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The coronavirus disease 2019 (COVID-19) has become a global pandemic. It is urgent to find treatments to control the infection and improve symptoms. Homologous modeling and clinical analyses suggest that histamine receptor antagonists have broad prospects in the treatment of COVID-19. This article introduces the research progress of histamine H1 receptor antagonist combined with azithromycin, histamine H2 receptor antagonist famotidine alone or combined with aspirin, and histamine H1 and H2 receptor antagonists used in combination in the treatment of COVID-19. Finally, the possible mechanism of histamine receptor antagonists in the treatment of COVID-19 was introduced and the application prospect of histamine receptor antagonists in the treatment of COVID-19 was analyzed.Copyright © 2022, Second Military Medical University Press. All rights reserved.
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Objectives: COVID-19 infected over 150 million people and caused over 1 million deaths in the US. This study evaluates several variables thought to be associated with mortality risk in the COVID-19 population. Method(s): The IQVIA longitudinal medical and pharmacy claims databases identified 17,682,111 patients with a COVID-19 diagnosis between 4/1/2020-4/30/2022 from a population of >277 million patients in the US. Patients were linked to Veritas Data Research fact-of-death records (90% complete compared to CDC reporting) and confirmed deaths were flagged. Confirmed mortality rates (CMR) were evaluated by age group, socioeconomic status (SES) using the Area Deprivation Index (v2.0, University of Wisconsin, 2015), co-morbidities and COVID-specific (approved and unapproved) treatments. Result(s): Of the 563,744 patients (3.2%) identified as dead (3.67% in men, 2.85% in women overall), CMR was lowest in patients aged 0-17 (0.08%), highest in age 65-75 (5.92%) and >75 (16.40%). Patients in the lowest 40% of SES had CMR of 4.43% while in the highest 20% was 1.56%. Respiratory failure, pneumonia and sepsis were the most common acute diagnoses accompanying COVID-19 deaths in all SES. In patients with comorbid dementia or Alzheimer's disease, CMR were 21.62% and 23.40% respectively. Additionally, congestive heart failure (15.79%), atrial fibrillation (15.50%), chronic kidney disease (15.30%) and COPD (12.19%) were associated with high CMR. Among patients receiving approved therapies, casirivimab/imdevimab and remdesivir had CMR of 1.41% and 12.63% respectively, while for those receiving unapproved therapies, ivermectin and hydroxychloroquine had CMR of 2.54% and 2.45%. Conclusion(s): Compared to the 1.1% case-mortality rate (Johns Hopkins 2023) among US COVID-19 patients, we found CMR exceeded 3% among those with a medical claim for COVID-19. Advanced age, dementia, and cardio-renal disease were associated with mortality. Patients with the lowest SES had approximately 3 times the confirmed mortality rate compared to those in the highest SES group.Copyright © 2023
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INTRODUCTION. The aetiology of Kawasaki disease (KD) remains unknown. Changes in infectious exposure during the COVID-19 pandemic owing to infection prevention measures may have affected the incidence of KD, supporting the pathogenic role of an infectious trigger. The purpose of this study was to evaluate the incidence, phenotype and outcome of KD before and during the COVID-19 pandemic in Denmark. METHODS. This was a retrospective cohort study based on patients diagnosed with KD at a Danish paediatric tertiary referral centre from 1 January 2008 to 1 September 2021. RESULTS. A total of 74 patients met the KD criteria of whom ten were observed during the COVID-19 pandemic in Denmark. Alof these patients were negative for SARS-CoV-2 DNA and antibodies. A high KD incidence was observed during the first six months of the pandemic, but no patients were diagnosed during the following 12 months. Clinical KD criteria were equally met in both groups. The fraction of intravenous immunoglobulin (IVIG) non-responders was higher in the pandemic group (60%) than in the in the pre-pandemic group (28.3%), although the rate of timely administered IVIG treatment was the same in both groups (>= 80%). Coronary artery dilation was observed in 21.9% in the pre-pandemic group compared with 0% in KD patients diagnosed during the pandemic. CONCLUSION. Changes in KD incidence and phenotype were seen during the COVID-19 pandemic. Patients diagnosed with KD during the pandemic had complete KD, higher liver transaminases and significant IVIG resistance but no coronary artery involvement.Copyright © 2023, Almindelige Danske Laegeforening. All rights reserved.
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Introduction: Adjuvant anti-cancer systemic therapy (SACT) following lung resection improves overall survival in stage II/II non-small cell lung cancer (NSCLC). The Getting It Right First Time (GIRFT) National Specialty Report for Lung Cancer recommends centres publish adjuvant SACT rates for National benchmarking and proposes a target of >40% of eligible patients undergo SACT. We report a regional audit into the uptake of adjuvant SACT in Greater Manchester (GM). Method(s): A retrospective case review of all patients undergoing curative-intent NSCLC surgery with a pathological stage of II/III from 01/01/21 to 30/04/21. Data collected included patient demographics, uptake of adjuvant SACT, reasons for no adjuvant SACT and tolerance and complications of SACT. Result(s): 58 patients underwent surgical resection within the audit period and were eligible for adjuvant SACT. Median age was 70 years (range 45 - 81) and 60% were female. 47% (27/58) commenced adjuvant SACT;41% (24/58) were treated with chemotherapy and 7% (4/58) were treated with tyrosine kinase inhibitors. 58% (14/24) of patients that commenced adjuvant chemotherapy completed 4 cycles. Carboplatin/Vinorelbine was the commonest regimen (82%, 18/22). There were no grade III-V complications and no chemotherapy-related deaths. Dose reduction due to toxicity was required in 14% (3/22). The reasons adjuvant systemic therapy was not given were patient choice in 32% (10/31), poor physical health such that risks outweighed benefits in 42% (13/31), and other reasons (e.g. need to treat synchronous primary tumours) in 26% (8/31). COVID-19 was not recorded as a cause for adjuvant omission/ dose reduction. Conclusion(s): This data provides national benchmarking information for adjuvant SACT in NSCLC and suggests the target of >40% is achievable and appropriate. Interventions that improve patient fitness pre- and post-operatively might increase adjuvant SACT uptake. This regional audit will be extended to review all eligible patients in 2021 and further data will be presented. Disclosure: No significant relationships.Copyright © 2023 Elsevier B.V.
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Given the time criticality of finding treatments for the novel COVID-19 pandemic disease, drug repurposing has proved to be a vital strategy as the first response while de novo drug and vaccine developments are underway. Furthermore, Artificial Intelligence (AI) has also accelerated drug development in general. Key desirable features of AI that support a rapid and sustained response along the pandemic timeline include technical flexibility and efficiency (i.e. speed, resource-efficiency, algorithm adaptability), and clinical applicability and acceptability (i.e. scientific rigor, physiological applicability and practical implementation of proposed drugs). This chapter reviews a selection of AI-based applications used in drug development targeting COVID-19, including IDentif.AI-a small data platform for a rapid identification of optimal drug combinations, to illustrate the potential of AI in drug repurposing. The benefits and limitations of using Real-World Data are also discussed. The response to the COVID-19 pandemic has offered multiple learnings which highlight the need to strengthen both short- and long-term strategies in developing AI technologies, scientific and regulatory frameworks as well as worldwide collaborations to enable effective preparedness for future epidemic and pandemic risks. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.
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Objectives: Developing a control group of a clinical trial using real world data is desirable and ethically sound despite challenges pertaining to internal validity. To examine the internal validity, we reproduced the control group in a Randomized Controlled Trial (RCT) using Electric Health Record (EHR) data and evaluated the difference between the outcome of the original trial and that of the reproduced analysis. Method(s): We selected an RCT, REMDACTA trial, that was performed to evaluate the efficacy of tocilizumab plus remdesivir against placebo plus remdesivir in patients with severe COVID-19 pneumonia. We reproduced its control group (patients with severe COVID-19 pneumonia taking only remdesivir), using Japanese EHR data, Millennial Medical Record provided by Life Data Initiative. Target patients for the main analysis were those prescribed remdesivir within 2 days after admission and diagnosed with COVID-19 (defined by ICD-10 code, U07.1) and/or with COVID-19 pneumonia (defined by diagnosis name). Patients in the sub analysis included only those with COVID-19 pneumonia diagnosis. Among the target patients, those undergoing image inspection, oxygen administration, and not taking any medicines for pneumonia before the first remdesivir prescription were eligible for the analyses. Median length of stay was compared in the reproduced group and in REMDACTA trial. Result(s): The database included 676 and 110 target patients for the main and sub analyses, respectively. However, only 57 and 14 patients met the eligibility criteria for the main and sub analyses, respectively. The reduction in the number of patients is attributed to the criteria of image inspection and oxygen administration. Median length of stay in the reproduced group were 13 and 11 days in the main and sub analyses, respectively. In REMDACTA trial, 95% CI of median time was 11.0-16.0. Conclusion(s): We successfully reproduced the median time of the control group by EHR data.Copyright © 2023
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Background: Since patients admitted to the intensive care unit have a compromised im-mune system and are more prone to infection than other patients, timely diagnosis and treatment of corneal ulcers among this group of patients can prevent vision loss. Therefore, it is necessary to treat eye infections and corneal ulcers promptly and economize prohibitive costs. Objective(s): Appropriate treatment with the most effective antibiotic before the answer is available to prevent corneal ulcer complications and blindness. Method(s): This study was conducted from November 2019 to November 2020 and after approval by the ethics committee of Hamedan University of Medical Sciences with the code of ethics: IR.UMSHA.REC.1398.716. First, the corneal secretions of 121 patients admitted to the intensive care unit of Sina Hospital are prepared by an ophthalmologist (after anesthetizing the cornea with tetra-caine drops and sterile swabs) and culture in four growth mediums (blood agar, chocolate agar, thio-glycolate, and EMB). Microbial cultures are examined after 48 hours and a fungal culture is examined one week later. Disc diffusions are placed in positive microbial cultures. Antibiotic susceptibility or resistance of the antibiogram was recorded. Other demographic data, including patients' age and sex, are extracted from ICU files. Also, test results and patient identifications are recorded in a checklist designed for this purpose. Result(s): Of all the antibiotics used against common bacteria, vancomycin (84%), colistin (80.43%), cefazolin (80%), and levofloxacin (60%) had the highest sensitivity and gentamicin (93.75%), ceftazidime (86.42%) Erythromycin (85%) had the highest resistance against isolated bacteria. Conclusion(s): The data obtained from this study showed that the most common microorganisms in the age group under the age of 30 years were Acinetobacter Baumannii, in the group of 30-60 years old was Klebsiella pneumonia, and age group over 61 years old was Staphylococcus aureus, and the most sensitive antibiotics in the age group under 30 years were vancomycin and levofloxacin and the age group30-60 were colistin and vancomycin and in the age group over 61 years were vancomycin and cefazolin.Copyright © 2023 Bentham Science Publishers.
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Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.
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The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.
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Background: Sickle cell disease (SCD) is one of the most common single gene disorders worldwide and is characterised by significant morbidity and early mortality.[1] Pregnancy in SCD is associated with an increased risk of maternal and foetal complications.[2,3] The 2011 RCOG and the 2021 BSH guidelines[5,6] on the management of pregnancy in SCD have provided the basis for best practice care in the UK over the past decade and is the guidance which we follow in Ireland. To date, there is no published data on outcomes for pregnant women with SCD in Ireland. The number of Irish patients with SCD has risen over the past 20 years. Without a national database, the exact prevalence is not known but currently there are at least 600 adults and children with SCD in Ireland, whose population is just over 5 million.[4] Aims: Our study assesses outcomes of pregnant patients with SCD from 2015 to 2022. Our aims were to: * Assess adherence to current guidelines * Assess pregnancy outcomes and maternal complications * Assess transfusion rates amongst our patient cohort. Method(s): This is a retrospective cohort study. We do not have a directly matched cohort, but have compared our findings to published data on Irish pregnancy outcomes from the Irish Maternity Indicator System National Report and have correlated our findings with studies of women with SCD who were managed in UK centres.[8,9,10] Results: We reviewed outcomes of 29 pregnancies in 19 women over a 7-year period. The median age was 29 (range 20-41) and the predominant maternal sickle genotype was HbSS (65.5%). Before conception, 55.2% of cases had pre-existing complications of SCD, including acute chest syndrome (ACS), pulmonary hypertension (PHTN) and prior stroke. In accordance with current guidelines, 100% of women (n=29) were prescribed folic acid, penicillin, and aspirin prophylaxis. 51.7% (n=15) of women had documented maternal complications during pregnancy, including ACS (34%), vaso-occlusive crisis (34%), gestational diabetes (10%), VTE (3%) and UTI (3%). Two women (7%) developed Covid-19 pneumonitis despite vaccination. There was one case of maternal bacteraemia (3%). 65.5% of cases (n=19) required blood transfusion during pregnancy. One woman was already on a blood transfusion programme for disease modification prior to pregnancy. In 6 cases (20.6%), a transfusion programme was commenced during pregnancy due to prior pregnancy complications or intrauterine growth restriction. During pregnancy, 27.6% (n=8) of women required emergency red cell exchange for ACS. Prior studies have suggested that between 30% and 70% of pregnant women with SCD require at least one blood transfusion during pregnancy.[8,9,10] By comparison, only 2.6% of the Irish general obstetric population required transfusion during pregnancy.[7] 20.6% (n=6) of births were preterm at <37 weeks' gestation. There was one live preterm birth (3%) at <34 weeks and one intrauterine death (3%) at 23 weeks' gestation. Similar to UK data[9], 31% of women required critical care stay (n=9) during pregnancy, in comparison with 1.44% nationwide in 2020.[7] Conclusion(s): It is well established that pregnancy in SCD is high risk, and despite adherence to current guidelines, we have shown very high rates of critical care admission, significant transfusion requirement and hospital admissions. Our findings are comparable to published UK outcomes and they further support the need for a comprehensive specialist care setting for this patient cohort.
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In recent times, numerous reports of systemic fungal infections have been a major concern. The angioinvasive fungal infection, mucormycosis has surged in patients with COVID-19 due to various factors, mainly uncontrolled diabetes and inappropriate corticosteroid use. The prevalence of this acute and fatal fungal infection caused by Mucorales-related fungal species has been highest in the Indian population. COVID-associated mucormycosis (CAM) has a propensity for contiguous spread, and exhibits high morbidity as well as mortality. Unless promptly detected and treated, it is associated with a poor prognosis. A high index of suspicion, aggressive surgical debridement and use of systemic antifungal agents continue to be the standard of care for CAM. Moreover, there is an imperative need to address this public health issue by increasing public awareness and education. This article provides a comprehensive overview on the emergence of CAM during the pandemic, the current burden, pathophysiology, diagnostic interventions and management of CAM in Indian clinical practice.
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Burkholderia pseudomallei is soil saprophytic Gram-negative bacilli that cause a fatal disease called melioidosis. Melioidosis is capable of causing cutaneous infection and systemic infections in the respiratory tract, cardiovascular, gastrointestinal, urinary, skin and soft tissue, and musculoskeletal and central nervous systems. Here, we report rare forms of pulmonary, cerebral, and splenic abscess case series of melioidosis caused by B. pseudomallei. Imported cases have been reported among tourists, immigrants, and soldiers who returned from endemic areas. The acquisition of infection is through percutaneous, inhalation, and ingestion of contaminated water;person-to-person transmission is very rare. Melioidosis cases are primarily found in the rainfall season and are usually associated with risk factors such as diabetes, alcoholism, and chronic renal diseases. However, 20-26% of cases were not associated with predisposing conditions. The identification is based on colony morphology, Gram stain, antibiotic susceptibility testing, and other supportive automated and molecular assays when we suspect B. pseudomallei. There are two phases, the intensive and eradication phases, in managing melioidosis. In the intensive phase, ceftazidime for 2 weeks showed efficacy in almost 50% of cases, and the eradication phase treatment with co-trimoxazole and doxycycline or amoxicillin/clavulanic acid for 3-6 months showed an excellent response. The improper clinical diagnosis and management of B. pseudomallei can lead to complications. Hence, early diagnosis with microbiological approaches such as culture, biochemical reactions, or automated systems available and antimicrobial sensitivity testing will cure the patient quickly without mortality.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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Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.
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Case: Wiskott-Aldrich Syndrome (WAS) is a rare X-linked inborn error of immunity caused by mutations in the WAS gene. It is classically characterized by immunodeficiency, eczema, and micro-thrombocytopenia. It has been known since the 1960s that patients with WAS have an increased risk of lymphoproliferative disease though the exact incidence remains unknown in the American population. Limited case reports have discussed EBV-related lymphoproliferative disease in patients with WAS. We present a case of a 9-year-old boy with known WAS complicated by eczematous rash, thrombocytopenia, recurrent ear infections, and monoclonal gammopathy who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. Family had been offered treatment with hematopoietic stem cell transplant but declined multiple times in the past. Earlier in the year, he presented with possible MIS-C with negative SARS-CoV-2 PCR. He presented to our hospital with mastoiditis and lymphadenopathy. Physical examination showed severe eczema on hands and tender right mastoid. Laboratory evaluation showed thrombocytopenia, elevated IgG of 6290, IgA of 744, IgE of 827, low IgM of 41, and 14% response to pneumococcal titers. He was empirically treated with intravenous antibiotics. ENT performed right postauricular incision and drainage and the culture grew Hemophilus influenza. Throughout his hospital stay, his submandibular lymphadenopathy became more prominent despite treatment. Core needle biopsy of right submandibular lymph node was suggestive of EBV-associated lymphoid hyperplasia. EBV PCR and antibodies were both positive. CT chest, abdomen, and pelvis revealed multifocal pulmonary lymphadenopathy and a diffuse, bilateral nodularity as well as retroperitoneal and mesenteric lymphadenopathy. He was given four doses of weekly Rituximab, which successfully decreased EBV viremia below linear detectability. Immunoglobulin replacement therapy (IgRT) was initiated. Bronchoalveolar lavage and lung biopsy were performed and are results are currently pending. Discussion(s): We present a case of a 9-year-old boy with known WAS awaiting transplant who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. While lymphoproliferative disease is a known complication of WAS, EBV-related lymphoproliferative disease in WAS patients has only been reported as case reports and remains a rare but known complication of patient with WAS.Copyright © 2023 Elsevier Inc.
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Is there an increased incidence of bacteraemia among COVID-19 patients requiring critical care admission who have received IL-6 inhibitors? Introduction: Interleukin-6 (IL-6) inhibitors have been shown to reduce mortality in hospitalised COVID-19 patients. There is, however, concern that induced immunosuppression may increase the risk of secondary nosocomial infection. Objective(s): Our primary aim was to determine if there was increased incidence of bacteraemia in COVID-19 patients requiring critical care admission who had received IL-6 inhibitors compared to those who had not. Method(s): A retrospective review of all COVID-19 admissions to two critical care units in Liverpool from 4th March 2020 to 31st October 2021. Patients were divided into those who received an IL-6 inhibitor (sarilumab or tociluzimab) and those who did not. Hospital antimicrobial policy was to administer a five day prophylactic course of co-amoxiclav and clarithromycin for patients with severe COVID-19 during the study period. Blood culture results from 14 days before admission to critical care and 90 days after admission were included. The blood culture results comprised cultures taken in both critical care and on the wards. Data were linked and analysed using Stata V15.1 (StataCorp, Stata Statistical Software: Release 15, College Station, Texas, USA). Result(s): 894 patients were included in the study. 134 patients had at least one positive blood culture result. The most commonly identified pathogens were Coliforms (23/134, 17.2%), Enterobacter (22/134, 16.4%) and Escherichia coli (16/134, 11.9%). Of patients administered an IL-6 antagonist, 16.8% (114/565) developed a positive blood culture compared to 11.6% (20/172) who did not, p=0.096. We did not observe an increased frequency of antimicrobial resistant culture in the IL-6 administered group 22.8% (26/114) vs. 20.0% (4/20) in this cohort, p=0.781. Data have not been adjusted for demographic and clinical factors in this preliminary analysis. Conclusion(s): We observed a trend toward increased frequency of blood culture positivity in patients administered an IL-6 antagonist within this COVID-19 positive cohort but this was not statistically significant. Further analysis is required to adjust for relevant demographic and clinical factors.
ABSTRACT
Background: The second wave of the COVID-19 pandemic caused significant demand for beds capable of delivering enhanced respiratory support. NHS England recommended the use of CPAP for patients with COVID-19 respiratory failure, a treatment which can be offered outside of a critical care facility, and on a Respiratory High Care/ Support Unit (RSU). The enhancement of Portsmouth's RSU provided CPAP and NIV for patients with COVID-19 respiratory failure. With our intensive care facilities at 300% their normal capacity, this greatly alleviated bed pressures on critical care. Varied levels of deprivation exist in Portsmouth's dense population. Deprivation has an impact on overall health, however the effect of postcode on outcomes for people going onto support for COVID-19 respiratory failure, is unknown. Method(s): Retrospective cohort analysis of consecutive patients admitted to Respiratory Support Unit during the second wave of the COVID-19 pandemic, from 02/11/2020 to 31/01/2021. 227 patients were included in the study with 8 removed due to incomplete data, all of the patients received respiratory support in the form of CPAP or NIV. We collected multivariate data including biochemical markers, demographics, oxygenation status, co-morbidities and outcomes. Outcomes measured were: 1) Death in RSU, 2) Discharge from RSU or 3) Intubation and Ventilation. To measure deprivation, we linked a persons postcode to an area called an LSOA (Lower-layer Super Output Area). These are small areas of similar population size, each of which has a deprivation score (ie. top 10%, to the lowest 10% areas of deprivation in the UK). This is measured using an 'index of multiple deprivation'. An individual's outcome from the RSU was then analysed in relation to the deprivation score allocated to their postcode. Result(s): We observed a significant number of patients discharged from RSU, without needing invasive mechanical ventilation. 80/219 were discharged directly. 45/219 died in RSU, and 94 were eventually admitted to ITU. The average stay on CPAP or NIV before needing admission to ITU was 3 days. Some biochemical markers which stood out in relation to the outcomes described were as follows: average LDH, D-dimer and Troponin levels were higher in those who were admitted to intensive care. In patients who died, the PCT was significantly higher on average when compared to the other two groups. In the group who were discharged, mean lymphocyte count was >1, in the other two groups this was <1. From our observations in Portsmouth, there is a negative correlation between deprivation and lower aged individuals admitted for COVID-19 related respiratory support. Overall, we also saw disproportionate representation of those from the most deprived 50% of the UK in our respiratory support unit. Conclusion(s): CPAP and NIV can effectively be used in an RSU during a spike of COVID-19, to safely minimise demand on critical care services. Deprivation may have an impact on outcomes in patients needing respiratory support related to COVID-19. Deprivation levels may help predict risk of needing enhanced respiratory support in certain age groups. Multiple biochemical markers may be of prognostic value in COVID-19.
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Background: During the coronavirus disease 2019 (COVID-19) pandemic, established best practices in cancer care were modified to diminish the risk of COVID-19 infection among patients and health-care workers. Objective(s): We aimed to study the modifications in cancer-directed therapy during the first wave of the COVID-19 pandemic. Material(s) and Method(s): A cross-sectional study of patients with cancers of the head and neck, thoracic, urologic, and central nervous systems who visited the medical oncology department of the Tata Memorial Hospital, Mumbai, India, between April 22, 2020 and June 01, 2020, was conducted. Data were prospectively collected in an online pro forma and supplemented from the electronic medical records. Result(s): Of a total of 514 patients, 363 (71%) were men. The most common malignancy was lung cancer in 234 patients (46%). Cancer-directed therapy was modified in 83 patients (16%). Deviations consisted of modification of the chemotherapy regimen (48%), temporary discontinuation of chemotherapy in 37%, and interim chemotherapy to delay surgery in 5%. Changes in the chemotherapy regimen included a shift to a less intensive regimen in 45%, changing from intravenous to oral in 40%, and less frequent dosing of immunotherapy in 7%. Considering missed appointments as a deviation from planned cancer therapy, 68% of patients had a deviation in the standard planned cancer care. Conclusion(s): Almost two-thirds of the patients could not reach the hospital during the COVID-19 pandemic lockdown in India. Of those who could reach the hospital, one of out every six patients with cancer had a change in their cancer-directed treatment, half of which consisted of a modification in the standard chemotherapy regimens. The effects of these therapy deviations are likely to be long-lasting. (Clinical Trials Registry-India, CTRI/2020/07/026533).Copyright © 2023 Neurology India, Neurological Society of India Published by Wolters Kluwer - Medknow.
ABSTRACT
Background & Aim: Adoptive T cell immunotherapy holds great promise for the treatment of viral complications. Our group has been developing and trialling virus-specific T cell therapies for more than 20 years. Recently, we have generated a repository of multi-virus-specific T cells for our clinical trials. Unfortunately, for many patients with viral complications, there is no suitable trial through which to access these therapies. In Australia, the Therapeutic Goods Administration has a Special Access Scheme (SAS) to enable provision of unapproved therapies for compassionate use. Our research group is now a leading Australian provider of "off-the-shelf" and custom-grown allogeneic virus-specific T cells to hospitals for patients with no other treatment options. Methods, Results & Conclusion(s): We have generated a repository of multi-virus-specific T cells from 20 healthy donors, with up to 150 doses of T cells per donor generated from a single blood sample. Each product batch is thoroughly characterised in terms of viral antigen specificity, HLA restriction and alloreactivity. These T cells target a combination of Epstein-Barr virus, cytomegalovirus, BK polyomavirus, John Cunningham virus and adenovirus epitopes. We have also generated a repository of SARS-CoV-2-specific T cells and occasionally grow custom patient-specific batches of T cells from nominated donors, on request. Since 2008, we have provided virus-specific T cells to 15 hospitals across Australia, and the volume of supply requests has significantly increased in recent years, as clinicians have gained interest in adoptive immunotherapy. In 2022, we provided T cells for 26 patients via the SAS. The majority were experiencing post-transplant complications, including cytomegalovirus disease, BK virus-associated haemorrhagic cystitis and post-transplant lymphoproliferative disorder. Through our clinical trials, we have developed rigorous processes for T cell therapy manufacture and characterisation, in addition to a computer-based selection algorithm, which we apply to SAS cases. As these cases are not part of a clinical trial, concomitant therapy varies, and monitoring is not uniform. However, we have received reports of clinical benefit from adoptive T cell therapy. These include cases of reduction in viral load, improvement in symptoms, and complete resolution of infection. We believe that these promising T cell therapies should be available to hospitals through a nationally funded centre for cellular therapies for critically ill patients.Copyright © 2023 International Society for Cell & Gene Therapy
ABSTRACT
Objective: To design an optimal formulation for quercetin and vitamin C nano-phytosome. Method(s): Nano-phytosomes are prepared by the thin layer hydration technique using a 2-level-5-factor design experimental. A total of 32 experimental formulas were used for data analysis. The ratio of quercetin: soy lecithin (X1), the ratio of quercetin: cholesterol (X2), stirring speed (X3), stirring temperature (X4), and stirring time (X5) were used as independent factors, while globule size as a dependent factor. Data analysis was carried out by Design Expert12 application. Characterization of the optimal formula included physicochemical evaluation, globule size analysis, zeta potential, polydispersity index, entrapment efficiency, Transition Electron Microscopy (TEM) analysis, and FTIR analysis. Result(s): The optimal formula consisted of quercetin: vitamin C: lecithin: cholesterol ratio of 1: 1: 1.046: 0.105 mol;stirring speed 763.986 rpm;stirring time of 59 min, at temperature 51.73 degreeC which produced 59.26 nm average globule size, PDI value 0.66;zeta potential value-35.93+/-0.95 mV and average SPAN value 0.61. This formulation showed entrapment efficiency of quercetin 91.69+/-0.18 % and vitamin C 90.82+/-0.13 %. The TEM and FITR analysis showed the morphological of the globules and interactions between the drugs, soy lecithin, and cholesterol to form nano-phytosomes. Conclusion(s): The conditions to obtain the optimal formula for quercetin vitamin C nano-phytosome consisted of quercetin: vitamin C: lecithin: cholesterol ratio of 1: 1: 1.046: 0.105 mol;stirring speed 763.986 rpm;stirring time of 59 min, and at temperature 51.73 degreeC.Copyright © 2023 The Authors.