Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC).

BACKGROUND: Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. METHODS: In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. RESULTS: In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DISCUSSION: Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

Early autologous and/or allogeneic stem cell transplantation for adult patients with advanced stage T- lymphoblastic leukemia/lymphoma or Burkitt lymphoma. A retrospective single-centre analysis.

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) and Burkitt lymphoma (BL) are uncommon, highly aggressive diseases originating either from immature precursor T cells or from mature B cells in BL. We retrospectively analyzed the outcome of an early autologous and/or allogeneic stem cell transplantation (SCT) concept in 28 patients with advanced stage T-ALL/LBL and BL after three to four remission induction/consolidation chemotherapy cycles. Considering only patients in first complete remission (CR), the 5-year overall survival (OS) and event-free survival (EFS) was 91% in patients with BL and 73% in patients with T-ALL/LBL with a 5-year relapse incidence (RI) of 9% in patients with BL and 27% in patients with T-ALL/LBL. All relapsing patients finally succumbed to the disease (n = 10) or complications/toxicity after having received a salvage allogeneic transplant (n = 5). Despite the low patient number our retrospective single-centre analysis by incorporating an early intensive high-dose chemo-/radiotherapy strategy with either autologous or allogeneic stem cell transplantation, although preliminary, show promising long-term outcome. Further studies are highly warranted to better define those patients who might benefit most from such a treatment approach.

Investigating self-reported efficacy of lifestyle medicine approaches to tackle erectile dysfunction: a cross-sectional eSurvey based study.

BACKGROUND: Erectile dysfunction (ED) is the most common sexual dysfunction in men. Some types of ED are amenable to treatment using lifestyle medicine approaches with or without pharmacotherapy. AIM: Investigate self-reported efficacy of lifestyle medicine approaches to tackle ED. METHODS: A cross-sectional online survey of 1177 community dwelling adults explored the prevalence and methods used to tackle ED in the community setting. We examined differences between participants with and without ED. Variables associated with ED in univariable analyses were included in a multivariable logistic regression to identify variables independently associated with the condition. OUTCOMES: Self-reported measure: perceived effectiveness of lifestyle medicine interventions to tackle ED. RESULTS: Most respondents (76.5%) had experienced ED, and this was associated with having a long-term condition, taking anti-hypertensive medication, hypercholesterolaemia and obesity. Medication was the most common management strategy overall (65.9%), followed by stress management (43.5%) and weight loss (40.4%). Over half (53.9%) did not use any lifestyle modification strategies to tackle ED. Only 7.0% of ED sufferers received a mental health assessment and 29.2% received other tests (e.g., blood test, medical imaging) by GPs. Cardiovascular training was identified as the best rated strategy by its users (37.8%). Supplements (35.1%) and weight training/physical activity (32.6%) were also positively rated. CLINICAL IMPLICATIONS: Structured education to general practitioners and community dwelling adults about the impact of lifestyle behaviour modification and how this could influence the appearance or trajectory of ED could help improve personal choice when tackling ED. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first study to collect eSurvey responses from community dwelling adults to gauge their reliance and perceived effectiveness of lifestyle medicine approaches to tackle ED. The principal limitation was the lack of follow-up, and not recording other information including lifestyle factors such as nutrition, smoking, and the use of alcohol and recreational drugs, which may have enabled a fuller exploration of the factors that could influence the primary outcome measures examined. CONCLUSION: Despite the high prevalence of ED, there is not enough awareness in the community setting about effective and low-cost lifestyle medicine strategies, including cardiovascular training and the use of supplements and weight training, to help tackle this common condition.

Erectile dysfunction (ED) is the most common sexual dysfunction in men. Some types of ED can be treated using lifestyle medicine approaches with or without the use of medicines. The aim of this study was to investigate self-reported efficacy of lifestyle medicine approaches to tackle ED. We conducted a cross-sectional online survey of 1177 community dwelling adults to explore the prevalence, methods and perceived effectiveness of lifestyle medicine approaches to tackle ED in the community setting. Most respondents (76.5%) had experienced ED, and this was associated with having a long-term condition, taking anti-hypertensive medication, high blood cholesterol and obesity. After medication stress management (43.5%) and weight loss (40.4%) were most frequently cited lifestyle medicine intervention. Cardiovascular training was identified as the best rated strategy by its users (37.8%). To our knowledge, this is the first study to collect eSurvey responses from community dwelling adults to gauge their reliance and perceived effectiveness of lifestyle medicine approaches to tackle ED. Despite the high prevalence of ED, there is not enough awareness in the community setting about effective and low-cost lifestyle medicine strategies, including cardiovascular training and the use of supplements and weight training, to help tackle this common condition.

Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo.

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Phytochemical Characterization, Antioxidant Activity, and Cytotoxicity of Methanolic Leaf Extract of Chlorophytum Comosum (Green Type) (Thunb.) Jacq.

Chlorophytum genus has been extensively studied due to its diverse biological activities. We evaluated the methanolic extract of leaves of Chlorophytum comosum (Green type) (Thunb.) Jacques, the species that is less studied compared to C. borivilianum. The aim was to identify phytoconstituents of the methanolic extract of leaves of C. comosum and biological properties of its different fractions. Water fraction was analyzed with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Nineteen compounds belonging to different chemical classes were identified in the methanolic extract of leaves of C. comosum (Green type) (Thunb.) Jacques. In addition to several fatty acids, isoprenoid and steroid compounds were found among the most abundant constituents. One of the identified compounds, 4'-methylphenyl-1C-sulfonyl-ß-d-galactoside, was not detected earlier in Chlorophytum extracts. The water fraction was toxic to HeLa cells but not to Vero cells. Our data demonstrate that methanolic extract of leaves of C. comosum can be a valuable source of bioactive constituents. The water fraction of the extract exhibited promising antitumor potential based on a high ratio of HeLa vs. Vero cytotoxicity.

Improvement in colorectal cancer outcomes over time is limited to patients with left-sided disease.

PURPOSE: Incidence and mortality of colorectal cancer (CRC) declined over the last decades. However, survival depends on the primary tumor location. It is unknown if all progress in outcomes vary depending on left-sided (LCRC) versus right-sided (RCC) colorectal cancer. We compare incidence and mortality rates over time according to the primary tumor location. METHODS: Data from the Austrian National Cancer Registry spanning from 1983 to 2018 were used to calculate annual incidence and mortality rates and survival stratified by primary tumor localization and stage. Joinpoint regression with linear regression models were used on different subgroups to identify significant changes of incidence- and mortality slopes. RESULTS: A total of 168,260 (incidence dataset) and 87,355 cases (mortality dataset) were identified. Survival of disseminated RCC was worse compared to LCRC (HR 1.14; CI 1.106-1.169). Total and LCRC incidence and mortality rates declined steadily over time, whereas the rates of RCC did not. Incidence of disseminated RCC declined significantly less (slope - 0.07; CI - 0.086; - 0.055) than in LCRC (slope - 0.159; CI - 0.183; - 0.136); mortality rate of RCC was unchanged over time. Incidence and mortality of localized RCC remained unchanged over time, whereas both rates declined independently of stage in LCRC. CONCLUSION: Colorectal cancer outcomes during the last 35 years have preferentially improved in LCRC but not in RCC, indicating that the progress made is limited to LCRC. It is necessary to define RCC as a distinct form of CRC and to focus on specific strategies for its early detection and treatment.

Serologic response to COVID-19 infection and/or vaccine in cancer patients on active treatment.

BACKGROUND: It was shown that immunocompromised patients have significantly reduced immunologic responses to COVID-19 vaccines. The immunogenicity of COVID-19 vaccine/infection in patients with solid tumors is reduced. We evaluated the immunologic response to COVID-19 and/or the BNT162b2 mRNA COVID-19 vaccine among cancer patients on active treatments and reviewed previous literature to identify subgroups that may require third vaccination. PATIENTS AND METHODS: Anti-SARS-CoV-2 S1/S2 antibodies were measured in a cohort of 202 cancer patients on active treatment with chemotherapy (96), immunologic (52), biologic (46), and hormonal (12) treatments for early (n = 66, 32.7%) or metastatic disease (n = 136, 67.3%). Of those, 172 had received two vaccine doses, and 30 had COVID-19 infection (20/30 also received one dose of vaccine). Specific anti-S receptor-binding domain antibodies were further measured in patients with equivocal anti-S1/S2 results. RESULTS: Among cancer patients, the SARS-CoV-2 antibody response rate was 89.1% (180/202) after COVID-19 vaccination or infection and 87.2% (150/172) in patients after vaccination without a history of COVID-19, compared with 100% positive serologic tests in a control group of 30 health care workers (P < 0.001). Chemotherapy treatment was independently associated with significantly reduced humoral response to infection or vaccination, with an 81.3% response rate, compared with 96.2% in patients on other treatments (P = 0.001). In vaccinated patients on chemotherapy, the positive response rate was 77.5%. In a multiple regression model, a neutralizing antibody titer (>60 AU/ml) was more likely with immunotherapy (odds ratio 2.44) and less likely with chemotherapy (odds ratio 0.39). CONCLUSIONS: Overall, both COVID-19 vaccine and natural infection are highly immunogenic among cancer patients. Our study, however, identifies those under chemotherapy as significantly less responsive, and with lower antibody levels. These findings justify close virological and serological surveillance along with consideration of these patients for booster (third dose) vaccine prioritization, as new highly spreading SARS-CoV-2 variants emerge.

Pro- and anti-inflammatory macrophages express a sub-type specific purinergic receptor profile.

Extracellular nucleotides act as danger signals that orchestrate inflammation by purinergic receptor activation. The expression pattern of different purinergic receptors may correlate with a pro- or anti-inflammatory phenotype. Macrophages function as pro-inflammatory M1 macrophages (M1) or anti-inflammatory M2 macrophages (M2). The present study found that murine bone marrow-derived macrophages express a unique purinergic receptor profile during in vitro polarization. As assessed by real-time polymerase chain reaction (PCR), Gαs-coupled P1 receptors A2A and A2B are upregulated in M1 and M2 compared to M0, but A2A 15 times higher in M1. The ionotropic P2 receptor P2X5 is selectively upregulated in M1- and M2-polarized macrophages. P2X7 is temporarily expressed in M1 macrophages. Metabotropic P2Y receptors showed a distinct expression profile in M1 and M2-polarized macrophages: Gαq coupled P2Y1 and P2Y6 are exclusively upregulated in M2, whereas Gαi P2Y13 and P2Y14 are overexpressed in M1. This consequently leads to functional differences between M1 and M2 in response to adenosine di-phosphate stimulation (ADP): In contrast to M1, M2 showed increased cytoplasmatic calcium after ADP stimulation. In the present study we show that bone marrow-derived macrophages express a unique repertoire of purinergic receptors. We show for the first time that the repertoire of purinergic receptors is highly flexible and quickly adapts upon pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.

Early autologous and allogeneic peripheral blood stem cell transplantation for adult patients with acute B and T cell precursor neoplasms: a 12-year single center experience.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

Real world analysis of high-cut-off (HCO) hemodialysis with bortezomib-based backbone therapy in patients with multiple myeloma and acute kidney injury.

BACKGROUND: In patients with multiple myeloma (MM) free light chain-induced cast nephropathy is a serious complication associated with poor survival. High-cut-off (HCO) hemodialysis can reduce the amount of serum free light chains (sFLC), but data on its impact on clinical outcome is limited and contradictory. To gain further insights we collected real world data from two major myeloma and nephrology centers in Austria and the Czech Republic. METHODS: Sixty-one patients with MM and acute kidney injury, who were treated between 2011 and 2019 with HCO hemodialysis and bortezomib-based MM therapy, were analyzed. RESULTS: The median number of HCO hemodialysis sessions was 11 (range 1-42). Median glomerular filtration rate at diagnosis was 7 ± 4.2 ml/min/1.73m2. sFLC after the first HCO hemodialysis decreased by 66.5% and by 89.2% at day 18. At 3 and 6 months, 26 (42.6%) and 30 (49.2%) of patients became dialysis-independent. CONCLUSION: The widely used strategy combining HCO hemodialysis and bortezomib-based antimyeloma treatment is dissatisfactory for half of the patients undergoing it and clearly in need of improvement.

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Autologous stem cell transplantation following simultaneous liver and kidney transplantation in severe amyloid light chain amyloidosis associated with multiple myeloma: a case report.

INTRODUCTION: The involvement of vital organs in multiple myeloma (MM) with systemic amyloid light-chain (AL) amyloidosis can lead to acute organ failure. In this case, the fear of recurrence or progression of multiple myeloma often excludes those patients from undergoing organ transplantation. Nevertheless, clinically fit patients might benefit from a different therapeutic approach. This case presentation might highlight this particular unmet need and strengthen a different treatment approach. CASE PRESENTATION: To our knowledge, we present the first case of successful simultaneous liver and kidney transplantation, followed by autologous stem cell transplantation in a 60-year-old Caucasian male patient suffering from MM (Durie-Salmon stage IIB; ISS-stage: III, RISS stage: III) with primary AL amyloidosis. Chemotherapy treatment led to end-stage kidney disease requiring dialysis. Liver failure also occurred after at least three cycles of CyBorD (bortezomib, cyclophosphamide, and dexamethasone) of induction therapy with a good hematologic response. Over three years after the initial diagnosis, the patient is reportedly showing an excellent quality of life and a complete remission. DISCUSSION AND CONCLUSION: We conclude that kidney and liver transplantation followed by autologous stem cell transplantation can be a treatment option for a selected group of patients with MM if AL amyloidosis is leading. In the end, the remission assessment by IMWG response criteria displayed a complete remission of MM together with complete reconstitution of organ functions (liver & renal function) as long as upfront clinical evaluation excludes significant cardiac involvement and other severe co-morbidities.

Bioremediation of PAH-contaminated shooting range soil using integrated approaches.

Serious contamination of polycyclic aromatic hydrocarbons (PAHs) occurs at outdoor shooting ranges due to the accumulation of clay target fragments containing coal tar or petroleum pitch. These contaminated sites are characterized with high-molecular-weight PAHs that are low in bioavailability and recalcitrant to bioremediation. We evaluated the effectiveness of different remediation strategies, used individually or in combinations, to decontaminate PAHs in a shooting range soil. The treatments included vegetation with bermudagrass [Cynodon dactylon (L.) Pers] or switchgrass [Panicum virgatum]), bioaugmentation of Mycobacterium vanbaalenii PYR-1, and addition of surfactants (Brij-35, rhamnolipid biosurfactant, or Brij-35/sodium dodecyl sulfate mixture). The initial total PAH concentration in the shooting range soil was 373 mg/kg and consisted of primarily high-molecular-weight PAHs (84%). Planting of bermudagrass and switchgrass resulted in 36% and 27% ∑16PAH reduction compared to the non-vegetated control, respectively. Bermudagrass enhanced soil dehydrogenase activity and both vegetation treatments also increased polyphenol oxidase activity. Bioaugmentation of M. vanbaalenii PYR-1 had a significant effect only on the dissipation of high-molecular-weight PAHs, leading to a 15% decrease (∑10PAH) compared to the control. In the non-vegetated soil, Brij-35/sodium dodecyl sulfate mixture increased PAH degradation compared to the no surfactant control. The increased PAH biodegradation in the vegetated and bioaugmented treatments improved lettuce [Lactuca sativa] seed germination, suggesting reduced toxicity in the treated soils. Phytoremediation using bermudagrass or switchgrass with bioaugmentation of M. vanbaalenii PYR-1 was an effective in situ remediation option for shooting range soils with heavy PAH contamination.

Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types.

Cancer cell lines are a cornerstone of cancer research but previous studies have shown that not all cell lines are equal in their ability to model primary tumors. Here we present a comprehensive pan-cancer analysis utilizing transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 tumor types. We perform correlation analysis and gene set enrichment analysis to understand the differences between cell lines and primary tumors. Additionally, we classify cell lines into tumor subtypes in 9 tumor types. We present our pancreatic cancer results as a case study and find that the commonly used cell line MIA PaCa-2 is transcriptionally unrepresentative of primary pancreatic adenocarcinomas. Lastly, we propose a new cell line panel, the TCGA-110-CL, for pan-cancer studies. This study provides a resource to help researchers select more representative cell line models.

Antibiotic resistant bacteria and resistance genes in biofilms in clinical wastewater networks.

Increasing isolation rates of resistant bacteria in the last years require identification of potential infection reservoirs in healthcare facilities. Especially the clinical wastewater network represents a potential source of antibiotic resistant bacteria. In this work, the siphons of the sanitary installations from 18 hospital rooms of two German hospitals were examined for antibiotic resistant bacteria and antibiotic residues including siphons of showers and washbasins and toilets in sanitary units of psychosomatic, haemato-oncological, and rehabilitation wards. In addition, in seven rooms of the haemato-oncological ward, the effect of 24 h of stagnation on the antibiotic concentrations and MDR (multi-drug-resistant) bacteria in biofilms was evaluated. Whereas no antibiotic residues were found in the psychosomatic ward, potential selective concentrations of piperacillin, meropenem and ciprofloxacin were detected at a rehabilitation ward and ciprofloxacin and trimethoprim were present at a haemato-oncology ward. Antibiotic resistant bacteria were isolated from the siphons of all wards, however in the psychosomatic ward, only one MDR strain with resistance to piperacillin, third generation cephalosporins and quinolones (3MRGN) was detected. In contrast, the other two wards yielded 11 carbapenemase producing MDR isolates and 15 3MRGN strains. The isolates from the haemato-oncological ward belonged mostly to two specific rare sequence types (ST) (P. aeruginosa ST823 and Enterobacter cloacae complex ST167). In conclusion, clinical wastewater systems represent a reservoir for multi-drug-resistant bacteria. Consequently, preventive and intervention measures should not start at the wastewater treatment in the treatment plant, but already in the immediate surroundings of the patient, in order to minimize the infection potential.

Randomized phase-II trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine.

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18-82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

Influence of rhamnolipid biosurfactant and Brij-35 synthetic surfactant on 14C-Pyrene mineralization in soil.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants in soil and are considered priority pollutants due to their carcinogenicity. Bioremediation of PAH-contaminated soils is often limited by the low solubility and strong sorption of PAHs in soil. Synthetic surfactants and biosurfactants have been used to enhance the bioavailability of PAHs and to accelerate microbial degradation. However, few studies have compared synthetic and biosurfactants in their efficiency in promoting PAH biodegradation in either native or bioaugmented soils. In this study, we evaluated mineralization of 14C-pyrene in soils with or without the augmentation of Mycobacterium vanbaalenii PYR-1, and characterized the effect of Brij-35 (synthetic) and rhamnolipid biosurfactant at different amendment rates. Treatment of rhamnolipid biosurfactant at 140 or 1400 µg surfactant g-dry soil-1 rates resulted in a significantly longer lag period in 14C-pyrene mineralization in both native and bioaugmented soils. In contrast, amendment of Brij-35 generally increased 14C-pyrene degradation, and the greatest enhancement occurred at 21.6 or 216 µg surfactant g-dry soil-1 rates, which may be attributed to increased bioavailability. Brij-35 and rhamnolipid biosurfactant were found to be non-toxic to M. vanbaalenii PYR-1 at 10X CMC, thus indicating rhamnolipid biosurfactant likely served as a preferential carbon source to the degrading bacteria in place of 14C-pyrene, leading to delayed and inhibited 14C-pyrene degradation. Mineralization of 14C-pyrene by M. vanbaalenii PYR-1 was rapid in the unamended soils, and up to 60% of pyrene was mineralized to 14CO2 after 10 d in the unamended or Brij-35 surfactant-amended soils. Findings of this study suggest that application of surfactants may not always lead to enhanced PAH biodegradation or removal. If the surfactant is preferentially used as an easier carbon substrate than PAHs for soil microorganisms, it may actually inhibit PAH biodegradation. Selection of surfactant types is therefore crucial for the effectiveness of surfactant-aided bioremediation of PAH-contaminated soils.