Plain language summary of isatuximab plus carfilzomib, lenalidomide, and dexamethasone for the treatment of people with high-risk newly diagnosed multiple myeloma.

What is this summary about? This is a summary of a publication about the GMMG-CONCEPT study that was published in the Journal of Clinical Oncology in September 2023. The study tested if a combination of cancer drugs (isatuximab plus carfilzomib, lenalidomide, and dexamethasone, or Isa-KRd for short) was a safe treatment for people with high­risk newly diagnosed multiple myeloma. The GMMG-CONCEPT study included participants who had not been treated before and were eligible to receive a procedure called autologous stem cell transplant, as well as participants who were not eligible to receive transplants.How was the study in this summary conducted? This report looked at a total of 125 participants; 99 were transplant-eligible and 26 were transplant-non-eligible. All participants were treated with Isa-KRd. The researchers measured the proportion of people who had 'no detectable levels' of myeloma cells in their body left while on treatment (called minimal residual disease negativity, or MRD negativity for short). The researchers measured the progression-free survival, or the average length of time it took between the participants joining the study until their cancer got worse or they died. The researchers also measured overall survival, which is the total amount of time people lived during the study, even if their cancer got worse. The researchers also monitored for side effects of Isa-KRd in all participants that received at least one treatment.What were the results of the study? At the end of the consolidation therapy (intensified therapy that happens after initial therapy), MRD negativity was observed in the majority of transplant-eligible and transplant non-eligible patients. For many patients, this effect lasted 6 or more months. After more than 3 years in transplant eligible participants and 2 years and 9 months for transplant non-eligible participants, most participants were alive and their disease did not get worse. In both groups, the most common side effects of Isa-KRd treatment were low blood cell counts and infections. Overall, most of the side effects did not last long or were easily treated.What were the main conclusions reported by the researchers? In the GMMG-CONCEPT study, Isa-KRd treatment reduced the number of myeloma cells to no detectable levels in more than two thirds of the participants with high-risk newly diagnosed multiple myeloma.Clinical Trial Registration: NCT03104842 (ClinicalTrials.gov).

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma.

PURPOSE: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity. METHODS: This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10-5, next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS). RESULTS: Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm. CONCLUSION: Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Favorable impact of therapy management by an interactive eHealth system on severe adverse events in patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer treated by palbociclib and endocrine therapy.

BACKGROUND: Oral cancer medications offer advantages but also pose challenges for therapy management and adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the patient's quality of life (QoL) continuously throughout the course of treatment. MATERIAL AND METHODS: AGO-B WSG PreCycle (NCT03220178) is a multicenter, randomized phase IV intergroup trial evaluating the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1) to CANKADO-active arm (supported by CANKADO PRO-React) or CANKADO-inform arm (drug intake documentation only) This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account. RESULTS: While distributions of adverse events (AEs) were similar by arm overall, patients in the CANKADO-active arm had a favorable hazard ratio of 0.67 (95%CI 0.46-0.97; p = 0.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. At 24 months, 22.9% [17.9%-27.8%] of patients in CANKADO-active had suffered an SAE vs. 30.3% [22.6%-38.0%] in CANKADO-inform. AE-related dose reductions affected approximately 20% of patients (CANKADO-active: 18.2%, CANKADO-inform: 21.1%). CONCLUSION: Exploratory safety analysis of PreCycle demonstrates for the first time in a randomized prospective trial that interactive autonomous eHealth-based support has a substantial favorable impact on the risk of SAEs and mitigates their severity for patients with advanced HR+/HER2- breast cancer on oral tumor therapy.

Nivolumab Switch Maintenance Therapy After Tyrosine Kinase Inhibitor Induction in Metastatic Renal Cell Carcinoma: A Randomized Clinical Trial by the Interdisciplinary Working Group on Renal Tumors of the German Cancer Society (NIVOSWITCH; AIO-NZK-0116ass).

BACKGROUND: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined. OBJECTIVE: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. DESIGN, SETTING, AND PARTICIPANTS: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function. INTERVENTION: Intravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis. RESULTS AND LIMITATIONS: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36-4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study. CONCLUSIONS: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC. PATIENT SUMMARY: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.

Five dimensions of cleansing: A holistic view on the facets and importance of skin cleansing.

Cleansing is an important human ritual practised for hygiene, well-being and relaxation over centuries. As part of body care it is often taken for granted, yet its relevance cannot be underestimated. Although cleansing the skin may seem trivial to some, it is accepted, that this fundamental function of skin cleansing products is highly complex, diverse and crucial for a variety of reasons in the personal, public, healthcare and dermatological settings. Employing a comprehensive and strategic approach in viewing cleansing and its rituals, supports innovation, understanding and development. Apart from being a fundamental function, as far as we know, there is no comprehensive presentation of skin cleansing with all its effects besides 'removing dirt'. To our knowledge, comprehensive analyses on the multi-dimensional facets of skin cleansing are either rare or not published. Against this background, we examine the importance of cleansing in terms of function, relevance and concepts. First, the key functions and efficacies of skin cleansing were investigated by literature research. Based on this survey, the functions were analysed, sorted and merged and a novel approach to skin cleansing 'dimensions' was developed. Herewith, we took into consideration the evolution of skin cleansing in terms of concept evolution, complexity and testing methods for cleansing products and their claims. Several multi-dimensional functions of skin cleansing were identified and then established into five skin cleansing dimensions, namely: hygienic and medical importance; socio-cultural and interpersonal relevance; mood, emotion and well-being; cosmetic and aesthetic function; corneobiological interactions. It became obvious, that these five dimensions with their corresponding 11 sub-dimensions, are influenced by each other throughout history by culture and society, technical progress, scientific knowledge and consumer trends. This article presents the enormous complexity of skin cleansing. Skin cleansing has evolved from basic care up to a highly complex and diverse cosmetic product category in terms of technology, efficacy and usage routine(s). In view of future challenges, such as the effects of climate and associated lifestyle changes, the development of skin cleansing will remain an exciting and important topic and thus will finally, again, further increase the complexity of skin cleansing itself.

OBJECTIF: La toilette est un rituel humain important pratiqué depuis des siècles pour l'hygiène, le bien-être et la relaxation. Les soins du corps sont souvent considérés comme allant de soi, mais leur importance ne doit pas être sous-estimée. Bien que le nettoyage de la peau puisse paraître trivial pour certains, il est admis que cette fonction fondamentale des produits de nettoyage de la peau est hautement complexe, variée et cruciale pour diverses raisons dans les contextes de l'hygiène personnelle et publique, de la santé en général et de la dermatologie. Adopter une approche globale et stratégique pour visualiser le nettoyage de la peau et ses rituels permet d'améliorer son innovation, sa compréhension et son développement. En dehors de sa fonction fondamentale, il n'existe pas, à notre connaissance, de présentation complète des effets du nettoyage de la peau au-delà de la simple « élimination des impuretés ¼. D'après ce que nous savons, des analyses complètes sur les facettes multiples du nettoyage de la peau sont rare, voire jamais publiées. Dans ce contexte, nous examinons l'importance du nettoyage en termes de fonction, de pertinence et de concepts. MÉTHODES: Tout d'abord, les fonctions clés et l'efficacité du nettoyage de la peau ont été étudiées en effectuant des recherches dans la littérature. Sur la base de cette enquête, ces fonctions ont été analysées, triées et fusionnées, et une nouvelle approche des différentes « dimensions ¼ du nettoyage de la peau a été développée. Ici, nous avons pris en compte l'évolution du nettoyage de la peau en ce qui concerne l'évolution de ses concepts, sa complexité et les méthodes de test des produits de nettoyage et de leurs caractéristiques. CONCLUSION: Plusieurs fonctions multidimensionnelles de nettoyage de la peau ont été identifiées, puis appliquées à cinq dimensions de nettoyage de la peau, à savoir : L'importance sanitaire et médicale ; la pertinence socioculturelle et interpersonnelle ; l'humeur, l'émotion et le bien-être ; la fonction esthétique et cosmétique ; les interactions cornéobiologiques. Il est devenu évident que ces cinq dimensions, avec leurs onze sous-dimensions respectives, se sont interinfluencées tout au long de l'histoire selon la culture, la société, les progrès techniques, les connaissances scientifiques et les tendances des consommateurs. Cet article présente l'énorme complexité du nettoyage de la peau. Le nettoyage de la peau est passé des soins de base à une catégorie de produits cosmétiques hautement complexes et variés en termes de technologie, d'efficacité et de routine(s) d'utilisation. Compte tenu des défis futurs, comme les effets du climat et les changements de mode de vie associés, le développement du nettoyage de la peau restera un sujet important et passionnant, et finira par augmenter encore davantage la complexité du nettoyage de la peau.

Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Subcutaneous rituximab in patients with diffuse large B cell lymphoma and follicular lymphoma: Final results of the non-interventional study MabSCale.

BACKGROUND: Rituximab has become a standard treatment for non-Hodgkin lymphoma. Clinical studies have demonstrated the efficacy of rituximab in combination with standard chemotherapies in the treatment of follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) patients. This non-interventional study aimed to evaluate the effectiveness and safety of subcutaneous (SC) rituximab in routine clinical practice. METHODS: Adult patients with previously untreated CD20 positive DLBCL or FL who received rituximab SC and chemotherapy as first-line treatment were observed between 07/2014 and 07/2019 at 99 institutions in Germany. Primary endpoint was the (unconfirmed) complete remission (CR/CRu) rate. Primary outcome was analyzed inferentially; other variables were evaluated descriptively. RESULTS: Overall 583 patients (247 FL; 336 DLBCL) were evaluated. CR/CRu rates were 51.4% (95% CI: 45.2; 57.6) in the FL set and 48.5% (95% CI: 43.2; 53.8) in the DLBCL set. Regarding progression-free survival in the FL group, the probability of being event-free was 94.2% in the first year and 86.2% in the second year. An overall response was achieved in 85.8% (FL) and 85.4% patients (DLBCL). Patient satisfaction at the end of study with the time saving simplification of the SC vs. intravenous route was 98% for FL and 97% for DLBCL. 45.3% of FL and 47.0% of DLBCL patients experienced an adverse event of grade ≥3. Serious adverse events of grade ≥3 occurred in 27.9% FL and 32.4% DLBCL patients, with the highest incidences for leucopenia, anemia, nausea, and fatigue. No new safety signals were detected. CONCLUSIONS: The results confirmed the effectiveness and safety of rituximab SC in both the FL and the DLBCL group. Satisfaction of patients and nurses with SC administration was high.

An updated review on efficacy and benefits of sweet almond, evening primrose and jojoba oils in skin care applications.

BACKGROUND: Renewed consumer and industry interest in natural ingredients has led to a large growth of natural cosmetics. This has put pressure on formulation skills and product claims when it comes to using natural compounds. Taking a strategic and comprehensive approach in viewing natural ingredients, including natural oils, as 'active' ingredients rather than just providing for so-called 'natural' claims, aids both innovation and development. Given the ever-increasing consumer demand for natural ingredients, and more importantly the demand for effective natural ingredients including plant oils, it is important for the cosmetic industry to re-evaluate them in this context. METHOD: The objectives of this review are to provide an update of three popular cosmetic plant oils - Sweet Almond, Evening Primrose and Jojoba - in terms of their cosmetic applications as 'active' ingredients. This review highlights the activity of these oils, in the management of dry skin, ageing skin, juvenile skin, atopic dermatitis, scalp conditions and their wider potential. Attention is given to formulation considerations where the content of these oils impacts product oxidation, skin penetration and stratum corneum homeostasis. RESULTS: Benefits of these oils have been well documented both pre-clinically and clinically. Historically, they have been used for hundreds if not thousands of years for their management and treatment of various skin and other ailments. Given the discrepancies in some clinical data presented for a variety of dermatoses, the importance of the choice of oil and how to formulate with them within the context of the epidermal barrier function, skin penetration and toxicity cannot be underestimated. Care should be taken in terms of the quality and stability of theses oils, as well as ensuring best formulation type, if the reported activities of these oils are to be achieved with consistency. Despite discrepancies in the literature and questionable study designs, it is clear that Sweet Almond, Evening Primrose and Jojoba oils do have skin care benefits for both adult and juvenile applications. CONCLUSION: They are effective ingredients for skin care preparations to strengthen stratum corneum integrity, recovery and lipid ratio. Nevertheless, further experimental data are required concerning the impact on stratum corneum physiology and structure.

CONTEXTE: Un regain d'intérêt des consommateurs et du secteur pour les ingrédients naturels a conduit à une forte croissance des cosmétiques d'origine naturelle. Cet engouement a exercé une pression sur les compétences en matière de formulation et les allégations liées aux produits lorsqu'il s'agit d'utiliser des composés naturels. L'adoption d'une approche stratégique et exhaustive axée sur les ingrédients naturels, notamment les huiles naturelles, considérés comme des ingrédients «actifs¼ plutôt que de fournir des allégations liées à des produits dits naturels contribue à l'innovation et au développement. Compte tenu de la demande croissante des consommateurs en ingrédients naturels et qui plus est, de la demande en ingrédients naturels efficaces, dont les huiles végétales, il est important pour le secteur des cosmétiques de les réévaluer dans ce contexte. MÉTHODE: Cette revue vise à actualiser les connaissances ayant trait à trois huiles végétales souvent utilisées comme cosmétiques, à savoir les huiles d'amande douce, d'onagre et de jojoba, dans le cadre des applications cosmétiques où elles jouent un rôle de substances actives. Elle souligne le caractère actif de ces huiles dans la prise en charge de la peau sèche, du vieillissement de la peau, de la peau jeune, de la dermatite atopique, des affections du cuir chevelu et de leur potentiel d'utilisation plus large. Une attention particulière est accordée aux questions relatives à la formulation lorsque la teneur en ces huiles affecte l'oxydation du produit, la pénétration dans la peau et l'homéostasie de la couche cornée. RÉSULTATS: Les bénéfices des huiles examinées apparaissent bien documentés, tant au niveau clinique que préclinique. Historiquement, ces huiles sont utilisées depuis des centaines, voire des milliers d'années, pour la prise en charge et le traitement de diverses affections cutanées et extra-cutanées. Compte tenu des divergences parmi certaines des données cliniques présentées pour de multiples dermatoses, il est important de ne pas sous-estimer l'importance du choix de l'huile et de sa formulation eu égard à la fonction barrière de l'épiderme, à la pénétration cutanée et à la toxicité. Des précautions doivent être prises en termes de qualité et de stabilité de ces huiles, ainsi que pour garantir une formulation choisie au mieux, si les activités signalées de ces huiles soient obtenues avec cohérence. Malgré les divergences d'une étude à l'autre et les conceptions critiquables de certaines études, il apparaît clairement que les huiles d'amande douce, d'onagre et de jojoba apportent des bénéfices tant dans leurs applications pour adultes que pour enfants. CONCLUSION: Ces huiles constituent des ingrédients efficaces pour les préparations de soins de la peau en termes de renforcement de l'intégrité de la couche cornée, ainsi que de l'amélioration de sa récupération et de son rapport lipidique. Toutefois, d'autres données expérimentales demeurent nécessaires en ce qui concerne leur impact sur la physiologie et la structure de la couche cornée.

A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung).

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2-2.0) months vs. 1.6 (1.4-6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3-5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0-33.0) months vs. nivolumab 6.9 (4.6-24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.

Sequential high-dose cytarabine and mitoxantrone (S-HAM) versus standard double induction in acute myeloid leukemia-a phase 3 study.

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = "dose-dense") and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = "standard"). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CRi) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

The Relation of pH and Skin Cleansing.

Several epidermal barrier functions, like skin barrier regeneration and antimicrobial response, are related to the acidic nature of the skin surface pH (ss-pH). However, the epidermal acidification is known to be fragile and it is commonly accepted that cosmetic products, especially soaps and skin cleansing products, can induce significant changes in ss-pH. As a consequence, epidermal barrier function and skin microflora are affected negatively. ss-pH even increases after a single washing procedure or after rinsing the skin with water alone. The skin pH recovery needs time up to several hours before it can reach the physiological level. For cosmetic-relevant skin conditions, skin disorders and specific consumer groups, maintaining of the acidic ss-pH is beneficial for epidermal physiology and cutaneous microflora. In this context, cleansing and skin care products with a pH level of 4.0-5.0 may be helpful. In addition, combining the acidic product pH level with the ideal mix of surfactants, thereby enhancing product compatibility and minimizing skin irritation and intolerance, is a major challenge for the future. Beyond innovative cleansing technology, further multifaceted cosmetic research is a prerequisite to get deeper knowledge on the interrelation of product pH level, surfactant composition and corneobiology.

Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab-Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results.

Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response. Methods: Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided. Results: A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01). Conclusions: This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.

Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study.

Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.

The transcriptional regulators SteA and StuA contribute to keratin degradation and sexual reproduction of the dermatophyte Arthroderma benhamiae.

Most superficial fungal infections are caused by dermatophytes, a specialized group of filamentous fungi which exclusively infect keratinized host structures such as hair, skin and nails. Since little is known about the molecular basis of pathogenicity and sexual reproduction in dermatophytes, here we functionally addressed two central transcriptional regulators, SteA and StuA. In the zoophilic species Arthroderma benhamiae a strategy for targeted genetic manipulation was recently established, and moreover, the species is teleomorphic and thus allows performing assays based on mating. By comparative genome analysis homologs of the developmental regulators SteA and StuA were identified in A. benhamiae. Knock-out mutants of the corresponding genes as well as complemented strains were generated and phenotypically characterized. In contrast to A. benhamiae wild type and complemented strains, both mutants failed to produce sexual reproductive structures in mating experiments. Analysis of growth on keratin substrates indicated that loss of steA resulted in the inability of ΔsteA mutants to produce hair perforation organs, but did not affect mycelia formation during growth on hair and nails. By contrast, ΔstuA mutants displayed a severe growth defect on these substrates, but were still able to produce hair perforations. Hence, formation of hair perforation organs and fungal growth on hair per se are differentially regulated processes. Our findings on the major role of SteA and StuA during sexual development and keratin degradation in A. benhamiae provide insights into their role in dermatophytes and further enhance our knowledge of basic biology and pathogenicity of these fungi.

Candida species Rewired Hyphae Developmental Programs for Chlamydospore Formation.

Chlamydospore formation is a characteristic of many fungal species, among them the closely related human-pathogenic dimorphic yeasts Candida albicans and C. dubliniensis. Whereas function and regulation of filamentation are well-studied in these species, the basis of chlamydospore formation is mostly unknown. Here, we investigate the contribution of environmental and genetic factors and identified central proteins involved in species-specific regulation of chlamydosporulation. We show that specific nutrient levels strongly impact chlamydospore initiation, with starvation favoring sporulation and elevated levels of saccharides or peptone inhibiting it. Thresholds for these nutritional effects differ between C. albicans and C. dubliniensis, which explain species-specific chlamydospore formation on certain diagnostic media. A C. albicans nrg1Δ mutant phenocopied C. dubliniensis, putting Nrg1 regulation at the basis of species-specific chlamydospore formation under various conditions. By screening a series of potential chlamydospore regulators, we identified the TOR and cAMP pathways as crucial for sporulation. As rapamycin treatment blocked chlamydosporulation, a low basal Tor1 activity seems to be essential. In addition, TOR effector pathways play an important role, and loss of the NCR (nitrogen catabolite repression) gene regulators Gat1 and Gln3 reduced chlamydospore formation. A severe reduction was seen for a C. albicans gcn4Δ deletion strain, implicating a link between regulation of amino acid biosynthesis and chlamydospore development. On the other hand, deletion of the GTPase gene RAS1 and the adenylyl cyclase gene CYR1 caused a defect in chlamydospore formation that was mostly rescued by cAMP supplementation. Thus, cAMP-signaling is a second major pathway to control chlamydospore production. Finally, we confirmed light exposure to have a repressive effect on chlamydosporulation. However, permanent illumination only reduced, but not abolished chlamydospore production of C. albicans whereas C. dubliniensis sporulation was unaffected. In summary, we describe novel environmental factors which determine chlamydosporulation and propose a first model for the regulatory network of chlamydospore formation by different Candida species.

Development and validation of the Patient Benefit Index for the dermatocosmetic treatment of aged skin.

This study aimed to develop and validate an instrument for the assessment of patient-relevant benefit in dermatocosmetic treatment, i.e., skin care, of aged skin. Based on an open item collection with 33 elderly persons, items on patient-relevant treatment goals were collected. An expert panel selected 20 items to be most relevant and feasible for the questionnaire named Patient Benefit Index for Aged Skin (PBI-AS). The instrument, which assesses goal importance and achievement, was tested in a cognitive debriefing and validated in a longitudinal study (n = 80) along with the Dry Skin Area and Severity Index (DASI) and the Dermatology Quality of Life Index (DLQI) as convergent validation criteria. The cognitive debriefing showed the good practicability and feasibility of the instrument. Significant correlation with change in DASI (r = -0.527; p < 0.001) supports convergent validity of the PBI-AS. By contrast, correlation with DLQI was poor, indicating the different constructs. The PBI-AS is a valid and feasible tool for the patient-centered assessment of dermatocosmetic treatment benefit in aged skin.

HapX Mediates Iron Homeostasis in the Pathogenic Dermatophyte Arthroderma benhamiae but Is Dispensable for Virulence.

For many pathogenic fungi, siderophore-mediated iron acquisition is essential for virulence. The process of siderophore production and further mechanisms to adapt to iron limitation are strictly controlled in fungi to maintain iron homeostasis. Here we demonstrate that the human pathogenic dermatophyte Arthroderma benhamiae produces the hydroxamate siderophores ferricrocin and ferrichrome C. Additionally, we show that the iron regulator HapX is crucial for the adaptation to iron starvation and iron excess, but is dispensable for virulence of A. benhamiae. Deletion of hapX caused downregulation of siderophore biosynthesis genes leading to a decreased production of siderophores during iron starvation. Furthermore, HapX was required for transcriptional repression of genes involved in iron-dependent pathways during iron-depleted conditions. Additionally, the ΔhapX mutant of A. benhamiae was sensitive to high-iron concentrations indicating that HapX also contributes to iron detoxification. In contrast to other pathogenic fungi, HapX of A. benhamiae was redundant for virulence and a ΔhapX mutant was still able to infect keratinized host tissues in vitro. Our findings underline the highly conserved role of the transcription factor HapX for maintaining iron homeostasis in ascomycetous fungi but, unlike in many other human and plant pathogenic fungi, HapX of A. benhamiae is not a virulence determinant.

Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML.

Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (-Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), -Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p ≤ 0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5-93.1), t(v; 22) 87 % (77.2-94.3), -Y 89.0 % (76.7-97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4-100) and major route 52.2 % (28.2-75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.