KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy. PATIENTS AND METHODS: KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study. RESULTS: On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes. CONCLUSIONS: This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients.

BACKGROUND: Data on temozolomide (TEM) and irinotecan (IRI) activity in recurrent Ewing sarcoma (EWS), especially in adult patients, are limited. METHODS: Patients receiving TEM 100 mg/m2/day oral, and IRI 40 mg/m2/day intravenous, days 1-5, every 21 days, were included in this multi-institutional retrospective study. Disease control rate (DCR) [overall response rate (ORR) [complete response (CR) + partial response (PR)] + stable disease (SD)], 6-months progression-free survival (6-mos PFS) and 1-year overall survival (OS) were assessed. RESULTS: The median age of the 51 patients was 21 years (range 3-65 years): 34 patients (66%) were adults (≥18 years of age), 24 (48%) had ECOG 1 and 35 (69%) were presented with multiple site recurrence. TEMIRI was used at first relapse/progression in 13 (25%) patients, while the remainder received TEMIRI for second or greater relapse/progression. Fourteen (27%) patients had received prior myeloablative therapy with busulfan and melphalan. We observed five (10%) CR, 12 (24%) PR and 19 (37%) SD, with a DCR of 71%. 6-mos PFS was 49% (95% CI 35-63) and it was significantly influenced by ECOG (6-mos PFS 64% [95% CI 45-83] for ECOG 0, 34% [95% CI 14-54] for ECOG ≥1; p = .006) and LDH (6-mos PFS 62% [95% CI 44-79] for normal LDH, 22% [95% CI 3-42] for high LDH; p = .02), with no difference according to line of treatment, age and metastatic pattern. One-year OS was 55% (95% CI 39-70), with RECIST response (p = .001) and ECOG (p = .0002) independently associated with outcome. Grade 3 and 4 toxicity included neutropenia in 12% of patients, thrombocytopenia in 4%, diarrhea in 4%. CONCLUSIONS: This series confirms the activity of TEMIRI in both adults and pediatric patients. This schedule offers a 71% DCR, independently of the line of chemotherapy. Predictive factors of response are ECOG and LDH.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Commitment, partnerships and operational research: three priorities for 11 EMR countries to achieve TB elimination.

BACKGROUND: In 2022, 11 of 22 Member States of the WHO Eastern Mediterranean Region (EMR) had an estimated TB incidence of <20 cases per 100,000 population. We assessed preparedness for elimination and provided recommendations to pursue the process. METHODS: We surveyed 11 EMR national TB programme managers and collected information on eight TB elimination framework domains using a close-ended data collection tool. We compiled, consolidated and validated data, including a virtual consultation before triangulating data with other sources. RESULTS: Implementation was sufficient (≥74%) for 5 of 8 domains, highest for TB infection management, TB preventive treatment, laboratory service, drug management, drug-resistant TB and TB-HIV collaboration (89%, 83% and 78%, respectively). Countries ranked lowest for commitment (73%), operational research and infection control (63%), and partnership/collaborations (41%). Five countries reached >80% when consolidating the responses, reaching sufficient from all domains. Two reached <50%. CONCLUSION: Key identified obstacles to TB elimination in EMR were insufficient commitment/financing, sub-optimal partnerships/collaborations and operational research calling for 1) all-stakeholder-inclusive, sustainably funded TB elimination plans, 2) cost-effective tools to exchange strategic information and build operational research capacity, and 3) improved collaboration.

CONTEXTE: En 2022, 11 des 22 États membres de la Région de la Méditerranée orientale de l'OMS avaient une incidence de la TB estimée à moins de 20 cas pour 100 000 habitants. Nous avons évalué l'état de préparation à l'élimination et formulé des recommandations pour poursuivre le processus. MÉTHODES: Nous avons interrogé 11 responsables de programmes nationaux de lutte contre la TB dans la région de la Méditerranée orientale et recueilli des informations sur huit domaines du cadre d'élimination de la TB à l'aide d'un outil de collecte de données à questions fermées. Nous avons compilé, consolidé et validé les données, y compris lors d'une consultation virtuelle, avant de les trianguler avec d'autres sources. RÉSULTATS: La mise en œuvre était suffisante (≥74%) pour 5 des 8 domaines, les plus élevés étant la gestion de l'infection tuberculeuse, le traitement préventif de la TB, les services de laboratoire, la gestion des médicaments, la TB pharmacorésistante et la collaboration TB-VIH (89%, 83% et 78%, respectivement). Les pays se sont classés au dernier rang pour l'engagement (73%), la recherche opérationnelle et la lutte contre l'infection (63%) et le partenariat/la collaboration (41%). Cinq pays ont atteint >80% lors de la consolidation des réponses, atteignant un niveau suffisant dans tous les domaines. Deux pays ont atteint un taux de réponse inférieur à 50%. CONCLUSION: Les principaux obstacles à l'élimination de la TB dans les pays de l'Union européenne sont un engagement/un financement insuffisant, des partenariats/collaborations sous-optimaux et une recherche opérationnelle nécessitant 1) des plans d'élimination de la TB incluant toutes les parties prenantes et bénéficiant d'un financement durable, 2) des outils rentables permettant d'échanger des informations stratégiques et de renforcer les capacités de recherche opérationnelle, et 3) une meilleure collaboration.

TB and interstitial lung disease: a systematic review and meta-analysis.

To determine the frequency of TB among patients with interstitial lung diseases (ILDs).We performed a comprehensive search in the PubMed/Medline, EMBASE and Scopus databases up to 1 August 2023 of studies reporting on the prevalence of TB among patients with ILDs.Twelve studies comprising 3,817 patients with ILD were found: the pooled prevalence of TB among ILD patients was 11.0% (95% CI 5.4-21.0). In the subgroup analysis, the TB rate among patients with silicosis and idiopathic pulmonary fibrosis (IPF) was respectively 35.6% (95% CI 32.6-38.8) and 4.4% (95% CI 3.6-5.3) (P = 0.00). The frequency of TB among ILD patients was higher in high TB burden countries than in low/intermediate-burden countries: 26.3%, 95% CI 17.7-37.3 vs. 4.9%, 95% CI 3.3-7.2; P = 0.00.This study shows the frequency of TB among ILD patients. The meta-analysis reveals a significantly increased prevalence of TB among ILD patients with silicosis compared to IPF, and among individuals in high TB burden countries than in those with low/intermediate burden. The study results can help physicians and policymakers make efficient decisions for prompt screening and anti-TB treatment initiation in ILD patients..

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Vaccination in post-tuberculosis lung disease management: A review of the evidence.

INTRODUCTION AND OBJECTIVES: Post-tuberculosis lung disease (PTLD), as other chronic respiratory disorders, may have infectious complications; some of them can be prevented with vaccinations. So far, no document has discussed the potential role of vaccination in PTLD. Therefore, the objective of this review was to describe vaccination recommendations to prevent infections potentially capable of complicating PTLD. MATERIALS AND METHODS: A non-systematic review of the literature was conducted. The following keywords were used: tuberculosis, vaccination, vaccines and PTLD. PubMed/MEDLINE and Embase were used as the search engine, focusing on English-language literature only. RESULTS: We identified 9 vaccines potentially useful in PTLD. Influenza, pneumococcal and anti-COVID-19 vaccinations should be recommended. Patients with PTLD can also benefit from vaccination against shingles. Vaccination against pertussis is mainly relevant during childhood. Diphtheria, tetanus and measles vaccination are recommended for general population and should be considered in patients with PTLD not previously vaccinated. Tdap (Tetanus, diphtheria, and pertussis) booster should be repeated in every adult every ten years. Vaccination against BCG retains its importance during early childhood in countries where TB is endemic. CONCLUSIONS: Vaccination deserves to be considered among the strategies to prevent and/or mitigate PTLD complications. Further evidence is necessary to better understand which vaccines have the greatest impact and cost-benefit.

A systematic review of the costs of diagnosis for multidrug-resistant/extensively drug-resistant TB in different settings.

BACKGROUND: We performed an analysis of the cost and relative merits of different strategies for the diagnosis of multidrug-resistant/extensively drug-resistant TB (MDR/XDR-TB) in different settings.METHODS: We systematically reviewed the published evidence on cost/cost-effectiveness of rapid MDR/pre-XDR-TB and other methods for XDR-TB testing up to September 2022. PRISMA guidelines were followed. Collected data were analysed using Stata v17 software. Cost data were reported in USD ($) and summarised by mean, standard deviation, and range. Country income level was defined according to the World Bank country classification. Three simplified scenarios were also used to explore testing implications, based on low, intermediate and high TB incidence.RESULTS: Of 157 records, 25 studies were included with 24 reporting the cost of Xpert/RIF and two that evaluated the implementation of the MTBDRplus test. The total rapid test cost ranged from $12.41-$218, including $1.13-$74.60 for reagents/consumables and $0.40-$14.34 for equipment.CONCLUSION: The cost of MDR/XDR-TB diagnostics is lower in low resource settings. However, the cost-effective implementation of MDR/XDR-TB diagnostic algorithms requires careful consideration of local resources to avoid missed identification and the use of inappropriate regimen.

Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice' care for the diagnosis, treatment and prevention of post-COVID-19 lung disease.METHODS: A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified; 45 completed a Delphi process. A 5-point Likert scale indicated level of agreement with the draft standards. The final version was approved by consensus (with 100% agreement).RESULTS: Four clinical standards were agreed for patients with a previous history of COVID-19: Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ≥4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to an individual patient's needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session.CONCLUSION: This is the first consensus-based set of clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. Our aim is to improve patient care and QoL by guiding clinicians, programme managers and public health officers in planning and implementing a PR programme to manage post-COVID-19 lung disease.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study.

PURPOSE: After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. EXPERIMENTAL DESIGN: Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided. RESULTS: Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥ 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. CONCLUSIONS: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

TB and MDR/XDR-TB in European Union and European Economic Area countries: managed or mismanaged?

In spite of the growing awareness of emerging drug-resistant Mycobacterium tuberculosis, the extent of inappropriate tuberculosis (TB) case management may be underestimated, even in Europe. We evaluated TB case management in the European Union/European Economic Area countries, with special focus on multidrug-resistant (MDR) and extensively drug-resistant (XDR)-TB, using a purposely developed, standardised survey tool. National reference centres in five countries representing different geographical, socioeconomic and epidemiological patterns of TB in Europe were surveyed. 40 consecutive, original clinical TB case records (30 MDR/XDR-TB cases) were reviewed in each of the five countries. The findings were recorded and, through the survey tool, compared with previously agreed and identified international standards. Deviations from international standards of TB care were observed in the following areas: surveillance (no information available on patient outcomes); infection control (lack of respiratory isolation rooms/procedures and negative-pressure ventilation rooms); clinical management of TB, MDR-TB and HIV co-infection (inadequate bacteriological diagnosis, regimen selection and treatment duration); laboratory support; and diagnostic/treatment algorithms. Gaps between present international standards of care and the management of MDR/XDR-TB patients were identified. Training, increased awareness, promotion of standards and allocation of appropriate resources are necessary to ensure appropriate care and management as well as to prevent further emergence of drug resistance.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Feasibility of bremsstrahlung dosimetry for direct dose estimation in patients undergoing treatment with 90Y-ibritumomab tiuxetan.

PURPOSE: Radioimmunotherapy with (90)Y-ibritumomab tiuxetan has been used successfully used in the treatment of CD20-positive non-Hodgkin's lymphoma (NHL). Pretherapy imaging with (111)In-ibritumomab tiuxetan has been used in provisional dosimetry studies. Posttherapy imaging of (90)Y-ibritumomab tiuxetan for clinical use is appealing as it would simplify the data acquisition process and allow measurements of actual doses absorbed during treatment. METHODS: The study included 29 patients with non-Hodgkin's lymphoma, of whom 16 (group I) received a pretherapy (111)In-ibritumomab tiuxetan diagnostic study and (90)Y-ibritumomab tiuxetan treatment 1 week later, and 13 (group II) received only (90)Y-ibritumomab tiuxetan treatment. Planar imaging and blood sampling were performed in all patients. The doses absorbed by organs at risk were calculated using a whole-body average attenuation correction factor (relative dosimetry approach) and, in the case of the (111)In-ibritumomab tiuxetan image sets, also using organ-specific attenuation correction factors (absolute dosimetry method). Red marrow absorbed doses were based on gamma counting of blood samples. RESULTS: The estimated red marrow absorbed doses from (111)In and (90)Y data were equivalent. In all cases, the doses absorbed by organs at risk were found to be within prescribed limits. The relative dosimetry approach applied to both the (90)Y and (111)In data significantly underestimated the doses relative to those obtained with the (111)In absolute dosimetry method which is generally accepted as the reference method (MIRD 16). In the case of (111)In, the relative dosimetry approach values were highly correlated (R(2) = 0.61) with the reference method values. Relative dosimetry estimates may be adjusted multiplying by a correction factor of 2.8. The (90)Y-ibritumomab tiuxetan relative dosimetry data correlated poorly with the reference method values (R (2) = 0.02). CONCLUSION: Based on patient-specific dosimetry, the administered activity may be increased by an average factor of 2.4, indicating that most patients could be undertreated. The relative dosimetry approach based on planar imaging largely underestimates doses relative to reference values. Dosimetry based on planar bremsstrahlung imaging is not a dependable alternative to (111)In dosimetry.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Clinical standards for drug-susceptible pulmonary TB.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Tuberculosis and COVID-19 interaction: A review of biological, clinical and public health effects.

Evidence is accumulating on the interaction between tuberculosis (TB) and COVID-19. The aim of the present review is to report the available evidence on the interaction between these two infections. Differences and similarities of TB and COVID-19, their immunological features, diagnostics, epidemiological and clinical characteristics and public health implications are discussed. The key published documents and guidelines on the topic have been reviewed. Based on the immunological mechanism involved, a shared dysregulation of immune responses in COVID-19 and TB has been found, suggesting a dual risk posed by co-infection worsening COVID-19 severity and favouring TB disease progression. The available evidence on clinical aspects suggests that COVID-19 happens regardless of TB occurrence either before, during or after an active TB diagnosis. More evidence is required to determine if COVID-19 may reactivate or worsen active TB disease. The role of sequeale and the need for further rehabilitation must be further studied Similarly, the potential role of drugs prescribed during the initial phase to treat COVID-19 and their interaction with anti-TB drugs require caution. Regarding risk of morbidity and mortality, several risk scores for COVID-19 and independent risk factors for TB have been identified: including, among others, age, poverty, malnutrition and co-morbidities (HIV co-infection, diabetes, etc.). Additional evidence is expected to be provided by the ongoing global TB/COVID-19 study.

Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study.

BACKGROUND: Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). PATIENTS AND METHODS: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons. RESULTS: Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). CONCLUSIONS: Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

TB management in the European Union/European Economic Area: a multi-centre survey.

BACKGROUND: Essential TB care in the European Union/European Economic Area (EU/EEA) comprises 21 standards for the diagnosis, treatment and prevention of TB that constitute the European Union Standards for Tuberculosis Care (ESTC).METHODS: In 2017, we conducted an audit on TB management and infection control measures against the ESTC standards. TB reference centres in five EU/EEA countries were purposely selected to represent the heterogeneous European TB burden and examine geographic variability.RESULTS: Data from 122 patients, diagnosed between 2012 and 2015 with multidrug-resistant TB (n = 49), extensively drug-resistant TB (XDR-TB) (n = 11), pre-XDR-TB (n = 29) and drug-susceptible TB (n = 33), showed that TB diagnosis and treatment practices were in general in agreement with the ESTC.CONCLUSION: Overall, TB management and infection control practices were in agreement with the ESTC in the selected EU/EEA reference centres. Areas for improvement include strengthening of integrated care services and further implementation of patient-centred approaches.