Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck

Background: Radiation dermatitis occurs to some degree in most patients receiving radiotherapy, with or without chemotherapy. Patients with squamous cell carcinoma of the head and neck (SCCHN) who receive radiotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, may develop a characteristic acne-like rash in addition to dermatitis. Design: An advisory board of 11 experienced radiation oncologists, medical oncologists and dermatologists discussed the management options for skin reactions in patients receiving EGFR inhibitors and radiotherapy for SCCHN. Skin toxicity was categorised according to the National Cancer Institute—Common Terminology Criteria for Adverse Events (version 3) grading. Results: Both general and grade-specific approaches for the management of dermatitis in this patient group are presented. It was concluded that where EGFR inhibitor-related acne-like rash and dermatitis coexist within irradiated fields, management should be based on the grade of dermatitis: for grade 1 (or no dermatitis), treatment recommendations for EGFR-related acne-like rash outside irradiated fields should be followed; for grades 2 and above, treatment recommendations for dermatitis were proposed. Conclusions: This paper presents comprehensive consensus guidelines for the treatment of dermatitis in patients with SCCHN receiving EGFR inhibitors in combination with radiotherap

Assessment of treatment outcomes of multidrug-resistant tuberculosis patients in D R Congo: A study based on drug regimens used between 2007 to 2017: Évaluation des issues thérapeutiques des patients atteints de la tuberculose à bacilles multi résistants : étude basée sur les régimes de médicaments utilisés en République Démocratique du Congo de 2007 à 2017

Context. Little is known about therapeutic successes in MDR-TB patients under regimens containing second-line molecules. The present study aimed to assess therapeutic outcomes in patients under therapeutic regimens applied in DR Congo. Methods. This historical cohort study has included confirmed MDR-TB patients who received treatment between 2007 and 2017 in 218 TB centers in DR Congo. Treatment outcome and survival at 36 months were analyzed using Zscore and chi square test. Kaplan-Meier method was performed to describe survival and Log Rank test helped in comparing curve based on the therapeutical regimen. Factors associated with therapeutic success and mortality predictors were assessed using multivariate logistic regression and Cox regression analysis, respectively. Results. The therapeutic success in the study group (n=1,724) was 72% (range 68-74%) for all regimen combined. The average death rate was 12.8% although the group of patients receiving Cyclosérine and Ofloxacine was the most affected (16%). The death rate was significantly higher in patients living in urban areas (15.2% versus 14.9%, p = 0.013) and also among MDR-TB/HIV co-infected patients (28.4% vs 15.7%, p<0.001) patients. The median survival of the study group was 722.7 days compared to 601.1 days for MDR-TB/HIV co-infected patients, and 736.7 days for HIV negative patients (p<0.001). Conclusion. Therapeutic successes are significant for the short regimen. However, the death rate remains high when Cycloserine and Ofloxacin are included in the regimen. The predictors of mortality are HIV infection and living in urban areas. Contexte. L’issue thérapeutique de la tuberculose multi résistante (TB-MR) sous les molécules de deuxième intention n’est pas très bien connue. La présente étude a évalué les régimes thérapeutiques appliqués, en termes de succès thérapeutique et de survie. Méthodes. L’étude de cohorte historique a inclu les patients TB-MR confirmés et traités entre 2007 et 2017 dans 218 centres de tuberculose en RD Congo. L’issue thérapeutique et la survie à 36 mois ont été analysées. Le score Z ou le test de chi carré ont comparé des issues. La méthode de Kaplan-Meier a décrit les courbes de survie et le test de Log Rank a comparé la survie en fonction du regime therapeutique. Les facteurs associés au succès thérapeutique et les prédicteurs de mortalité ont été analysés respectivement, par l’analyse multivariée de régression logistique et de Cox. Résultats. Dans le groupe étudié (n=1724), le succès thérapeutique a été de 72% (68-74%) pour l’ensemble des régimes. Le taux était plus élevé pour le régime court (74%) et plus faible pour le régime contenant la Cyclosérine et l’Ofloxacine (68%). La moyenne de décès était de 12,8% ; mais plus élevée dans le groupe sous regime contenant la Cyclosérine et l’Ofloxacine (16%). Le taux de décès était significativement plus élevé en milieu urbain (15,2% versus 14,9 %, p = 0,013) et également chez les sujets co-infectés par la MDR-TB  et le VIH (28.4% vs 15.7%, p <0,001). La survie médiane dans le groupe était de 722,7 jours contre 601,1 jours chez les co-infectés MDR-TB/VIH, et de 736,7 jours) chez les patients VIH négatifs (p<0,001). Conclusion. Les succès thérapeutiques sont acceptables en particulier, pour le régime court ; toutefois, le taux de décès demeure encore très élevé dans le groupe sous Cyclosérine et Ofloxacine. Les prédicteurs de mortalité sont l’infection à VIH et la vie citadine. &nbsp

Tendances de la tuberculose pulmonaire bactériologiquement confirmée et issues thérapeutiques en République Démocratique du Congo : 2007-2017: Trends of bacteriologically confirmed pulmonary tuberculosis and treatment outcomes in Democratic Republic of the Congo: 2007-2017

Context and objective. DR Congo ranks among high burden countries for tuberculosis. However, the real incidence of the disease is unknown. The study aimed to describe the trends in the estimated incidence of the bacteriologically confirmed pulmonary TB and therapeutic outcomes of patients. Methods. A retrospective analysis of data from TB patients recorded during the period of 2007 to 2017 through all the country. Linear regtression model and z-score helped to assess the year to year variations in notification rate and treatment outcomes. Results. A total of 884,458 patients were enrolled including 820,858 new patients (NP TP+) and 63,600 with a previous TB treatment. The increase reached 28.95% during this decade. The annual average inrease was of 2, 41% +/- 3, and 28 % for NP TP+ and of 5, 7% +/-0.26 for default patients. Treatment outcome assessment included 848,163 patients among them, 789, 716 NP TP+ and 58,447 with a previous TB treatment. The success rate was 88% in the former group, of 70% in those with relapse, 64.3% in patients with failure and 67.8% in the group of ancient defaulters. A total of 70,515 (8.3%) patients remained smear positive. Conclusion. The study shows an increase in the incidence of reported TP+ patients with a treatment outcome reaching the WHO’s expectations. However the high proportion of smear positive patients suggests a high risk of further acquired TB resistance. Contexte et objectifs. La République Démocratique du Congo compte parmi les pays à lourd fardeau pour la tuberculose (TB), l’incidence réelle de la maladie n’est pas formellement connue. La présente étude vise à décrire les tendances de l’incidence notifiée des patients atteints de tuberculose pulmonaire bactériologiquement confirmée (TP+) et leurs issues thérapeutiques. Méthodes. Cette étude documentaire, analyse les données des patients diagnostiqués et traités pour tuberculose de 2007 à 2017 en RDC. L’incidence notifiée des patients TP+, le taux d’accroissement annuel, les issues thérapeutiques ont été recherchés. Les variations du nombre de patients sont exprimées par les proportions. Les tendances sont présentées à travers les courbes de régression linéaire. Les issues thérapeutiques sont comparées à l’aide du z-score avec un seuil significatif de p˂ 0,05. Résultats. Au total 884 458 patients TP+ ont été rapportés, dont 820 858 nouveaux patients (NP TP+) et 63 600 déjà traités. Le taux d’accroissement au cours de cette décade était de 28,95%, soit de 66099 en 2007 à 93767 en 2017 pour les NP TP+. L’augmentation annuelle moyenne était de 2,41% +/- 3,28 pour les NP TP+ et de 5,7% +/- 0,26 par an pour les rechutes. La notification des échecs de traitement initial et repris après abandon de traitement ont une tendance à la baisse. L’évaluation thérapeutique de tous les cas cumulés a concerné 848 163 patients dont 789 716 NP TP+ et 58447 en retraitement. Le succès thérapeutique était de 88,0 % pour les NP TP+ et 70,0 % pour les rechutes, de 64,3 % pour les échecs et de 67,8% pour les repris en traitement après abandon. En somme 70 515 (8,3%) patients ont gardé des expectorations positives. Conclusion. Cette étude montre une tendance à la hausse de notification des cas incidents dont l’issue de traitement répond aux standards de l’OMS. En outre, un nombre des personnes demeurent porteurs de germes persistants précurseurs d’une TB pharmacorésistante acquise

Determinants of patients' adherence to malaria treatment in the Democratic Republic of the Congo

(1) Background: Malaria heavily affects the Democratic Republic of the Congo (DRC) despite the use of effective drugs. Poor adherence to malaria treatment may contribute to this problem. (2) Methods: In one rural and one urban health area in each of the 11 former provinces of the DRC, all households with a case of malaria in the 15 days preceding the survey were selected and the patients or caregivers were interviewed. Adherence to malaria treatment was assessed by self-declaration about its completion. Logistic regression was used to assess predictors. (3) Results: 1732 households participated. Quinine was the most used drug; adherence to artesunate-amodiaquine was the lowest and the main reason for treatment discontinuation was adverse reactions. Predictors of adherence were residence in an urban area, university education, catholic religion, and adoption of recommended behaviour towards a malaria case. Adherence was significantly lower for responders who obtained information on antimalarials from Community Health Workers (CHW). (4) Conclusions: Usage of recommended drugs and adherence to malaria treatment need to be promoted, especially in rural areas, and CHW involvement needs to be improved. Awareness messages need to be made accessible and comprehensible to poorly educated populations and churches need to be involved

Knowledge of antimalarials and health seeking behaviour of households in case of suspected malaria in Democratic Republic of the Congo

(1) Background: The Democratic Republic of the Congo (DRC) is heavily affected by malaria despite availability of effective treatments. Ignorance and unrecommended behaviour toward a suspected malaria case in households may contribute to this problem. (2) Method: In communities of one rural and one urban Health Centres in each of the 11 previous provinces of DRC, all households with a case of malaria in the 15 days prior to the survey were selected. The patient or caregiver (responder) were interviewed. Logistic regression was used to assess predictors of knowledge of recommended antimalarials and adequate behaviour in case of suspected malaria. (3) Results: 1732 households participated; about 62% (1060/1721) of the responders were informed about antimalarials, 70.1% (742/1059) knew the recommended antimalarials and 58.6% (995/1699) resorted to self-medication. Predictors of knowledge of antimalarials were education to secondary school or university, information from media and smaller households. Predictors of good behaviour were Catholic religion and smaller households. Receiving information from Community Health Workers (CHWs) failed to be determinants of knowledge or adequate behaviour. (4) Conclusion: malaria control in DRC is hampered by ignorance and non-adherence to national recommendations. These aspects are influenced by unsuccessful communication, size of households and level of education

Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score.

PURPOSE: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS: Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS: Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION: Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC

Natural products as starting points for future anti-malarial therapies: going back to our roots?

Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal medicinal products already used by the community. This first step forms a solid basis of observations, before moving to in vivo pharmacological characterization and ultimately identifying the active ingredient. A large part of the population uses herbal medicinal products despite limited numbers of well-controlled clinical studies. Increased awareness by the regulators and public health bodies of the need for safety information on herbal medicinal products also lends support to obtaining more clinical data on such products. Conclusions The relative paucity of new herbal medicinal product scaffolds active against malaria results discovered in recent years suggest it is time to re-evaluate the ‘smash and grab’ approach of randomly testing purified natural products and replace it with a patient-data led approach. This will require a change of perspective form many in the field. It will require an investment in standardisation in several areas, including: the ethnopharmacology and design and reporting of clinical observation studies, systems for characterizing anti-malarial activity of patient plasma samples ex vivo followed by chemical and pharmacological characterisation of extracts from promising sources. Such work falls outside of the core mandate of the product development partnerships, such as MMV, and so will require additional support. This call is timely, given the strong interest from researchers in disease endemic countries to support the research arm of a malaria eradication agenda. Para-national institutions such as the African Network for Drugs and Diagnostics Innovation (ANDi) will play a major role in facilitating the development of their natural products patrimony and possibly clinical best practice to bring forward new therapeutics. As in the past, with quinine, lapinone and artemisinin, once the activity of herbal medicinal products in humans is characterised, it can be used to identify new molecular scaffolds which will form the basis of the next generation of anti-malarial therapies.</p

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study

BACKGROUND: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe. METHODS: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing. FINDINGS: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57–77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19–0·61) and 28 days (0·34 [0·16–0·79]), complications due to COVID-19 (0·26 [0·17–0·46]), and hospitalisation due to COVID-19 (0·17 [0·09–0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15–0·34]) and oxygen therapy (0·24 [0·14–0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase. INTERPRETATION: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19. FUNDING: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust