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1.
Nat Commun ; 13(1): 5943, 2022 Oct 08.
Article in English | MEDLINE | ID: covidwho-2062207

ABSTRACT

While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of the nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification to metanephric nephron progenitors results in elongated and radially aligned proximalised nephrons with distinct S1 - S3 proximal tubule cell types. Such PT-enhanced organoids possess improved albumin and organic cation uptake, appropriate KIM-1 upregulation in response to cisplatin, and improved expression of SARS-CoV-2 entry factors resulting in increased viral replication. The striking proximo-distal orientation of nephrons resulted from localized WNT antagonism originating from the organoid stromal core. PT-enhanced organoids represent an improved model to study inherited and acquired proximal tubular disease as well as drug and viral responses.


Subject(s)
COVID-19 , Communicable Diseases , Albumins/metabolism , Cell Differentiation/physiology , Cisplatin/metabolism , Cisplatin/pharmacology , Communicable Diseases/metabolism , Humans , Kidney , Nephrons/metabolism , Organoids/metabolism , SARS-CoV-2
2.
Thorac Cancer ; 13(18): 2654-2658, 2022 09.
Article in English | MEDLINE | ID: covidwho-1968050

ABSTRACT

Cancer patients are considered highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, it is not well known when chemotherapy can be safely restarted in cancer patients after coronavirus disease 2019 (COVID-19). Here, we describe the case of an 18-year-old man diagnosed with primary mediastinal nonseminomatous germ cell tumor (PMNSGCT) in which chemotherapy could be safely restarted after COVID-19. On day 11 of the third cycle of bleomycin, etoposide, plus cisplatin (BEP), he was diagnosed with mild COVID-19. On day 16 after the onset of COVID-19 (day 26 of third cycle of BEP), chemotherapy for his PMNSGCT was restarted. He received surgery after the fourth cycle of BEP without recurrence of COVID-19. Chemotherapy could be restarted and followed by surgery in this post-COVID-19 patient who had experienced mild illness after the discharge criteria were met and all symptoms had disappeared. We report this case with a review of the literature on restarting chemotherapy after SARS-CoV2 infection.


Subject(s)
COVID-19 , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bleomycin/therapeutic use , Cisplatin/therapeutic use , Etoposide/therapeutic use , Humans , Male , Neoplasms, Germ Cell and Embryonal , RNA, Viral , SARS-CoV-2 , Testicular Neoplasms
3.
Medicine (Baltimore) ; 101(30): e29281, 2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1967934

ABSTRACT

RATIONALE: Germ cell tumors in the head and neck are very rare. In cases of germ cell tumors, it is uncommon for lymph node metastasis to be the only and initial symptom, and this can easily lead to a misdiagnosis. Herein, we report about a 28-year-old woman with lymph node metastasis, in whom a primary tumor appeared in the nasal cavity. PATIENT CONCERNS: A 28-year-old woman presented with enlarged left submandibular lymph nodes. No other mass was found on whole-body screening using positron emission tomography-computed tomography. DIAGNOSIS: After partial submandibular lymphadenectomy was performed, histopathological and immunohistochemical examinations revealed a metastatic germ cell tumor. However, it was difficult to further classify and affirm the origin. INTERVENTIONS: As the patient was receiving four cycles of bleomycin, etoposide, and cisplatin chemotherapy, a primary tumor emerged in the nasal cavity, which was finally confirmed as an immature teratoma of a high World Health Organization histological grade and Norris grade 3. This tumor was found to contain similar components to lymph nodes with respect to histopathological and immunohistochemical characteristics, especially the immature neural tubes or nervous tissue in the nasal cavity. Fortunately, the patient recovered well with no signs of relapse, and the size of residual lymph nodes remained unchanged after she received another four cycles of bleomycin, etoposide, and cisplatin chemotherapy and two cycles of doxorubicin and ifosfamide (AI) chemotherapy. OUTCOMES: Unfortunately, 11 months later, during the coronavirus disease pandemic, the patient died owing to respiratory failure and pulmonary infection. CONCLUSIONS: In cases of malignant tumor in the submandibular lymph nodes of adults, the metastasis of a germ cell tumor should be considered an important differential diagnosis even if a primary tumor does not emerge. In this case, adequate postoperative chemotherapy is necessary.


Subject(s)
Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bleomycin/therapeutic use , Cisplatin/therapeutic use , Etoposide/therapeutic use , Female , Humans , Lymph Node Excision , Lymphatic Metastasis , Male , Neoplasm Recurrence, Local/drug therapy , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/therapy , Testicular Neoplasms/pathology
4.
J Infus Nurs ; 45(3): 142-153, 2022.
Article in English | MEDLINE | ID: covidwho-1927466

ABSTRACT

Immune checkpoint inhibitors, such as programmed cell death ligand 1 inhibitors pembrolizumab, nivolumab, atezolizumab, and avelumab, are used to treat patients with advanced urothelial carcinoma (UC). Based on data from the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance is now considered the standard-of-care treatment for patients with locally advanced or metastatic UC who responded or experienced disease stabilization after 1L platinum-containing chemotherapy, and it is the only category 1 preferred checkpoint inhibitor maintenance option in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for patients with cisplatin-eligible and cisplatin-ineligible locally advanced or metastatic UC. This article reviews key considerations related to avelumab 1L maintenance therapy that infusion nurses should be familiar with, including dosing, administration, and immune-related adverse event recognition and management, to ensure safe and appropriate use of this important and impactful therapy.


Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Antibodies, Monoclonal, Humanized , Carcinoma, Transitional Cell/drug therapy , Cisplatin/therapeutic use , Female , Humans , Male , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology
5.
BMJ ; 377: e068714, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1807349

ABSTRACT

OBJECTIVE: To evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma. DESIGN: Multicentre, randomised, double blind, phase 3 trial. SETTING: 66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021. PARTICIPANTS: 659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment. INTERVENTION: Participants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on days 1-5). MAIN OUTCOME MEASURES: Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1. RESULTS: 659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively. CONCLUSIONS: Compared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising. TRIAL REGISTRATION: ClinicalTrials.gov NCT03748134.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Adolescent , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/therapeutic use , Double-Blind Method , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Fluorouracil/therapeutic use , Humans , Paclitaxel/therapeutic use
6.
Environ Int ; 164: 107230, 2022 06.
Article in English | MEDLINE | ID: covidwho-1778115

ABSTRACT

BACKGROUND: Widespread environmental contamination can directly interact with human immune system functions. Environmental effects on the immune system may influence human susceptibility to respiratory infections as well as the severity of infectious diseases, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, the efficacy of vaccines to respiratory diseases may be impacted by environmental exposures through immune perturbations. Given the quick pace of research about COVID-19 and associated risk factors, it is critical to identify and curate the streams of evidence quickly and effectively. OBJECTIVE: We developed this systematic evidence map protocol to identify and organize existing human and animal literature on high-priority environmental chemical classes (Per- and polyfluoroalkyl substances, pesticides, phthalates, quaternary ammonium compounds, and air pollutants) and their potential to influence three key outcomes: (1) susceptibility to respiratory infection, including SARS-CoV-2 (2) severity of the resultant disease progression, and (3) impact on vaccine efficacy. The result of this project will be an online, interactive database which will show what evidence is currently available between involuntary exposures to select environmental chemicals and immune health effects, data gaps that require further research, and data rich areas that may support further analysis. SEARCH AND STUDY ELIGIBILITY: We will search PubMed for epidemiological or toxicological literature on select toxicants from each of the chemical classes and each of the three outcomes listed above. STUDY APPRAISAL AND SYNTHESIS OF METHODS: For each study, two independent reviewers will conduct title and abstract screening as well as full text review for data extraction of study characteristics. Study quality will not be evaluated in this evidence mapping. The main findings from the systematic evidence map will be visualized using a publicly available and interactive database hosted on Tableau Public.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antineoplastic Combined Chemotherapy Protocols , Cisplatin , Doxorubicin , Environmental Exposure/adverse effects , Immunity , Mitomycin
8.
Oral Oncol ; 116: 105240, 2021 05.
Article in English | MEDLINE | ID: covidwho-1091682

ABSTRACT

OBJECTIVES: Fever-range whole body hyperthermia (FRWBH) has been shown to improve tumor oxygenation in vivo. A prospective pilot study addressed the question if addition of FRWBH to re-irradiation is feasible in recurrent head and neck squamous cell carcinomas (HNSCC) with unfavorable prognostic features. MATERIALS AND METHODS: The study completed accrual with the recruitment of ten patients between April 2018 and March 2020. Re-irradiation was administered using volumetric arc hyperfractionated radiotherapy with bi-daily 1.2 Gray (Gy) single fractions and a total dose of 66 Gy to all macroscopic tumor lesions. Concomitant chemotherapy consisted mostly of cisplatin (7 patients). FRWBH was scheduled weekly during re-irradiation. The study was registered in the clinicaltrials.gov database (NCT03547388). RESULTS: Only five patients received all cycles of FRWBH. Poor patient compliance, active infections during treatment and study restrictions due to the Covid-19 pandemic were the main reasons for omitting FRWBH. No increase of acute toxicity was observed by FRWBH. Exploratory evaluation of outcome data suggests that FRWBH treatment according to protocol does not seem to have a detrimental effect on tumor control or survival and might even increase treatment efficacy. CONCLUSION: FRWBH is difficult to apply concomitant to re-irradiation in HNSCC. No excess toxicity was observed in patients receiving FRWBH and exploratory analyses suggest potential anti-tumor activity and decreased patient-reported depression scores after FRWBH.


Subject(s)
COVID-19/prevention & control , Hyperthermia, Induced , Re-Irradiation , Squamous Cell Carcinoma of Head and Neck/therapy , Aged , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Combined Modality Therapy , Depression/etiology , Dose Fractionation, Radiation , Female , Humans , Male , Middle Aged , Patient Compliance , Pilot Projects , Prospective Studies , Quality of Life , SARS-CoV-2 , Squamous Cell Carcinoma of Head and Neck/psychology , Survival Rate
9.
Oncologist ; 26(6): 483-491, 2021 06.
Article in English | MEDLINE | ID: covidwho-1081640

ABSTRACT

BACKGROUND: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience. MATERIAL AND METHODS: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data. RESULTS: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events. CONCLUSION: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care. IMPLICATIONS FOR PRACTICE: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.


Subject(s)
COVID-19 , Electronic Nicotine Delivery Systems , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/adverse effects , Cisplatin/adverse effects , Etoposide/adverse effects , Humans , Male , Neoplasms, Germ Cell and Embryonal/drug therapy , SARS-CoV-2 , Testicular Neoplasms/drug therapy
10.
Oncoimmunology ; 9(1): 1789284, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-1066080

ABSTRACT

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Azithromycin/administration & dosage , COVID-19/drug therapy , Hydroxychloroquine/administration & dosage , Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Azithromycin/pharmacokinetics , COVID-19/immunology , COVID-19/virology , Cell Line, Tumor , Cisplatin/administration & dosage , Cisplatin/pharmacokinetics , Clinical Trials, Phase II as Topic , Crizotinib/administration & dosage , Crizotinib/pharmacokinetics , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Interactions , Drug Therapy, Combination/methods , Female , France , Humans , Hydroxychloroquine/pharmacokinetics , Mice , Neoplasms/immunology , Oxaliplatin/administration & dosage , Oxaliplatin/pharmacokinetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
11.
J Am Soc Nephrol ; 31(2): 257-278, 2020 02.
Article in English | MEDLINE | ID: covidwho-992926

ABSTRACT

BACKGROUND: Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS: We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury. RESULTS: Adult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury. CONCLUSIONS: Distinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.


Subject(s)
Dendritic Cells/immunology , Kidney/immunology , Macrophages/immunology , Nephritis/immunology , Acute Kidney Injury/immunology , Age Factors , Animals , CD11b Antigen/analysis , CX3C Chemokine Receptor 1/analysis , Calcium-Binding Proteins/analysis , Cisplatin/pharmacology , Histocompatibility Antigens Class II/analysis , Kidney/drug effects , Kidney/metabolism , Lectins, C-Type/analysis , Mice , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/analysis , Receptors, Immunologic/analysis
13.
BMJ Case Rep ; 13(7)2020 Jul 08.
Article in English | MEDLINE | ID: covidwho-640059

ABSTRACT

A 17-year-old man with osteosarcoma of the proximal humerus was planned for possible limb salvage surgery after standard neoadjuvant chemotherapy. However, during the surgical phase of treatment, the COVID-19 or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) outbreak occurred changing the healthcare landscape due to uncertainty regarding the virus, risk of COVID-19 infection and complications, and implementation of an enhanced community quarantine restricting movement of people within cities. Instead of limb salvage surgery, the patient underwent a forequarter amputation. Exposure to the virus in a high-risk hospital setting was minimised with patient discharge after a short hospital stay and home convalescence monitored by video conferencing. Multidisciplinary sarcoma team meetings with family members and a sarcoma navigator nurse were crucial in managing expectations and deciding on appropriate treatment in the setting of a novel infectious disease causing a pandemic.


Subject(s)
Amputation/methods , Bone Neoplasms , Cisplatin/administration & dosage , Coronavirus Infections , Doxorubicin/administration & dosage , Humerus , Limb Salvage/methods , Osteosarcoma , Pandemics , Pneumonia, Viral , Adolescent , Antineoplastic Agents , Betacoronavirus , Bone Neoplasms/pathology , Bone Neoplasms/therapy , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Humans , Humerus/diagnostic imaging , Humerus/surgery , Magnetic Resonance Imaging/methods , Male , Neoplasm Staging , Osteosarcoma/pathology , Osteosarcoma/therapy , Pandemics/prevention & control , Patient Selection , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , SARS-CoV-2
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