Conclusion. Benzydamine significantly increases the efficacy of COVID-19 treatment.
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Background: Patients with cancer have worse outcomes from COVID-19 infection. However, the specific impact of COVID-19 on patients with (HNC) is largely unknown. The COVID-19 and Cancer Consortium (CCC19) maintains an international registry (NCT04354701) aimed to investigate the clinical course and complications of COVID-19 in patients with cancer. Here, we report severity of COVID-19 and its complications among HNC patients. Methods: The CCC19 registry was queried for patients with HNC and laboratory confirmed SARS-CoV-2 infection. The co-primary outcomes were severity of COVID-19 illness on an ordinal scale (0: no complications;1: hospitalized, no oxygen (O2);2: hospitalized, required O2;3: ICU admission;4: mechanical ventilation (MV);5: death), and severity of complications (mild, moderate, serious). The outcomes were further stratified by demographics, recent treatment (systemic vs local;surgery, radiation (RT) vs systemic), treatment intent (palliative vs curative), and cancer status (remission, responding, stable, progressing). Results: From March 2020 to December 2021, 356 HNC patients were identified. Median age was 65 (interquartile range 58-74), 29% were female, 56% were white, 67% were former or current smokers, 20% had a BMI >30, 15% had an ECOG performance status >2, and 57% had >2 comorbidities. 154 (43%) had no complications, 61 (17%) were hospitalized without O2, 135 (38%) were hospitalized with O2, 50 (14%) required ICU, 32 (9%) required MV, and 74 (21%) died. 88 (25%) had mild, 59 (17%) had moderate, and 132 (37%) had serious complications. 33% of patients who received systemic therapy and 30% who received RT within 3 mo prior to COVID-19 diagnosis died. Mortality was higher in patients receiving palliative when compared to curative intent treatment (44% vs 16%). In addition, 50% of patients with actively progressing cancer, and 45% who had serious complications died. Importantly, 37 (n=12 palliative systemic therapy and n=25 local therapy) patients had a treatment delay due to COVID-19 diagnosis. Conclusions: Our study is the largest cohort to date describing COVID-19 outcomes in HNC patients and suggest a high rate of mortality even in those receiving local and curative intent treatment. Variables stratified by COVID-19 severity. Note: Ordinal levels 3 and 4 not shown due to small case numbers.
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The work led to the formulation of a powder of calcium phosphate coated liposomes containing cyclosporine A (CsA). The formulation was designed to reduce the dose of CsA to be administered following lung transplantation. Potentially this formulation can be used also to contain the inflammatory process due to SARS-CoV-2. Calcium phosphate (CaP) is a material found in bones and teeth and considered non-toxic and biocompatible and this coating could reduce the recognition by alveolar macrophages and increase the cell uptake. Moreover, CaP is insoluble at physiological pH (7.4), while it solubilizes easily at pH below 5. This could favor drug release in the cell after pinocytosis and in inflamed tissues, while reducing drug release at physiological pH [1]. The liposomes produced were evaluated in terms of size, surface charge and drug loading. The presence of the CaP coating was verified by calcium titration, variation of the zeta potential and by cryogenic transmission electron microscopy (cryo-TEM). The highest loading was obtained in the formulation containing CsA at 7% (w/w). Cholesterol was added to liposomes at two different concentrations in order to improve the stability of the nanostructure and reduce the drug leakage. However, cholesterol did not bring any improvement to the formulation. The inhalation powder produced by spray drying with the best aerosolization performance (fine particle fraction of coated liposomes powder 33.69 - 1.6% and 50.50- 0.6% for the uncoated liposomes powder) was obtained using a 1:3 weight ratio between liposomes and excipients using mannitol as bulking agent and 15% L-leucine. Key Message: This work aimed to develop a respirable dry powder for inhalation containing CsA for the local treatment of lung immune diseases. CsA was efficiently loaded into CaP-coated liposomes and transformed into a respirable powder by spray-drying. The inhaled immunosuppressive product would offer multiple advantages related to drug deposition at the target site. Furthermore, the coating of the liposomes governs the release of the drug which will occur only at only at biological acidic conditions.
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Background: The efficacy and safety of pazopanib (PZP) have been evaluated in pivotal randomized, clinical trials Real-world evidence (RWE) is required to further assess its use, effectiveness and safety in mRCC in clinical routine practices. Methods: APOLON is a non-interventional, multicentric prospective study with mRCC patients who receive frontline PZP treatment. The study is designed to assess PZP Progression-Free Survival (PFS) (under treatment), Overall Survival (OS), Objective Response Rate (ORR) assessed by investigators, tolerability and subsequent post-pazopanib therapy sequences. Impact of COVID-19 on patient's care was also assessed. Eligible patients were recruited from Nov 2017 to Jan 2019 in 55 participant sites in France. This interim analysis presents results 30 months (mo) after last patient was enrolled in the study. Results: The 217 patients were 71.1% males, with a median age of 69.6 years and had mRCC with a favourable (27.1%), intermediate (52.1%) or poor (20.8%) IMDC risk score according to physician. ECOG-PS was 0, 1 and ≥2 in respectively 43.3%, 39% and 17.6% of patients. Metastases were mainly located in lungs (64.1%), bones (28.6%), mediastinal (18%)/abdominal (17.1%). Patients had an history of partial/total nephrectomy in 54.8% of cases and previous local treatments for metastases in 27.6%. Median PFS, assessed by investigator, was 10.5 mo (95%CI: 9-12.4), similarly in patients < 65-year-old (YO) with 11.3 mo (95%CI: 7-16.3) and in those ≥ 65 YO with 9.9 mo (95%CI: 8.9-12). When assessed according to the IMDC risk score, mPFS was 18.1 mo (95%CI: 9.9-23.3) in favourable, 11.5 mo (95%CI: 8.7-14.4) in intermediate and 6.2 mo (95%CI: 3.5-9.5) in poor mRCC. The median OS was 27.3 mo (95%CI: 24.3 - ND). Investigator-assessed ORR was 48.3% with a CR in 6 patients (3.5%) and a PR in 77 (44.8%). After a median treatment duration of 10.1 mo, 190 patients (87.6%) discontinued PZP and 67.9% received at least one post-PZP line. Second line post-PZP consisted in nivolumab (71.3%), cabozantinib (14.7%), sunitinib (7%) or other (7%). Adverse Event (AE) leading to PZP dose reduction and discontinuation were reported in 42% and 40.9% of patients and treatment-related serious AE in 22.2% of patients. No safety signal was newly identified. The impact of the Covid 19 pandemic was limited on patients' cares and study follow-up. Visits during the pandemic included 84.1% of tumour evaluation. For 29 patients (14.1%), follow-up visits were carried out as a teleconsultation. Few patients (5,7%) had no visits during the pandemic. Conclusions: The APOLON study confirms PZP effectiveness and safety in patients with mRCC in real-life setting. The efficacy of pazopanib remains significant in patients aged 65 years and older. It is highly associated with risk score. The COVID pandemics had limited impact on patients' cares.
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Background: There is a need for a low toxicity option for men with prostate cancer with biochemical recurrence (BCR) following primary curative therapy. Cannabinoids (CBD) have antitumor activity in preclinical studies, but products may vary in activity without clear standardization. As epidiolex is a standardized FDA approved oral CBD solution for treatment of certain types of seizures, we studied epidiolex in patients with BCR of prostate cancer to determine safety and dosing of this therapy to support future studies. Methods: We present an open-label, single center, phase I dose escalation study followed by a dose expansion. Patients with BCR prostate cancer after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy) were eligible. Majority of our patients' prostate-specific antigen (PSA) doubling time was ≤ 12 months. All patients were screened for urine tetrahydrocannabinol (THC) prior to enrollment. With use of a Bayesian optimal interval design, patients received escalating doses of epidiolex starting at 600mg daily and up to 800mg daily. All patients were treated for 90 days followed by a 10 day taper. The Primary endpoints were safety and tolerability. Patients were monitored for both acute (30 days) and chronic (90 days) treatment-related toxicities. Secondary endpoints included change in PSA levels and testosterone levels from baseline throughout the treatment period. Results: A total of 21 patients were enrolled but four withdrew from the study (one patient was hospitalized with COVID-19 and three patients requested to stop due to grade 2 adverse events (AEs). There were seven patients included in the dose escalation phase. Four patients received 600mg daily;two of the four in this phase did not finish the first 30 days (one with COVID-19 and one withdrew). The other three patients received 800 mg daily. No dose-limiting toxicities were observed at any dose level so an additional 14 patients were enrolled at the 800mg dose. Treatment-related chronic AEs occurring in >10% of patients were grade 1 or 2 diarrhea (47.6%), grade 1 or 2 nausea (23.8%) and grade 1 or 2 fatigue (19%). The mean PSA at baseline was 2.9 ng/ml. One patient developed oligo-metastasis disease, two patients progressed after the study period, and one patient died from a non-treatment or disease-related cause. Conclusions: Epidiolex at a dose of 800mg daily appears to be safe and tolerable in patients with BCR of prostate cancer, supporting a safe dose for future studies to determine if there is clinical activity to delay development of hormone refractory metastatic disease.
ABSTRACT
Introduction & Objectives: The COVID-19 outbreak has become the dominant issue throughout the world whilst the governments, nations and health services are trying to deal with its impact. The aim of our study is to assess the impact of COVID-19 on patients treated with Radical Prostatectomy (RP) for Prostate Cancer (PCa) at European referral centers in terms of Surgical Volume (SV), waiting list meant as time from biopsy to surgery (WL) and risk of adverse pathologic findings at RP due to the selection of men with more adverse disease characteristics at final pathology. Materials & Methods: Consecutive patients with histologically proven disease treated with Radical Prostatectomy (RP) were collected between March 11th 2020 (WHO declaration of pandemic) and December 2020. Metastatic patients not eligible to local treatment and patients with recurrent prostate cancer after RP or RT were excluded. Patients treated in the same time span of the year before with comparable inclusion criteria were considered as the control group. Disease characteristics were compared. Multivariable logistic regression analysis tested the impact of the COVID-19 outbreak on the risk of adverse pathologic findings at RP after adjusting for confounders. The percentage change of SV and WL was assessed comparing the months of pandemic with the equivalent timespan of the previous year. Results: A total of 2,574 RP were collected (927 study group and 1647 control group) in 8 European centers. A reduction of MRI for staging and a higher PI-RADS score (p<0.01) was observed in patients managed after the COVID-19 outbreak in comparison to the control group. Multivariable analysis adjusted for age, PSA at diagnosis, cT stage, ISUP at biopsy and PI-RADS score, showed that patients who were treated during the pandemic had higher risk of extra prostatic disease (OR:1.35, 95% CI 1.00-1.81, p=0.047). An average 23% reduction of the SV with the equivalent timespan of the previous year allowed an illusory reduction of the WL after the peak gained during the first wave of COVID-19 (fig1).(Figure Presented) Conclusions: The COVID-19 outbreak induced a stage migration phenomenon in surgically managed PCa patients. Further evaluations are necessary to assess possible implication in the oncologic outcomes of the PCa disease.
ABSTRACT
Background. COVID-19 was declared a global Public Health Emergency by the WHO in January 2020. Limited treatment options existed early in the pandemic. As COVID-19 spread across the globe and new therapeutics emerged, different interpretations of the literature grew, and major societies relayed conflictive recommendations. There is a paucity of data on COVID-19 management in low- and middle-income countries. As a result, we performed a nationwide survey of local treatment practices in the Dominican Republic (DR). Methods. We performed an anonymous survey of infectious diseases specialists in the DR and US. The survey collected hospital characteristics and COVID-19 management protocols during different quarters of 2020-21. Management was categorized by drug and disease severity based on supplemental oxygen requirements. A convenience sample in the US representing community and academic sites was surveyed for point comparison between the US and DR. Results. The survey was completed by physicians from a total of 11 sites located in 4 cities of the DR: Santo Domingo (3), Santiago (4), La Vega (2) and San Francisco (2). These cities were representative of all regions in the country. The survey included 7 (64%) hospitals with < 200 beds, 3 (27%) with 201-300 beds, and 1 (9%) with >400 beds. Seven (47%) were private, 2 (13%) public, and 6 (40%) were teaching hospitals. In the US, 2 academic hospitals with >400 beds and 2 community hospitals with < 200 beds in a major city were surveyed. Management of COVID-19 at sites in the DR and US throughout the pandemic is plotted in Figure 1. Remdesivir use by disease severity is plotted in Figure 2. Conclusion. Throughout the pandemic, as therapeutic options evolved, hospitals and physicians had to adapt to changing guidelines and availability of novel drugs. Variability between countries and sites emerged. The use of hydroxychloroquine and convalescent plasma waned more rapidly in the US. Dexamethasone was widely used at all sites. Tocilizumab and remdesivir were used more liberally in the DR. Antimicrobial stewardship limited these agents at US sites to more narrow therapeutic windows which could explain the discrepancies seen between the US and DR. Uncertainty of benefit in certain disease states, limited availability, and cost may also play a role.
ABSTRACT
BACKGROUND: Melanoma brain metastasis is a common cause of death in melanoma patients and is associated with a poor prognosis. There are relatively few reports on intracranial infections after brain metastasis resection. CASE SUMMARY: Here we report a case of melanoma brain metastases in a patient harboring a BRAF V600E mutation, who experienced intracranial tumor progression despite previous combined treatment with a programmed death (PD)-1 inhibitor, axitinib, and vemurafenib. She repeatedly underwent local therapy, including stereotactic radiosurgery and intracranial surgery, and developed central nervous system infection. Treatment with vemurafenib combined with cobimetinib resulted in an intracranial progression-free survival of 10 mo. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not visit the hospital for regular vemurafenib treatment, and experienced intracranial progression after involuntary drug reduction for 1 mo. The patient subsequently received various systemic treatments including vemurafenib, PD-1 inhibitor, and chemotherapy, with an overall survival of 29 mo as of September 2020. CONCLUSION: We report the first case of melanoma brain metastases with co-occurring intracranial infection and unintended drug reduction during the COVID-19 outbreak. Long-term control of the intracranial lesions was achieved with systemic and local therapies.