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Background: People living with cancer are reported to be at increased risk of hospitalization and death following infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is proposed to be dependent on a combination of intrinsic patient and cancer factors such as cancer subtype, and emerging SARS-CoV-2 variants with differing pathogenicity. However, COVID-19 phenotype evolution across the pandemic from 2020 has not yet been systematically evaluated in cancer patients. Method(s): This study is a population-scale real-world evaluation of Coronavirus outcomes in the United Kingdom for cancer patients from 1st November 2020-31st August 2022. The cancer cohort comprises individuals from Public Health England's national cancer dataset, excluding individuals less than 18 years old. Case-outcome rates, including hospitalization, intensive care and casefatality rates were used to assess the evolution in disease phenotype of COVID-19 in cancer patients. Multivariable logistic regression models were fitted to compare risk of Coronavirus outcomes in the cancer cohort relative to the non-cancer population during the Omicron wave in 2022. Result(s): The cancer cohort comprised of 198,819 positive SARS-CoV-2 tests from 127,322 individual infections. Coronavirus case-outcome rates were evaluated by reference to 18,188,573 positive tests from 15,801,004 individual infections in the non-cancer population. From 2020 to 2022, the SARS-CoV-2 disease phenotype became less severe in both patients with cancer and the non-cancer population, though cancer patients remain at higher risk. In 2022, the relative risk of Coronavirus hospital admission, inpatient hospitalization, intensive care admission and mortality in cancer patients was 3.02x, 2.10x, 2.53x and 2.54x compared to the non-cancer population following multivariable adjustment, respectively. Higher risk of hospital admission and inpatient hospitalization were associated with receipt of B/T cell antibody and/or targeted therapy which also corresponded with an increased risk of Coronavirus mortality. Conclusion(s): The disease phenotype of SARS-CoV-2 in cancer patients in 2022 has evolved significantly from the disease phenotype in 2020. Direct effects of the virus in terms of SARS-CoV-2 hospitalization, intensive care and case fatality rates have fallen significantly over time. However, relative to the general population, people living with cancer and hematological malignancies remain at elevated risk. In order to mitigate the indirect effects of the SARS-CoV-2 pandemic in terms of disruption to cancer care, there should be increased focus on preventative measures. Used in conjunction with vaccination and early treatment programs, this will maximize quality of life for those with cancer during the ongoing pandemic and ensure the best cancer outcomes.
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Recent advancements in nanotechnology have resulted in improved medicine delivery to the target site. Nanosponges are three-dimensional drug delivery systems that are nanoscale in size and created by cross-linking polymers. The introduction of Nanosponges has been a significant step toward overcoming issues such as drug toxicity, low bioavailability, and predictable medication release. Using a new way of nanotechnology, nanosponges, which are porous with small sponges (below one microm) flowing throughout the body, have demonstrated excellent results in delivering drugs. As a result, they reach the target place, attach to the skin's surface, and slowly release the medicine. Nanosponges can be used to encapsulate a wide range of medicines, including both hydrophilic and lipophilic pharmaceuticals. The medication delivery method using nanosponges is one of the most promising fields in pharmacy. It can be used as a biocatalyst carrier for vaccines, antibodies, enzymes, and proteins to be released. The existing study enlightens on the preparation method, evaluation, and prospective application in a medication delivery system and also focuses on patents filed in the field of nanosponges.Copyright © 2023 The Authors.
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In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.
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Background: Lymphoproliferation is the persistent proliferation of lymphoid cells and it's incidence in inborn errors of immunity varies from 0.7 to 18%. Material(s) and Method(s): This is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. Result(s): A total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin's lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. Conclusion(s): All children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.Copyright © 2023 Elsevier Inc.
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Background: Polymorphonuclear neutrophils (PMNs) recruited to the airway lumen in cystic fibrosis (CF) undergo a rapid transcriptional program, resulting in exocytosis of granules and inhibition of bacterial killing. As a result, chronic infection, feed-forward inflammation, and structural tissue damage occur. Because CF airway PMNs are also highly pinocytic, we hypothesized that we could deliver protein- and ribonucleic acid (RNA)-based therapies to modulate their function to benefit patients. We elected to use extracellular vesicles (EVs) as a delivery vector because they are highly customizable, and airway PMNs have previously been shown by our group to process and use their cargo efficiently [1]. Furthermore, our prior work on CF airway PMNs [2] led to identification of the long noncoding RNA MALAT1, the transcription factor Ehf, and the histone deacetylase/long-chain fatty deacylase HDAC11 as potential targets to modulate CF airway PMN dysfunction. Method(s): H441 human club epithelial cells were chosen for EV production because they efficiently communicate with lung-recruited primary human PMNs [1]. Relevant constructs were cloned into an expression plasmid downstream of a constitutive cytomegalovirus or U6 promoter with an additional puromycin selection cassette. EVs were generated in serumdepleted media and purified by differential centrifugation. Quality and concentration of EVs was determined by electron microscopy and nanoparticle tracking analysis and cargo content by western blot (protein) or qualitative reverse transcription polymerase chain reaction (RNA). Enhanced green fluorescent protein and messenger ribonucleic acid (mRNA) were used as controls. To test delivery to primary human PMNs, generated EVs were applied in the apical fluid of an airway transmigration model [2]. PMN activation was assessed by flow cytometry, and bacterial (PA01 and Staphylococcus aureus 8325-4) killing and viral (influenza Avirus [IAV] H1N1/PR/8/34;SARS-CoV-2/Washington) clearance assays were conducted. Result(s): To package protein, we used EV-loading motifs such as the tetraspanin CD63, Basp1 amino acids 1-9, and the palmitoylation signal of Lyn kinase. To load mRNA, a C'D box motif recognized by the RNA-binding protein L7Ae was included in the 3' untranslated region of the expressed RNA, and CD63-L7Ae was co-expressed. Airway-recruited PMNs treated with EVs containing small interfering RNAs against MALAT1 or HDAC11 showed greater ability to clear bacteria. Conversely, PMNs treated with constructs encasing MALAT1 or HDAC11 efficiently cleared IAV and SARSCoV- 2. PMNs expressing Ehf showed greater clearance of bacteria and viruses. Conclusion(s): Our findings suggest mutually exclusive roles of MALAT-1 and HDAC11 in regulating bacterial and viral clearance by airway-recruited PMNs. Expression of Ehf in airway PMNs may be a pathogen-agnostic approach to enhancing clearance by airway-recruited PMNs. Overall, our study brings proof-of-concept data for therapeutic RNA/protein transfer to airway-recruited PMNs in CF and other lung diseases and for use of EVs as a promising method for cargo delivery to these cells. It is our expectation that, by treating the immune compartment of CF airway disease, pathogentherapies, such as antibiotics will be more effective, and epithelial-targeted therapies, such as CFTR modulators, will have greater penetrance into the cell types of interest.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: To describe characteristics of COVID-19 infection among patients requiring admission to pediatric intensive care units (PICU) in the USA. Method(s): Observational surveillance study of COVID-19 infected patients admitted to PICUs in 27 US states between April 1, 2020 - May 1, 2021. Result(s): Four hundred fifty-three patients were included;the majority were from institutions in the South and Midwest regions (40% and 34%). The population was mainly male (57%) and Hispanic (36%), with a median age of 10 years (IQR 4-15). 76% had 1 or more comorbidity. Patient's or caregiver's reported sources for COVID-19 infection were household and community contacts (31% and 24%). One hundred sixty-seven (40%) individuals were diagnosed with the multisystem inflammatory syndrome in children (MISC) within 7 days of PICU admission. Compared to COVID-19 cases without MISC, gastrointestinal, mucocutaneous, and neurological signs and symptoms were more frequent at PICU admission. Nasal cannula (20%) and high-flow oxygen (12.4%) were the most common respiratory support strategies at day 1 of admission, and mechanical ventilation by day 7. Overall, 104 (23%) and 8 (1.8%) individuals were placed on mechanical ventilation and extracorporeal membrane oxygenation (ECMO) within the interval of observation. Steroids and remdesivir were the most delivered COVID-19 targeted therapies (60% and 33%), and only 3% of the patients received convalescent plasma;IVIG (86.8%) and anakinra (61%) were commonly used among individuals with MISC. The overall mortality proportion (MP) was 2.65 (n= 12), and mortality was more frequent among individuals > 2 years old. Of the 167 children with MISC, only 1 died, MP (0.6). Conclusion(s): Mortality associated with pediatric COVID-19 infection is less frequent than in critically ill COVID-19-infected adults. Among pediatric/ adolescent patients, children > 2 years are the most vulnerable to adverse COVID-19-associated outcomes. MISC cases were frequent, yet mortality was low.
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The article demonstrates estimated data of influenza and COVID-19 morbidity and infection fatality rate (IFR) mortality in the context of restrictions and vaccination (years 2020-2021 mostly developed countries). A division into two age groups was included: Up to 65 years of age and over 65 years of age. Influenza mortality (IFR) did not change between 2020 and 2021 and was about 0.05% among all, and 0.005 among those under 65 years of age. IFR COVID-19 was on average approx. 0.5% overall, and in groups under 65 years of age a minimum of 0.07%. COVID-19 morbidity varied greatly from about 50/100,000 in Japan to 600/100,000 in Peru during 2020 plus 2021. In the United States and Poland, about 250 per 100 thousand in 2 years. The morbidity rate of COVID-19 in lower risk groups was 70/100 thousand in the United States. The pre-2020 flu morbidity rate in the United States ranged from 1-10 per 100,000 per season. In the 2020/21 season, it decreased to 1/100 thousand. In groups 65 age old and younger, influenza morbidity in the United States was about 0.3 per 100,000 in the 2020/2021 season, and in typical seasons 0.3 to 3/100,000. Examples of absolute numbers. In the United States, in 2021, COVID-19 471,000 victims (a year of available vaccinations). Influenza season 2021 max. 4,500 victims. The average flu season in unrestricted seasons, was about 25,000 victims. Predictions of the consequenc-es of the lack of restrictions and vaccinations are theoretical, because the preliminary ones talk about 2-3 million COVID-19 victims and even more than ten million additional hospitalizations in the United States, which may mean the collapse of the health system, and thus in practice a greater number of victims. The data presented did not result from diagnostic errors. A proper epidemic assessment confirms the effectiveness of vaccination and targeted therapy. COVID-19 vaccination reduced IFR mortality by about 10-fold.Copyright © 2023, Termedia Publishing House Ltd.. All rights reserved.
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INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory condition characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss. Upadacitinib is an oral, selective, small molecule Janus Kinase (JAK) inhibitor that was recently approved in the United States for moderate to severe UC. Clinical trials evaluating the efficacy of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor;therefore, the efficacy of upadacitinib in patients with previous exposure to tofacitinib remains largely unknown. METHOD(S): We present a small retrospective case series of all patients with a diagnosis of ulcerative colitis seen at our institution between with a prior exposure to tofacitinib who were initiated on upadacitinib between May and August of 2022. Demographic data was collected as well as outcome data on clinical improvement, steroid-free remission, biochemical improvement, colectomy status, and adverse events. RESULT(S): Eleven tofacitinib-refractory patients with ulcerative colitis were initiated on upadacitinib. Mean age was 38.1 years, five (45.5%) patients were female, nine (81.8%) patients were white, seven (63.6%) patients had pancolitis, and mean duration of UC was 7.4 years (Table 1). In this group, there were high rates of prior targeted therapy failures. These patients were followed for a mean of 121 days. The clinical course of each patient is presented in Table 2. Of the 11 patients included in our study, nine (81.8%) patients reported symptomatic improvement, six (54.5%) patients were able to successfully taper corticosteroids, and two (18.2%) patients underwent colectomy, one of which was elective and planned prior to initiating upadacitinib. The mean fecal calprotectin improvement was 1430mg/kg of patients with both baseline and follow-up testing. Three (27.3%) patients experienced an adverse event;two (18.2%) patients with mild COVID-19 not requiring hospitalization and one (9.1%) patient with Enteropathogenic E. Coli. DISCUSSION: This real-world single-center case series of 11 patients, suggests that upadacitinib may be an effective option for patients with a previous tofacitinib exposure. Larger prospective studies are needed to confirm these findings. [Formula presented] [Formula presented]Copyright © 2023
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Background: Advances in computational methodologies have enabled processing of large datasets originating from imaging studies. However, most imaging biomarkers suffer from a lack of direct links with underlying biology, as they are only observationally correlated with pathophysiology. Purpose(s): To develop and validate a novel AI-assisted image analysis platform, by applying quantitative radiotranscriptomics that quantifies cytokinedriven vascular inflammation from routine CT angiograms (CTA) performed as part of clinical care in COVID-19. Method(s): We used this platform to train the radiotranscriptomic signature C19-RS, derived from the perivascular space around the aorta and the internal mammary artery in routine chest CTAs, to best describe cytokinedriven vascular inflammation, defined using transcriptomic profiles from RNA sequencing data from human arterial biopsies (A). This signature was validated externally in 358 clinically indicated CT pulmonary angiograms from patients with or without COVID-19 from 3 different geographical regions. Result(s): First, 22 patients who had a CTA before the pandemic underwent repeat CTA <6 months post COVID-19 infection (B). Compared with 22 controls (matched for age, gender, and BMI) C19-RS was increased only in the COVID-19 group (C). Next, C19-RS was calculated in a cohort of 331 patients hospitalised during the pandemic, and was higher in COVID-19 positives (adjusted OR=2.97 [95% CI: 1.43-6.27], p=0.004, D). C19-RS had prognostic value for in-hospital mortality in COVID-19, with HR=3.31 ([95% CI: 1.49-7.33], p=0.003) and 2.58 ([95% CI: 1.10-6.05], p=0.028) in two testing cohorts respectively (E, F), adjusted for clinical factors and biochemical biomarkers of inflammation and myocardial injury. The corrected HR for in-hospital mortality was 8.24 [95% CI: 2.16-31.36], p=0.002 for those who received no treatment with dexamethasone, but only 2.27 [95% CI: 0.69-7.55], p=0.18 in those who received dexamethasone subsequently to the C19-RS based image analysis, suggesting that vascular inflammation may have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0.61, p=0.0003) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. Conclusion(s): We present the first proof of concept study that combines transcriptomics with radiomics to provide a platform for the development of machine learning derived radiotranscriptomics analysis of routine clinical CT scans for the development of non-invasive imaging biomarkers. Application in COVID-19 produced C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation, that predicts inhospital mortality and identifies people who will have better response to anti-inflammatory treatments, allowing targeted therapy. This AI-assisted image analysis platform may have applications across a wide range of vascular diseases, from infections to autoimmune diseases.
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INTRODUCTION: While available since 1996, genetic testing for breast cancer patients has been limited by stigma, cost, and poor access. Many patients were not captured by traditional NCCN criteria, particularly those with healthcare barriers. Previously, genetic testing was used in high-risk screening and determining prophylactic utility, but with recent targeted therapies, has allowed personalized therapeutic benefit for patients. We expanded genetic testing counseling at a three-hospital Midwestern community hospital system from only NCCN high-risk patients to all patients diagnosed with breast cancer. METHOD(S): The implementation of universal genetic counseling to all newly diagnosed breast cancer patients began at our system in 2020. Under IRB approval, all new breast cancer patients were retrospectively reviewed from January 2019 through December 2019 (genetics based on NCCN guidelines group) and January 2021 through December 2021 (genetics offered to all group). Patient data regarding completion of genetic testing, pathologic mutations identified, stage, race/ethnicity, insurance type, primary language, and age was included in the analysis. Categorical variables were compared using Pearson's chi-square or Fisher's exact test;age was analyzed using ANOVA. RESULT(S): We reviewed a total of 973 patients, 439 diagnosed in 2019 and 534 in 2021. Demographic differences between 2019 and 2021 were similar including age, race/ethnicity, insurance, primary language. Despite the SARS CoV-2 pandemic, the stage of diagnosis between 2019 and 2021 was also similar (p=0.194). Completion of genetic testing increased significantly from 204 (48.6%) in 2019 to 338 (63.3%) (p=0.000) in 2021 with the universal access group. Across all demographic groups, genetic testing increased with significant findings in Medicare patients (p=0.005) and older patients (p=0.041) and near significant findings in non-white populations (0.059).[Table] Overall number of pathological mutations increased, 32 (7.29% of all patients) in 2019 to 39 (7.30%) in 2021, with the most common being BRCA2 (n=11), CFTR (n=9), CHEK2 (n=8), and BRCA1 (n=6). CONCLUSION(S): Implementation of universal access to breast cancer genetic counseling allowed for a significant expansion in genetic testing completion and overall increase in pathological mutations found. We saw an increase within sub-populations that may have not been targeted by NCCN guidelines previously including older patients, minority groups, and varying insurance types. (Table Presented).
ABSTRACT
Introduction: As part of the reorganization of our outpatient activity in onco-hematology (OH), questions were raised about the relevance of dedicating a specific structure to clinical research in this field. These questions arise all the more so as the proportion of OH clinical trials (CT) in our center has increased from 10% to 45% of all CT between 2000 and 2020. The aim of this study is to assess the evolution of this activity and thus to consider the interest of such a structure. Material(s) and Method(s): A retrospective data review of new CT related to OH in our center from 2016 to 2021 was performed. The evolution of 3 key indicators was assessed: distribution of OH CT among all CT, main OH indications and preferred routes of administration. Results and discussion: Over the period 2016-2021, OH CT represented an average of 32% of newly activated CT corresponding to 34% in 2016 and 48% in 2021 (approximately 90 CT start each year for a total of 420 CT in our center). A short decrease was observed in 2019 and 2020, 25% and 24% respectively, probably related to Covid-19. In terms of sterile preparations, OH represented steadily more than 60% of our activity over the period. The main indications were lymphomas (30%), acute myeloid leukemias (AML - 19%), myelodysplastic syndromes (12%) and CT related to transplant center (12%) in steady distribution overtime. Only new CT in myeloma increased from 7% to 18% in relation with increased subcutaneous (SC) use of daratumumab. Regarding preferred routes of administration, an increased trend in oral and SC routes is observed (respectively 53% and 7% in 2016 vs. 69%and 28% in 2021). The increasing use of SC intensified in 2017 as part of the arrival of AML treatments combining azacitidine (SC) with venetoclax (oral). New CT using the intravenous route decreased from 70% in 2016 to 51% in 2021 even if bispecific antibodies araised in 2021. Focusing in 2021, 1359 visits (772 in day hospital for protocol chemotherapy and 597 for oral treatment) were observed, i.e. 6 patients per day. Conclusion(s): This review showed OH's activity growth in our center. The increasingly frequent use of SC and oral routes requires that patients be fully informed and trained about their own management. In this context, a pharmacist has its place and could best inform patients about the adverse effects of new complex therapies (antibodies, targeted therapy). A unique place, organized and dedicated to clinical research in OH, would allow patients benefiting from a structured and exhaustive support as well as meeting all the healthcare professionals involved and finally ensuring the conditions for optimal care.
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Since December 2019, the novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) infection has broken out worldwide, causing enormous social and economic burdens. Sudden exacerbations in SARS - CoV -2 infected people may be caused by infection - related cytokine storms. The basic state of the body and the strength of the immune response determine the prognosis of SARS-CoV-2. The interaction between proinflammatory factors and anti - inflammatory factors, and continued proinflammatory response cause lung edema, exudation, progression to acute respiratory distress syndrome involving the lung tissues and organs, multi - organ failure, and even death. The efficacy of antiviral therapy alone for immune complications like cytokine storm during viral infection is not ideal, and the targeted therapy of cytokines has become a potentially popular therapeutic strategy. Early identification and appropriate treatment of immune complications contribute to reduce the morbidity and mortality of severe viral infections.Copyright © 2021 Heilongjiang Institute of Science and Technology Information. All rights reserved.
ABSTRACT
INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory condition characterized by diarrhea, abdominal pain, rectal bleeding, and weight loss. Upadacitinib is an oral, selective, small molecule Janus Kinase (JAK) inhibitor that was recently approved in the United States for moderate to severe UC. Clinical trials evaluating the efficacy of upadacitinib excluded patients with a previous exposure to tofacitinib, a nonselective JAK inhibitor;therefore, the efficacy of upadacitinib in patients with previous exposure to tofacitinib remains largely unknown. METHOD(S): We present a small retrospective case series of all patients with a diagnosis of ulcerative colitis seen at our institution between with a prior exposure to tofacitinib who were initiated on upadacitinib between May and August of 2022. Demographic data was collected as well as outcome data on clinical improvement, steroid-free remission, biochemical improvement, colectomy status, and adverse events. RESULT(S): Eleven tofacitinib-refractory patients with ulcerative colitis were initiated on upadacitinib. Mean age was 38.1 years, five (45.5%) patients were female, nine (81.8%) patients were white, seven (63.6%) patients had pancolitis, and mean duration of UC was 7.4 years (Table 1). In this group, there were high rates of prior targeted therapy failures. These patients were followed for a mean of 121 days. The clinical course of each patient is presented in Table 2. Of the 11 patients included in our study, nine (81.8%) patients reported symptomatic improvement, six (54.5%) patients were able to successfully taper corticosteroids, and two (18.2%) patients underwent colectomy, one of which was elective and planned prior to initiating upadacitinib. The mean fecal calprotectin improvement was 1430mg/kg of patients with both baseline and follow-up testing. Three (27.3%) patients experienced an adverse event;two (18.2%) patients with mild COVID-19 not requiring hospitalization and one (9.1%) patient with Enteropathogenic E. Coli. DISCUSSION: This real-world single-center case series of 11 patients, suggests that upadacitinib may be an effective option for patients with a previous tofacitinib exposure. Larger prospective studies are needed to confirm these findings. (Table Presented).
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
Background: HER2+ mBC remains incurable, with a need for new HER2-directed therapies and regimens, including chemotherapy-free options. Zanidatamab (zani) is a novel HER2-targeted bispecific antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of antitumor activity, including complement-dependent cytotoxicity. A CDK4/6 inhibitor combined with endocrine therapy is an approved treatment for HER2-negative/HR+ mBC and this combination has also demonstrated encouraging antitumor activity when paired with HER2-targeted therapy(ies) in HER2+/HR+ mBC. Here, we report results from ZWI-ZW25-202 (NCT04224272), an ongoing singlearm phase 2 study of zani combined with palbociclib (palbo) and fulvestrant (fulv) in pts with HER2+/HR+ mBC. Method(s): Eligibility requirements include: HER2+/HR+ unresectable, locally advanced BC or mBC;ECOG PS of 0 or 1;prior treatment with trastuzumab, pertuzumab and T DM1 (additional prior HER2-targeting agents are permitted);and no prior treatment with CDK4/6 inhibitors. Part 1 of the study evaluated the safety and tolerability of the zani/palbo/fulv combination and determined the recommended doses for use in Part 2, where the antitumor activity of the combination is being evaluated. Endpoints include safety outcomes, progression-free survival at 6 months (PFS6), confirmed objective response rate (cORR) per RECIST v1.1;disease control rate (DCR=complete response [CR] plus partial response [PR] plus stable disease [SD]);duration of response (DOR);PFS;and overall survival. Result(s): As of 24 Feb 2022, 34 pts (33 HER2+/HR+ per central analysis) with a median age of 52 (range 36-77) have been treated. In the metastatic setting, pts had received a median (range) of 4 (1-10) prior systemic regimens, including 3 (1-8) different prior HER2 targeted therapies, and 1 (0-4) endocrine therapy. Seven pts (20%) had prior T DXd treatment and 7 pts had prior fulv treatment. All pts received zani (20 mg/kg Q2W) and standard doses of palbo and fulv. Eighteen pts (53%) remained on treatment;median duration of zani treatment was 6.9 mo (range 0.5- 16.3). A dose-limiting toxicity (DLT) of neutropenia occurred in 1 of 7 DLT-evaluable pts in Part 1. Among all pts (n=34), the most common (>20%) treatment (zani, palbo and/or fulv)-related adverse events (TRAEs) were diarrhea (74%), neutrophil count decreased/neutropenia (62%), stomatitis (41%), asthenia (26%), nausea (24%), and anemia (21%). Grade (Gr) >=3 TRAEs in 2 or more pts included neutrophil count decreased/neutropenia (50%), anemia (6%), diarrhea (6%), and thrombocytopenia (6%). AEs of special interest were all Gr <=2 and included 4 pts with cardiac events (LVEF decrease of >=10% from baseline) and 1 pt with infusion-related reaction. There were no treatment-related serious AEs. Palbo was discontinued for 1 pt due to an AE (AST increase);no pt discontinued zani treatment as a result of AEs. Two deaths occurred: 1 due to disease progression and 1 due to an unrelated AE of pneumonia caused by COVID-19. In 29 pts with measurable disease, the cORR was 34.5% (95% CI: 17.9, 54.3), all responses were cPRs, of which 1 is pending CR confirmation. DOR ranged from 2.3 to 14.9+ mo, with 8 confirmed responses ongoing, and the DCR was 93.1% (95% CI: 77.2, 99.2). Interim median PFS was 11.3 mo (range 0.03-16.7;95% CI: 5.6, not estimable). PFS6 analysis is planned following the completion of enrollment. Conclusion(s): Zani in combination with palbo and fulv shows encouraging antitumor activity with durable responses in heavily pretreated pts and a manageable safety profile. This regimen has the potential to be a chemotherapy-free treatment option in pts with HER2+/HR+ mBC. Enrollment in the study is continuing.
ABSTRACT
Background: Cardio-pulmonary exercise test (CPET) can differentiate causes of persistent dyspnea beyond cardiopulmonary limitation. Dysfunctional breathing (DB) has been increasingly identified in long COVID in two main forms, hyperventilation [HV] or periodic deep sighing [PDS]. Aims and objectives: We aimed to contrast the CPET ventilatory parameters in post COVID patients without cardiopulmonary limitations. Four groups were compared a) normal CPET, b) PDS, c) HV and d) mixed pattern (PDS & HV). Method(s): CPET patterns (N, HV, PDS and mixed) were determined in 76 SARS-CoV2 patients [Mean age 48.2 (SD15.0), women (n=49, 64%)]. We compared breath by breath ventilatory parameters using raw data and coefficients of variation focusing on breathing frequency, tidal volume, VE/VCO2 and ins- and expiratory time. Result(s): Normal CPET were found in 26 (30%), HV in 12 (16%), PDS in 25 (33%) and mixed in 16 (21%)., dyspnea level and timing of evaluation between COVID and CPET (mean 230 days) were similar between groups. See figure for ventilatory parameters at rest and exercise. Conclusion(s): In long COVID patients with normal lung function and normal oxygen consumption but persistent dyspnea, assessment of the variability of ventilation at rest and exercise using CPET can reliably identify DB and differentiate its main forms (PDS or HV), thus offering a physiological explanation for dyspnea and allowing targeted therapy.
ABSTRACT
Background: The safety and efficacy of pulmonary thromboendarterectomy (PTE) surgery after COVID-19 infection is unknown. Objective(s): Assess the outcomes of PTE in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who had COVID-19 infection. Method(s): Retrospective, chart review of PTE cases at UCSD from March 2020 through December 2021. Result(s): 315 patients underwent PTE surgery during the analysis period;23 cases (7.3%) had previous COVID-19 infection. All were asymptomatic from COVID-19 infection at time of surgery. Mean age was 46 (range 16-75;mean 55 for non-COVID group), 13 women, 10 men, mean BMI 34.8 +/- 8.1 (mean 30.7 +/- 7.5 non-COVID). 12 patients (52.2%) were on PH targeted therapy (50.5% non-COVID). Preoperative PVR was 479.2 +/- 288.4 dynes s cm (536.6 +/- 353.7 dynes s cm non-COVID);postoperative PVR was 192.7 +/- 77.1 dynes s cm (216.6 +/- 105.6 dynes s cm non-COVID). Average circulatory arrest time was 40.3 +/- 17.9 minutes (45.3 +/- 19.7 minutes non-COVID, p=0.2), with majority of cases having Level 2 UCSD surgical classification. Average ventilator time was 1.9 days (2.2 days non-COVID, p=0.7), ICU stay 4.4 days (4.4 days non-COVID, p=1.0), length of hospitalization 10.9 days (11.6 days non-COVID, p=0.4). There was 1 case (4.3%) of airway hemorrhage, 3 cases (13.0%) of reperfusion lung injury, and 2 cases (8.7%) of post-operative respiratory infection. 10 patients (43.5%) were discharged on supplemental oxygen (60.0% for non-COVID). There were no in-hospital deaths. Compared with cases operated without COVID-19 infection over the same time period, no major differences were observed. Conclusion(s): History of COVID-19 infection did not affect outcomes of PTE surgery.
ABSTRACT
Background Phospholamban (PLN), an inhibitor of sarcoplasmic reticulum (SR) Ca2+-ATPase, is a regulator of Ca2+ release during excitation-contraction coupling. We present a case of recurrent polymorphic ventricular tachycardia (PMVT)/ventricular fibrillation (VF) due to a PLN mutation. Case 38 year-old male presents after resuscitation following VF arrest. An ICD was implanted. Seven years later, he presented with VF storm requiring ventricular assist device support and he underwent catheter ablation of PVC triggers of VF arising from the moderator band. Because he had an ECG that was concerning for early repolarization syndrome, he was placed on quinidine and metoprolol. After an episode of VT in 2020 in the setting of COVID infection, whole genome sequencing was obtained and identified a pathogenic PLN mutation. PLN L39Ter has been associated with dilated and hypertrophic cardiomyopathy as well as sudden death. The patient has a history of normal left ventricular function and wall thickness by echocardiography. Decision-making Given the involvement of PLN on SR handling of Ca2+, flecainide may be a more effective therapy for the treatment of PMVT/VF in this patient. Conclusion PLN mutations have been associated with cardiomyopathies. This case illustrates a patient with the pathogenic PLN L39X variant with short-coupled PMVT with no imaging evidence of structural heart disease. Whether a more targeted therapy such as flecainide may be more effective in this patient remains to be determined. [Formula presented]Copyright © 2023 American College of Cardiology Foundation
ABSTRACT
Essential oils are potential therapeutics for coronavirus disease 2019 (COVID-19), in which some of the volatile compounds of essential oils have been well known for their broad antiviral activities. These therapeutic candidates have been shown to regulate the excessive secretion of pro-inflammatory cytokines, which underlies the pathogenesis of severe COVID-19. We aimed to identify molecular targets of essential oils in disrupting the cell entry and replication of SARS-CoV-2, hence being active as antivirals. Literature searches were performed on PubMed, Scopus, Scillit, and CaPlus/SciFinder (7 December 2022) with a truncated title implying the anti-SARS-CoV-2 activity of essential oil. Data were collected from the eligible studies and described narratively. Quality appraisal was performed on the included studies. A total of eight studies were included in this review;four of which used enzyme inhibition assay, one—pseudo-SARS-CoV-2 culture;two—whole SARS-CoV-2 culture;and one—ACE2-expressing cancer cells. Essential oils may prevent the SARS-CoV-2 infection by targeting its receptors on the cells (ACE2 and TMPRSS2). Menthol, 1,8-cineole, and camphor are among the volatile compounds which serve as potential ACE2 blockers. β-caryophyllene may selectively target the SARS-CoV-2 spike protein and inhibit viral entry. Other interactions with SARS-CoV-2 proteases and RdRp are observed based on molecular docking. In conclusion, essential oils could target proteins related to the SARS-CoV-2 entry and replication. Further studies with improved and uniform study designs should be carried out to optimize essential oils as COVID-19 therapies. © 2023 by the authors.