Nomogram for predicting survival after first-line anti-PD-1-based immunotherapy in unresectable stage IV melanoma: a multicenter international study.

BACKGROUND: The introduction of anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment landscape for melanoma, enhancing both response rates and survival outcomes in patients with advanced stages of the disease. Despite these remarkable advances, a noteworthy subset of patients (40%-60%) does not derive advantage from this therapeutic approach. This study aims to identify key predictive factors and create a user-friendly predictive nomogram for stage IV melanoma patients receiving first-line anti-PD-1-based immunotherapy, improving treatment decisions. MATERIALS AND METHODS: In this retrospective study, we included patients with unresectable stage IV melanoma who received first-line treatment with either anti-PD-1 monotherapy or anti-PD-1 plus anti-cytotoxic T-lymphocyte associated protein 4 between 2014 and 2018. We documented clinicopathological features and blood markers upon therapy initiation. By employing the random survival forest model and backward variable selection of the Cox model, we identified variables associated with progression-free survival (PFS) after the first-line anti-PD-1-based treatment. We developed and validated a predictive nomogram for PFS utilizing the identified variables. We assessed calibration and discrimination performance metrics as part of the evaluation process. RESULTS: The study involved 719 patients, divided into a training cohort of 405 (56%) patients and a validation cohort of 314 (44%) patients. We combined findings from the random survival forest and the Cox model to create a nomogram that incorporates the following factors: lactate dehydrogenase (LDH), S100, melanoma subtype, neutrophil-to-lymphocyte ratio (NLR), body mass index, type of immune checkpoint inhibitor, and presence of liver or brain metastasis. The resultant model had a C-index of 0.67 in the training cohort and 0.66 in the validation cohort. Performance remained in different patient subgroups. Calibration analysis revealed a favorable correlation between predicted and actual PFS rates. CONCLUSIONS: We developed and validated a predictive nomogram for long-term PFS in patients with unresectable stage IV melanoma undergoing first-line anti-PD-1-based immunotherapy.

Theoretical study of nitrodibenzofurans: A possible relationship between molecular properties and mutagenic activity.

In this study we present a theoretical investigation of the molecular properties of nitrodibenzofurans (NDFs) and dinitrodibenzofurans (DNDFs) and their relation to mutagenic activity. Equilibrium geometries, relative energies, vertical ionization potentials (IP), vertical electron activities (EA), electronic dipole polarizabilities, and dipole moments of all NDFs and three DNDFs calculated by Density Functional Theory (DFT) methods are reported. The Ziegler/Rauk Energy Decomposition Analysis (EDA) is employed for a direct estimate of the variations of the orbital interaction and steric repulsion terms corresponding to the nitro group and the oxygen of the central ring of NDFs. The results indicate differences among NDF isomers for the cleavage of the related bonds and steric effects in the active site. The results show a good linear relationship between polarizability (<α>), anisotropy of polarizability (Δα), the summation of IR intensities (ΣIIR) and the summation of Raman activities (ΣARaman) over all 3N-6 vibrational modes and experimental mutagenic activities of NDF isomers in Salmonella typhimurium TA98 strain. The polarizability changes with respect to the νsNO+CN vibrational mode are in correlation with the mutagenic activities of NDFs and suggest that intermolecular interactions are favoured along this coordinate.

Differential susceptibility of primary cultured human skin cells to hypericin PDT in an in vitro model.

Skin cancer is the most common cancer worldwide, and its incidence rate in South Africa is increasing. Photodynamic therapy (PDT) has been shown to be an effective treatment modality, through topical administration, for treatment of non-melanoma skin cancers. Our group investigates hypericin-induced PDT (HYP-PDT) for the treatment of both non-melanoma and melanoma skin cancers. However, a prerequisite for effective cancer treatments is efficient and selective targeting of the tumoral cells with minimal collateral damage to the surrounding normal cells, as it is well established that cancer therapies have bystander effects on normal cells in the body, often causing undesirable side effects. The aim of this study was to investigate the cellular and molecular effects of HYP-PDT on normal primary human keratinocytes (Kc), melanocytes (Mc) and fibroblasts (Fb) in an in vitro tissue culture model which represented both the epidermal and dermal cellular compartments of human skin. Cell viability analysis revealed a differential cytotoxic response to a range of HYP-PDT doses in all the human skin cell types, showing that Fb (LD50=1.75µM) were the most susceptible to HYP-PDT, followed by Mc (LD50=3.5µM) and Kc (LD50>4µM HYP-PDT) These results correlated with the morphological analysis which displayed distinct morphological changes in Fb and Mc, 24h post treatment with non-lethal (1µM) and lethal (3µM) doses of HYP-PDT, but the highest HYP-PDT doses had no effect on Kc morphology. Fluorescent microscopy displayed cytoplasmic localization of HYP in all the 3 skin cell types and additionally, HYP was excluded from the nuclei in all the cell types. Intracellular ROS levels measured in Fb at 3µM HYP-PDT, displayed a significant 3.8 fold (p<0.05) increase in ROS, but no significant difference in ROS levels occurred in Mc or Kc. Furthermore, 64% (p<0.005) early apoptotic Fb and 20% (p<0.05) early apoptotic Mc were evident; using fluorescence activated cell sorting (FACS), 24h post 3µM HYP-PDT. These results depict a differential response to HYP-PDT by different human skin cells thus highlighting the efficacy and indeed, the potential bystander effect of if administered in vivo. This study contributes toward our knowledge of the cellular response of the epidermis to photodynamic therapies and will possibly enhance the efficacy of future photobiological treatments.

Molecular and morphological variability within the Aphidius colemani group with redescription of Aphidius platensis Brethes (Hymenoptera: Braconidae: Aphidiinae).

We have identified the following three taxa related to the Aphidius colemani species group, which are important biological control agents: Aphidius colemani, Aphidius transcaspicus and Aphidius platensis. Using partial sequences of the mitochondrial cytochrome oxidase subunit I (mtCOI) gene and geometric morphometric analysis of the forewing shape, we have explored the genetic structure and morphological variability of the A. colemani group from different aphid host/plant associations covering a wide distribution area. The topology of the maximum parsimony and maximum likelihood trees were identical with 98-100% bootstrap support, clustering A. colemani, A. platensis and A. transcaspicus into separate species. The distances among the taxa ranged from 2.2 to 4.7%, which is a common rate for the between-species divergence within the subfamily Aphidiinae. Differences in the shape of the forewing investigated within the biotypes of A. colemani group are congruent with their genetic diversification. Both A. platensis and A. colemani share a common host range pattern, and it would be interesting to estimate and compare the role of these two species in future biological control strategies against aphids of economic importance. Our results indicate that 'genetic screening' is a reliable approach for identification within the A. colemani group. The high variation in the wing shape among species, including a significant divergence in the wing shape among specimens that emerged from different hosts, makes the forewing shape and wing venation less reliable for species determination. Aphidius platensis is diagnostified and redescribed, and the key for the A. colemani group is presented.

Robot- and computer-assisted craniotomy (CRANIO): from active systems to synergistic man-machine interaction.

Computer and robot assistance in craniotomy/craniectomy procedures is intended to increase precision and efficiency of the removal of calvarial tumours, enabling the preoperative design and manufacturing of the corresponding implant. In the framework of the CRANIO project, an active robotic system was developed to automate the milling processes based on a predefined resection planning. This approach allows for a very efficient milling process, but lacks feedback of the intra-operative process to the surgeon. To better integrate the surgeon into the process, a new teleoperated synergistic architecture was designed. This enables the surgeon to realize changes during the procedure and use their human cognitive capabilities. The preoperative planning information is used as guidance for the user interacting with the system through a master-slave architecture. In this article, the CRANIO system is presented together with this new synergistic approach. Experiments have been performed to evaluate the accuracy of the system in active and synergistic modes for the bone milling procedure. The laboratory studies showed the general feasibility of the new concept for the selected medical procedure and determined the accuracy of the system. Although the integration of the surgeon partially reduces the efficiency of the milling process compared with a purely active (automatic) milling, it provides more feedback and flexibility to the user during the intra-operative procedure.

Expression and prognostic role of syndecan-2 in prostate cancer.

Syndecans are a four-member family of transmembrane heparan sulphate proteoglycans that have different functions in cell signalling, adhesion, cytoskeleton organization, migration, proliferation, and angiogenesis. Several studies investigated the role of syndecan-2 (SDC2) in different carcinomas; however, only one being focused on SDC2 in prostate cancer. SDC2 expression and relationship with established prognostic features were assessed in a cohort of 86 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma. SDC2 expression was present in the majority of prostate cancers and absent in only 11.6% of cases. SDC2 expression was also recorded in cells of prostatic intraepithelial neoplasia, whereas normal prostatic epithelial tissue and stroma did not express SDC2. SDC2 overexpression in prostate cancer was significantly associated with established features indicative of worse prognosis such as higher preoperative PSA (P=0.011), higher Gleason score (P<0.001), positive surgical margins (P<0.003), and extraprostatic extension of disease (P<0.003). Moreover, expression of SDC2 was also associated with biochemical disease progression on univariate analysis (P<0.001). Study results supported the potential role of SDC2 in prostatic carcinogenesis and cancer progression. Moreover, SDC2 could serve as an additional prognostic marker that might help in further stratifying the risk of disease progression in patients with prostate cancer.

Monitoring of trace element atmospheric deposition using dry and wet moss bags: accumulation capacity versus exposure time.

To clarify the peculiarities of trace element accumulation in moss bags technique (active biomonitoring), samples of the moss Sphagnum girgensohnii Rusow were exposed in bags with and without irrigation for 15 days up to 5 months consequently in the semi-urban area of Belgrade (Serbia) starting from July 2007. The accumulation capacity for 49 elements determined by ICP-MS in wet and dry moss bags was compared. The concentration of some elements, i.e. Al, V, Cr, Fe, Zn, As, Se, Sr, Pb, and Sm increased continuously with exposure time in both dry and wet moss bags, whereas concentration of Na, Cl, K, Mn, Rb, Cs, and Ta decreased. Irrigation of moss resulted in a higher accumulation capacity for most of the elements, especially for Cr, Zn, As, Se, Br, and Sr. Principal component analysis was performed on the datasets of element concentrations in wet and dry moss bags for source identification. Results of the factor analysis were similar but not identical in the two cases due to possible differences in element accumulation mechanisms.

Active moss biomonitoring of trace elements with Sphagnum girgensohnii moss bags in relation to atmospheric bulk deposition in Belgrade, Serbia.

Active biomonitoring with wet and dry moss bags was used to examine trace element atmospheric deposition in the urban area of Belgrade. The element accumulation capability of Sphagnum girgensohnii Russow was tested in relation to atmospheric bulk deposition. Moss bags were mounted for five 3-month periods (July 2005-October 2006) at three representative urban sites. For the same period monthly bulk atmospheric deposition samples were collected. The concentrations of Al, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Cd, and Pb were determined by instrumental neutron activation analyses and atomic absorption spectrometry. Significant accumulation of most elements occurred in the exposed moss bags compared with the initial moss content. High correlations between the elements in moss and bulk deposits were found for V, Cu, As, and Ni. The enrichment factors of the elements for both types of monitor followed the same pattern at the corresponding sites.

Analysis of surgical management of calvarial tumours and first results of a newly designed robotic trepanation system.

This study was performed to evaluate the surgical strategy in patients with calvarial tumours, in order to design and modify a robot-assisted trepanation system. A total of 75 patients underwent craniectomy for the treatment of calvarial tumours during the 10-year period from 1993 to 2002. The patients' complaints, the size, location and histology of the tumour, and the various cranioplasty techniques used were analysed retrospectively. In a second procedure several craniectomies at typical locations according to the study's results were performed in a laboratory setting using a hexapod robotic tool, constructed at the Helmholtz-Institute, RWTH Aachen University, and plastic model heads. The workflow was documented and the reproducibility and the accuracy of the procedure were registered. A total of 83 surgical procedures were performed on 75 patients. The majority (87 %) of lesions treated surgically were located in the frontal, temporal and anterior parts of the parietal region. Histological examination revealed benign lesions in 66 % of the patients and dural involvement in 46 %. According to these results craniectomies were performed using the robotic system. Mean positioning accuracy of the robotic system while milling was 0.24 mm, with a standard deviation of 0.04 mm, and maximum error under 1 mm. Craniectomies leaving a 1-mm layer of the tabula interna intact to ensure a healthy dura were performed in several regions successfully. The majority of calvarial tumours, requiring surgical treatment in our patients, were located in cosmetically relevant areas in which drilling can be carried out with the robotic trepanation system. Consequently, the surgical approach had to be planned carefully in order to achieve a good cosmetic outcome.

Robot- and computer-assisted craniotomy: resection planning, implant modelling and robot safety.

BACKGROUND: In cases of cranial tumour, manual resection of the cancerous tissue can be very stressful and time-consuming, due to the adhesion of the subjacent dura mater. Computer-assisted planning, navigation and robotic craniotomy, with optional skull reconstruction using customized implants, are of increasing clinical interest in craniofacial and neurosurgery. METHODS: Using preoperative computed tomography (CT) images, an automatic segmentation of the tumour is performed, followed by resection planning. The skull reconstruction is performed using computer-assisted implant modeling and manufacturing. Risk analysis of the robot-guided intervention led to the development of a new hexapod robot system. RESULTS: Results from registration and robot accuracy on plastic and Anatomical skull are shown. The concept of a stand-alone safety system is presented to supervise the robot during the intervention. The entire process from preoperative CT scan to intraoperative robot assisted removal of tumourous bone is shown in laboratory and anatomical trials. CONCLUSION: The laboratory and anatomy studies conducted so far provided a substantial basis for further improvement of the system's integration in the surgical workflow and the final approval of the system for initial clinical studies.

[CRANIO--development of a system for computer- and robot-assisted craniotomy]. / CRANIO--Entwicklung eines Systems zur Computer- und roboterunterstützten Kraniotomie.

In the framework of the DFG project CRANIO, we are dealing with the problems of computer-assisted planning and robot-assisted realization of craniotomy, with optional skull reconstruction. A CT dataset was obtained from a phantom skull model and basic operation planning as well as different registration methods were performed. As one option it is possible to mill a contour on the skull or even to remove the entire area with a robot-guided microsurgical milling tool. In this context, work space tests were performed with a hexapod parallel robot. The milling of any contour geometry could be realized with different tool angles using the existing CRIGOS robot system without additional axes.

Sublimation properties of CoF(3): mass spectrometric and quantum chemical studies.

The sublimation of cobalt trifluoride was studied using the Knudsen effusion method combined with mass spectrometry. The pressure of F was directly measured for decomposition of CoF(3)(s) into CoF(2)(s). The average kinetic energy of CoF(2)(+), CoF(+) and Co(+) fragment ions was determined and the relative ionisation cross section curves measured from 6 eV to 100 eV. Thermodynamic functions of gaseous CoF(3) and Co(2)F(6), were evaluated from geometrical and vibrational parameters provided from theoretical calculations. Heats of formation of CoF(3)(s), CoF(3)(g), Co(2)F(6)(g) were established as (-784 +/- 6) kJ/mol, (-565 +/- 11) kJ/mol and (-1289 +/- 22) kJ/mol, respectively.

Preinfarction angina prevents left ventricular remodeling in patients treated with thrombolysis for myocardial infarction.

BACKGROUND: It has been shown that preinfarction angina may have beneficial effects on infarct size and mortality. However, there are no studies that have serially assessed the impact of preinfarction angina on left ventricular (LV) function in a large series of patients. HYPOTHESIS: The study was undertaken to determine whether preinfarction angina (within 7 days before infarction) influences LV remodeling. METHODS: In all, 119 consecutive patients with acute myocardial infarction were serially evaluated by 2-dimensional echocardiography (on Days 1, 2, 3, and 7; at 3 and 6 weeks; and at 3, 6, and 12 months following infarction). Left ventricular volumes were determined using Simpson's biplane formula and normalized for body surface area. Wall motion score index and sphericity index were calculated for each study. Coronary angiography was performed before discharge. RESULTS: Preinfarction angina was detected in 39 of 119 patients. Initial echocardiographic and clinical data as well as the incidence of patent infarct-related artery and collaterals were similar for patients with and without preinfarction angina. In the subset of thrombolysed patients, patients with preinfarction angina showed decrease of LV end-diastolic and end-systolic volumes during the follow-up period (p = 0.033 and p = 0.001, respectively), and improvement of wall motion score index (p < 0.001) and ejection fraction occurred (p = 0.001), without changing of LV shape (p > 0.05); in addition, patients with preinfarction angina had smaller LV volumes and higher ejection fraction than did those without angina, from 3 weeks onward. These favorable effects were not detected in patients not treated with thrombolysis. CONCLUSIONS: These data indicate that preinfarction angina has an inhibiting effect on long-term LV remodeling in patients who underwent thrombolysis for first acute myocardial infarction. It appears that preinfarction angina has no impact on infarct size and early postinfarction LV function.

Trace and major element pollution originating from coal ash suspension and transport processes.

Coal ash obtained by coal combustion in the "Nikola Tesla A" power plant in Obrenovac, near Belgrade, Yugoslavia, is mixed with water of the Sava river and transported to the dump. In order to assess pollution caused by leaching of some minor and major elements during ash transport through the pipeline, two sets of samples (six samples each) were subjected to a modified sequential extraction. The first set consisted of coal ash samples taken immediately after combustion, while the second set was obtained by extraction with river water, imitating the processes that occur in the pipeline. Samples were extracted consecutively with distilled water and a 1 M solution of KCl, pH 7, and the differences in extractability were compared in order to predict potential pollution. Considering concentrations of seven trace elements as well as five major elements in extracts from a total of 12 samples, it can be concluded that lead and cadmium do not present an environmental threat during and immediately after ash transport to the dump. Portions of zinc, nickel and chromium are released during the ash transport, and arsenic and manganese are released continuously. Copper and iron do not present an environmental threat due to element leaching during and immediately after the coal ash suspension and transport. On the contrary, these elements, as well as chromium, become concentrated during coal ash transport. Adsorbed portions of calcium, magnesium and potassium are also leached during coal ash transport.

Single-day loading dose of oral amiodarone for the prevention of new-onset atrial fibrillation after coronary artery bypass surgery.

BACKGROUND: Various regimens have been proposed for the prevention of postoperative atrial fibrillation, including the use of intravenous and oral amiodarone. The purpose of this study was to determine the effectiveness of a single-day loading dose of oral amiodarone in prophylaxis of atrial fibrillation during the 7 days after coronary artery bypass surgery. METHODS: We conducted a double-blind, randomized, placebo-controlled study encompassing 315 consecutive patients who underwent coronary artery bypass surgery. They received either amiodarone (159 patients) or placebo (156 patients). Therapy consisted of a single oral loading dose of 1200 mg of amiodarone 1 day before surgery, followed by the maintenance dose of 200 mg daily during the next 7 days. Only episodes of atrial fibrillation lasting more than 1 hour or associated with hemodynamic compromise were taken into consideration. RESULTS: Overall, the incidence of atrial fibrillation was similar in patients who received amiodarone (31/159, 19.5%) and placebo (33/156, 21.2%) (P = .78). However, amiodarone reduced the incidence of atrial fibrillation in elderly patients (age > or = 60 years): it occurred in 20 of 75 (26.7%) patients on amiodarone and in 28 of 65 (43.1%) patients in the placebo group (P = .05). There were no differences between the study groups regarding the postoperative intrahospital morbidity and mortality and the duration of hospital stay. CONCLUSIONS: A single-day loading dose of oral amiodarone (1200 mg) does not prevent postoperative atrial fibrillation in a general population of patients undergoing coronary artery bypass surgery. However, it appears that this regimen reduces the occurrence of postoperative atrial fibrillation in elderly patients.

Short early filling deceleration time on day 1 after acute myocardial infarction is associated with short and long term left ventricular remodelling.

OBJECTIVE: To assess the relations between early filling deceleration time, left ventricular remodelling, and cardiac mortality in an unselected group of postinfarction patients. DESIGN AND PATIENTS: Prospective evaluation of 131 consecutive patients with first acute myocardial infarction. Echocardiography was performed on day 1, day 2, day 3, day 7, at three and six weeks, and at three, six, and 12 months after infarction. According to deceleration time on day 1, patients were divided into groups with short (< 150 ms) and normal deceleration time (>/= 150 ms). SETTING: Tertiary care centre. RESULTS: Patients with a short deceleration time had higher end systolic and end diastolic volume indices and a higher wall motion score index, but a lower ejection fraction, in the year after infarction. These patients also showed a significant increase in end diastolic (p < 0.001) and end systolic volume indices (p = 0.007) during the follow up period, while ejection fraction and wall motion score index remained unchanged. In the group with normal deceleration time, end diastolic volume index increased (p < 0.001) but end systolic volume index did not change; in addition, the ejection fraction increased (p = 0.002) and the wall motion score index decreased (p < 0.001). One year and five year survival analysis showed greater cardiac mortality in patients with a short deceleration time (p = 0.04 and p = 0.02, respectively). In a Cox model, which included initial ejection fraction, infarct location, and infarct size, deceleration time on day 1 was the only significant predictor of five year mortality. CONCLUSIONS: A short deceleration time on day 1 after acute myocardial infarction can identify patients who are likely to undergo left ventricular remodelling in the following year. These patients have a higher one year and five year cardiac mortality.

Echocardiographic evaluation of valvular stenosis: the gold standard for the next millennium?

Over the past decade, utilization of cardiac catheterization for preoperative hemodynamic assessment of patients with mitral and aortic stenosis has steadily decreased. The reason for this trend is the use of echocardiography, which is emerging as a gold standard for clinical characterization of valvular lesions. Since cardiac catheterization is an invasive procedure that is associated with a significant percentage of complications, echocardiographic evaluation of patients with valvular stenosis is safer and more cost-effective. In the next millennium, echocardiography will probably completely replace the use of catheterization for hemodynamic assessment of the severity of mitral and aortic stenosis.

[Reversible left ventricular dysfunction in coronary disease (part one): myocardial stunning]. / Reverzibilna disfunkcija leve komore u koronarnoj bolesti (prvi deo): osamucenost miokarda.

INTRODUCTION: The concept of myocardial stunning has been proposed by Braunwald and Kloner in early 1980's and is defined as transient postischemic myocardial dysfunction that persists after reperfusion, despite the absence of irreversible damage and restoration of normal or near normal coronary flow. Thus, the hallmark of stunned myocardium is the mismatch between coronary flow and myocardial function. MYOCARDIAL STUNNING: The two most plausible hypotheses used to explain the pathogenetic mechanisms of myocardial stunning are calcium and oxyradical hypotheses. According to the first one, myocardial stunning is the result of impaired calcium homeostasis caused either by calcium overload or decreased responsiveness of myofilaments to calcium. The oxyradical hypothesis postulates that generation of free oxygen radicals depresses myocardial function after the ischemic episode. The exact mechanism is unknown, but it is probably due to extreme reactivity of oxyradicals that bind to some cellular components, impairing membrane permeability and function of various cell organelle. Stunned myocardium can be seen in numerous clinical situations in which myocardial ischemia has been followed by reperfusion. These include: coronary artery bypass surgery, acute myocardial infarction, stable, unstable and variant angina, percutaneous transluminal coronary angioplasty and cardiac transplantation. DISCUSSION AND CONCLUSION: In majority of these situations, stunned myocardium is usually well tolerated. However, there is a group of high-risk patients in whom prolonged myocardial dysfunction due to stunning can cause serious hemodynamic instability, which requires pharmacological and/or mechanical support. Therefore, in order to avoid these situations, some authors have suggested that stunned myocardium should be prevented, rather than treated. Since stunned myocardium is by definition reperfused, with normal or near normal coronary flow, treatment is reserved only for those patients in whom stunned region is large enough to cause low cardiac output and hypotension. Revascularisation is usually unnecessary; however, there are situations in which episodes of repetitive stunning cause chronic myocardial dysfunction along with hibernated myocardium, when myocardial revascularization would be beneficial.