Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Chemical, radiological and microbiological characterization of a drinking water source: a case study.

This study examined water samples from a local stream in Central Serbia, which was consumed as drinking water. The chemical parameters (chemical oxygen demand, COD; pH, total concentration of dissolved substances and electrical conductivity), the concentration of major, trace and radioactive elements in the water as well as the content of those from the environment, were examined. In addition, the microbiological quality of the water was inspected. The water samples were acidic (pH from 5·27-5·69) and COD ranged in upper permissible limits (up to 6·25 mg O2 l-1 [WR]). The concentrations of major, trace and radioactive elements, including radon, were below maximum contaminant levels. The water contained a higher number of total coliform bacteria (TCB) than it was allowed (˃10 colony-forming units (CFU) in 100 ml of water) as well as enterococci and Escherichia coli. The characterization of the isolated bacteria indicated that two isolates demonstrated proteolytic activity, while full antibiotic resistance was not detected. The isolates showed moderate to strong ability to produce biofilm, while the isolates of E. coli were nonpathogenic. The results indicated that examined water samples were not microbiologically and chemically safe, therefore, the usage of analysed water was not recommended as a water supply. Further research needs to include more frequent monitoring in order to propose measures for the improvement of the water quality and prevention of health risks for consumers.

MFI, BEA and FAU zeolite scavenging role in neonicotinoids and radical species elimination.

Ecotoxicity caused by neonicotinoid pesticides is largely due to oxidative stress on non-target species. Due to the fact that reactive radical species reach the environment, materials intended for pesticide removal should be applicable for the simultaneous removal of reactive radicals, as well. This work uses the spectroscopic, adsorptive and antioxidant responses from MFI, FAU and BEA zeolites as descriptors of their potential environmental importance. Different network structures and Si/Al ratios were correlated with excellent zeolite adsorption properties, as over 200 mg g-1 of investigated neonicotinoids, acetamiprid and imidacloprid, was achieved in one cycle. Additionally, after two regeneration steps, over 450 mg g-1 adsorbed pesticides were retained, in three adsorption cycles. Overall the best results were detected for the FAU zeotype in both tested applications, insecticide adsorption and radical-scavenging performance, with and without insecticides present. The proposed mechanism for adsorption relies on kinetic investigation, isotherm modelling and spectroscopic post-adsorption analysis and targets zeolite hydroxyl/siloxane groups as active sites for insecticide adsorption via hydrogen bonding. Neat, well-defined zeolite structures enable their prospective application in ecotoxic species removal.

Live imaging of micro and macro wettability variations of carbonate oil reservoirs for enhanced oil recovery and CO2 trapping/storage.

Carbonate hydrocarbon reservoirs are considered as potential candidates for chemically enhanced oil recovery and for CO2 geological storage. However, investigation of one main controlling parameter-wettability-is usually performed by conventional integral methods at the core-scale. Moreover, literature reports show that wettability distribution may vary at the micro-scale due to the chemical heterogeneity of the reservoir and residing fluids. These differences may profoundly affect the derivation of other reservoir parameters such as relative permeability and capillary pressure, thus rendering subsequent simulations inaccurate. Here we developed an innovative approach by comparing the wettability distribution on carbonates at micro and macro-scale by combining live-imaging of controlled condensation experiments and X-ray mapping with sessile drop technique. The wettability was quantified by measuring the differences in contact angles before and after aging in palmitic, stearic and naphthenic acids. Furthermore, the influence of organic acids on wettability was examined at micro-scale, which revealed wetting heterogeneity of the surface (i.e., mixed wettability), while corresponding macro-scale measurements indicated hydrophobic wetting properties. The thickness of the adsorbed acid layer was determined, and it was correlated with the wetting properties. These findings bring into question the applicability of macro-scale data in reservoir modeling for enhanced oil recovery and geological storage of greenhouse gases.

Impact of preoperative antibiotic use in preventing complications of cochlear implantation surgery.

OBJECTIVE: To examine the impact of preoperative antibiotic prophylaxis on the occurrence of postoperative complications. MATERIALS AND METHODS: Data of 491 patients undergoing cochlear implantation were included in a non-randomized retrospective comparative cohort study. Demographic data, cochlear implant and surgical details, use of preoperative antibiotics and occurrence of postoperative complications were analyzed using a binary logistic regression model. RESULTS: There were 317 patients (64.56%) who did not receive preoperative antibiotic prophylaxis and 174 (35.44%) patients who received preoperative antibiotic prophylaxis with ceftriaxone. The overall rate of complications requiring surgical treatment was 2.85%. Younger patient age was identified as a positive predictive factor for administering preoperative antibiotic prophylaxis (p<0.001, OR 1.05 CI 95% 1.0124-1.0826). No difference in complication rate was observed between the two groups. No correlation between sex, age, manufacturer, surgeon and postoperative complications were noted (p=0.45). CONCLUSION: There is insufficient evidence to inform decision making regarding preoperative intravenous ceftriaxone use for prevention of infection after cochlear implantation surgery, with data failing to show that administration of preoperative antibiotics leads to a decrease in complication rate. Considering a very low overall complication rate, with few complications related to infection, routine use of preoperative antibiotic prophylaxis should be analyzed further.

Comparison of transcatheter edge-to-edge and surgical repair in patients with functional mitral regurgitation using a meta-analytic approach.

Background: Evidence regarding favorable treatment of patients with functional mitral regurgitation (FMR) using transcatheter edge-to-edge repair (TEER) is constantly growing. However, there is only few data directly comparing TEER and surgical mitral valve repair (SMVr). Aims: To compare baseline characteristics, short-term and 1-year outcomes in FMR patients undergoing mitral valve (MV) TEER or SMVr using a meta-analytic approach. Methods: Systematic database search identified 1,703 studies reporting on TEER or SMVr for treatment of FMR between January 2010 and December 2020. A meta-analytic approach was used to compare outcomes from single-arm and randomized studies based on measures by means of their corresponding 95% confidence intervals (CI). Statistical significance was assumed if CIs did not overlap. A total of 21 TEER and 37 SMVr studies comprising 4,304 and 3,983 patients were included. Results: Patients in the TEER cohort presented with higher age (72.0 ± 1.7 vs. 64.7 ± 4.7 years, p < 0.001), greater burden of comorbidities like hypertension (p < 0.001), atrial fibrillation (p < 0.001), lung disease (p < 0.001) and chronic renal disease (p = 0.005) as well as poorer left ventricular ejection fraction (30.9 ± 5.7 vs. 36.6 ± 5.3%, p < 0.001). In-hospital mortality was significantly lower with TEER [3% (95%-CI 0.02-0.03) vs. 5% (95%-CI 0.04-0.07)] and 1-year mortality did not differ significantly [18% (95%-CI 0.15-0.21) vs. 11% (0.07-0.18)]. NYHA [1.06 (95%-CI 0.87-1.26) vs. 1.15 (0.74-1.56)] and MR reduction [1.74 (95%-CI 1.52-1.97) vs. 2.08 (1.57-2.59)] were comparable between both cohorts. Conclusion: Despite considerably higher age and comorbidity burden, in-hospital mortality was significantly lower in FMR patients treated with TEER, whereas a tendency toward increased 1-year mortality was observed in this high-risk population. In terms of functional status and MR grade reduction, comparable 1-year results were achieved.

Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

Spectroscopic analysis of XIV century wall paintings from Patriarchate of Pec Monastery, Serbia.

The Church of the Holy Mother of God Hodegetria in Pec is decorated with wall paintings that date from the beginning of the 14th century. In terms of style they correspond to Byzantine wall paintings from the epoch of Paleologos. The painting technique and pigment pallete has been examined on micro fragments in thin cross-sections by means of optical microscopy (OM), scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) and micro- Raman spectroscopy. Use of the fresco technique and two supporting plaster layers was noted on the majority of samples, while in large blue painted areas, a combination of fresco and secco techniques was used. The SEM-EDS results showed the presence of Ca as the main component of plaster besides the traces of Si and Mg. In some samples egg white as a binder was identified. The paint film is often multilayered. Twelve pigments were identified, mainly natural earth pigments such as red ochre, yellow ochre and green earth. A mixture of pigments was used for attaining desirable optical and aesthetical impressions. As decay product only weddelite was detected in many preparatory and painted samples.

Infusion of autograft natural killer cell/CD14+HLA-DRDIM cell ratio predicts survival in lymphoma post autologous stem cell transplantation.

The infusion of autograft absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are prognostic factors for overall survival (OS) and PFS in non-Hodgkin's lymphoma (NHL) patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). The human monocytic CD14+HLA-DRDIM cells are associated with worse prognosis in NHL. Thus, we investigated whether the autograft A-NKC/A-CD14+HLA-DRDIM ratio predicts survival in NHL. In a total of 111 NHL patients, we analyzed apheresis collection samples for the content of A-NKC and A-CD14+HLA-DRDIM. With a median follow-up of 57.2 months (range: 2.1-84.6 months), patients with an A-NKC/A-CD14+HLA-DRDIM ratio of ⩾0.29 experienced superior OS (5-year OS rates of 84% (95% confidence interval (CI), 72-91%) vs 48% (95% CI, 34-62%), P<0.0002, respectively) and PFS (5-year PFS rates of 59% (95% CI, 47-71%) vs 32% (95% CI, 20-48%), P<0.002, respectively). Multivariate analysis revealed that A-NKC/A-CD14+HLA-DRDIM ratio was an independent predictor for PFS (hazard ratio (HR)=0.56, 95% CI, 0.32-0.96, P<0.03) and OS (HR=0.34, 95% CI, 0.16-0.68, P<0.002). The A-NKC/A-CD14+HLA-DRDIM ratio provides a platform to target specific autograft immune effector cells to improve clinical outcomes in NHL patients undergoing APBHSCT.

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.

Investigation of mechanism and critical parameters for removal of arsenic from water using Zr-TiO2 composite.

Using the microwave-hydrothermal method for the synthesis of composite, high surface density of hydroxyl groups, as an active adsorption sites for arsenic, was obtained. Adsorption mechanisms of As(III) and As(V) onto zirconium-doped titanium dioxide (Zr-TiO2) were investigated and proposed using macroscopic and microscopic methods. Obtained results are suggesting inner-sphere and outer-sphere adsorption mechanisms for As(III) and As(V), respectively. This allowed us to identify parameters that are critical for the successful removal of arsenic from water, which is essential information for further optimization of the removal process. The composite was further applied for the removal of As(III) and As(V) from water in a dynamic flow through the reactor. Column study proved that the removal of both arsenic species below the value recommended by WHO can be achieved. Elution of As(III) and As(V) from the composite can be done by using small amounts of 0.01 M NaOH solution resulting in preconcentration of arsenic species and possible multiple usage of composite.

[Percutaneus coronary interventions for ostial lesions]. / Perkutane koronare Intervention ostialer Läsionen.

An ostial lesion is defined as a lesion near to the ostium (≤3 mm) and is characterized by a rigid fibrotic texture with pronounced sclerosis associated with a very high tendency to recoil. Under certain circumstances this may lead to a modest primary interventional result accompanied by a higher complication rate and in particular a higher rate of restenosis. Ostial lesions of the right coronary artery in particular represent a greater challenge for percutaneous interventions with a higher rate of restenosis despite the introduction of various new techniques. In contrast ostial stenosis of the left main trunk shows very good results after percutaneous interventions and implantation of drug-eluting stents. The indications for percutaneous transluminal coronary angioplasty (PTCA) of an ostial lesion correspond to the indications for treatment of all other lesions. The article gives an overview of the experiences and recommendations with respect to the diagnostics and interventional therapy of ostial lesions.

Study of the decomposition pathway of 12-molybdophosphoric acid in aqueous solutions by micro Raman spectroscopy.

Micro Raman spectroscopy was applied to investigate the speciation of heteropoly and isopoly molybdates in 0.05 and 0.005 M aqueous solutions of 12-molybdophosphoric acid at pH values between 1 and 6. For comparative purposes, (31)P NMR spectroscopy was applied too. It is shown that stability of Keggin anion is influenced both by pH and concentration of solution. The Keggin structure is stable in acidic solutions (pH<1.6) while defective Keggin structures are formed with further alkalization (up to pH5.6). Monolacunary anion PMo11O(39)(7-) is the main component in the pH region from 1.6 to 3.4. Further removal of molybdenyl species causes the appearance of other vacant Keggin structures such as PMo9O31(OH)(3)(6-) and PMo6O(25)(9-) at about pH4. At pH5.0, anion PMo6O(25)(9-) is the main species. In solutions with pH greater than 5.0, heteropolymolybdates disappear completely and isopolymolybdates Mo7O(24)(6-) and MoO(4)(2-) are formed in higher amounts. In more diluted solution of 0.005 M, the decomposition scheme of 12-molybdophosphoric acid solution with increasing of pH takes place without observation of significant amounts of Mo7O(24)(6-) species. If alkalinization is performed with 0.5 M instead of 5 M NaOH, there are no significant changes in the Raman spectra of solutions. It is shown that the spectra of evaporated samples may be used for the identification of molecular species in corresponding concentrated solutions. However, Raman spectra of dry residues of more diluted solutions differ from spectra of corresponding solutions due to the reactions performed during the process of drying and cannot be used for unambiguous identification of species in solution. Acidification of 0.05 M solution of Na2MoO4 shows that at pH>5.6, molybdate anion MoO(4)(2-) dominates, while in the pH range between 5.6 and 1, heptamolybdate anion Mo7O(24)(6-) is preferentially formed.

Evaluation of the SIOPEN semi-quantitative scoring system in planar simpatico-adrenal MIBG scintigraphy in children with neuroblastoma.

Neuroblastoma is the most common malignancy in children comprising 7.6% of all infantile cancers. MIBG scintigraphy is a mandatory neuroblastoma diagnostic test, which is among others methods, semi-quantified by the SIOPEN method. The aim of this study was to test both the skeletal and the soft tissue segments of the SIOPEN scoring method in the diagnostic milieu and to correlate them with the Curie score. Since there is little knowledge of their diagnostic power, the following variables were tested: VMA, HVA, LDH, and MYCN, ferritin, bone marrow infiltration, the INSS and the INPC classification. The cross-sectional study with repeated measurements of 143 scintigrams was performed on 76 pediatric patients with suspected or proven neuroblastoma, who had been referred to the Center for Nuclear Medicine of the Clinical Center of Serbia in the period 2007-2012. The range of the SIOPEN soft tissue scores was 0-5. The range of the SIOPEN skeletal scores was 0-57. The range of the Curie scores was 0-26. The skeletal SIOPEN scores were significantly higher in bone marrow positive children, in children with pathologically elevated urinary VMA levels and in children having a more advanced clinical stage. There was no difference in the SIOPEN soft tissue score due to higher VMA levels, or depending on the clinical stage and positive bone marrow assessment. There was no difference between the SIOPEN skeletal and soft tissue scores on one hand and the histological grade of the tumor; elevated or normal levels of HVA, LDH, NSE and ferritin, or the presence or absence of MYNC amplification in the neuroblastoma cell line, on the other hand. The results of both SIOPEN scores showed a high linear correlation with the Curie score. The conclusion is that the soft tissue segment of the SIOPEN score needs further elucidation in a more controlled milieu. Excellent correlation between all segments of the two semi-quantitative scoring methods speaks in favor of the application of the complete SIOPEN scoring system in every day mIBG scanning.

Intermolecular and low-frequency intramolecular Raman scattering study of racemic ibuprofen.

We report the low-temperature Raman scattering study of racemic ibuprofen. Detailed analysis of the racemic ibuprofen crystal symmetry, related to the vibrational properties of the system, has been presented. The first principle calculations of a single ibuprofen molecule dynamical properties are compered with experimental data. Nineteen, out of 26 modes expected for the spectral region below 200cm(-1), have been observed.

Dermal and conjunctival melanocytic proliferations in diffuse uveal melanocytic proliferation.

AIM: The goal of this case report is to describe the dermatologic and conjunctival findings in a case of bilateral diffuse uveal melanocytic proliferation (BDUMP), a paraneoplastic syndrome usually associated with gynecologic cancers. There is little information about other dermatologic melanocytic findings in these patients. METHODS: Histologic and fluorescent in situ hybridization (FISH) analysis of three separate skin biopsies, one of which was separated by 21 months from the others, were performed in a 71-year-old patient with BDUMP to assess for histologic and chromosomal abnormality. Conjunctival histologic evaluation was also done. RESULTS: Dermal melanocytic proliferation was seen in each specimen. The cells were spindle type with mitotic activity. FISH analysis showed a normal copy of chromosomes. The conjunctival sample also showed normal FISH analysis. CONCLUSION: BDUMP is associated with multifocal dermal and conjunctival melanocytic proliferation.

Bowel perforation in intestinal lymphoma: incidence and clinical features.

BACKGROUND: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma. PATIENTS AND METHODS: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features. RESULTS: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%). CONCLUSION: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.