Incidence of cardiotoxicity and validation of the Heart Failure Association-International Cardio-Oncology Society risk stratification tool in patients treated with trastuzumab for HER2-positive early breast cancer.

PURPOSE: Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates [left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation] and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice. METHODS: Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher's exact test, Chi-squared and logistic regression were used. RESULTS: 931 patients were included in the analysis. Median age was 54 years (range 24-83) and Charlson comorbidity index 0 (0-6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1-18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III-IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high; p = 0.002). CONCLUSIONS: Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.

Buffering Capacity in Sepsis: A Prospective Cohort Study in Critically Ill Patients.

BACKGROUND: The concept of buffering generally refers to the ability of a system/organism to withstand attempted changes. For acid-base balance in particular, it is the body's ability to limit pH aberrations when factors that potentially affect it change. Buffering is vital for maintaining homeostasis of an organism. The present study was undertaken in order to investigate the probable buffering capacity changes in septic patients. MATERIALS AND METHODS: This prospective cohort study included 113 ICU patients (96 septic and 17 critically-ill non-septic/controls). The buffering capacity indices were assessed upon ICU admission and reassessed only in septic patients, either at improvement or upon severe deterioration. Applying Stewart's approach, the buffering capacity was assessed with indices calculated from the observed central venous-arterial gradients: a) ΔPCO2/Δ[H+] or ΔpH, b) ΔSID/Δ[H+] or ΔpH. RESULTS: In a generalized estimating equation linear regression model, septic patients displayed significant differences in ΔPCO2/ΔpH [beta coefficient = -47.63, 95% CI (-80.09) - (-15.17), p = 0.004], compared to non-septic patients on admission. Lower absolute value of ΔPCO2/ΔpH (%) on admission was associated with a significant reduction in ICU mortality (HR 0.98, 95% CI: 0.97-0.99, p = 0.02). At septic-group reassessment (remission or deterioration), one-unit increase of ΔPCO2/Δ[H+] reduced the ICU death hazard by 44% (HR 0.56, 95% CI: 0.33-0.96, p = 0.03). CONCLUSIONS: In the particular cohort of patients studied, a difference in the buffering capacity was recorded between septic and non-septic patients on admission. Moreover, buffering capacity was an independent predictor of fatal ICU outcome at both assessments, ICU-admission and sepsis remission or deterioration.

Subcutaneous Trastuzumab Combined with Pertuzumab and Docetaxel as First-line Treatment of Advanced HER2-positive Breast Cancer.

BACKGROUND/AIM: Subcutaneous (s.c.) trastuzumab was introduced in the (neo)adjuvant setting, based on the non-inferiority results and patient preference. In the advanced setting, preliminary safety data have only been reported. We conducted an observational study of s.c. trastuzumab in combination with i.v. pertuzumab and docetaxel in the first-line setting of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. PATIENTS AND METHODS: In this single-institution study, patients received 600 mg s.c. trastuzumab in combination with 840 mg pertuzumab for the first cycle and 420 mg for the following cycles, and 75-100 mg/m2 docetaxel, followed by maintenance with s.c. trastuzumab and pertuzumab until disease progression or unacceptable toxicity. Endpoints were efficacy and safety. RESULTS: Forty patients were enrolled. The median number of cycles with docetaxel was six, while the median number of maintenance cycles was 21. With a median follow-up of 37 months, median progression-free survival and overall survival were 24 and 35 months. CONCLUSION: Subcutaneous trastuzumab in combination with pertuzumab and docetaxel is well tolerated and effective in HER2-positive advanced breast cancer.

Variation of endothelium-related hemostatic factors during sepsis.

OBJECTIVE: The thrombomodulin/protein C and VWF/ADAMTS-13 pathways are disturbed in sepsis and have been implicated in the coagulation disorders that characterize the septic syndrome. We aimed to assess the variation of these endothelial parameters during sepsis and their putative association with outcome, in critically ill, septic patients. METHODS: We monitored 34 septic patients, 23 of whom improved (group A) while 11 deteriorated (group B). We assessed ADAMTS-13 levels, VWF activity, soluble thrombomodulin, and protein C activity upon admission to the ICU (time point 0) and at the time of a change in the clinical condition (remission or deterioration, time point 1). RESULTS: In group A, thrombomodulin and VWF increased at time point 1 compared to time point 0 (P = 0.011, P = 0.028, respectively). In group B, protein C and ADAMTS-13 significantly decreased (P = 0.023, P = 0.026, respectively), while VWF, VWF/ADAMTS-13 ratio, and the thrombomodulin/protein C ratio increased (P = 0.02, P = 0.002, P = 0.01, respectively). Protein C (> or ≤17%) and ADAMTS-13 percentage difference (> or ≤22%) were independently associated with sepsis outcome among the endothelial variables tested. CONCLUSIONS: An ongoing endothelial/hemostatic disorder was established during sepsis, observed even at clinical improvement. Among the variables tested, protein C and ADAMTS-13 change were associated with outcome.

Biweekly Gemcitabine/Nab-Paclitaxel as First-line Treatment for Advanced Pancreatic Cancer.

BACKGROUND/AIM: During recent years, a survival advantage was reported for first-line treatment of advanced pancreatic cancer with two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel, over gemcitabine monotherapy. Gemcitabine/nab-paclitaxel administration on days 1, 8 and 15 of a 4-week cycle is associated with some practical disadvantages. We adopted a biweekly regimen with the same dose density. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group performance status 0-2 diagnosed with advanced histologically or cytologically confirmed pancreatic cancer and no prior treatment were included in the study. Study combination included 1.5 g/m2 gemcitabine and 175 mg/m2 nab-paclitaxel given every 2 weeks. Survival analysis was performed using the Kaplan-Meier method. RESULTS: Forty-six patients were treated with this regimen. Adverse events were similar to those of the original regimen. Median progression-free and overall survival were 5 and 10 months, respectively. CONCLUSION: Biweekly gemcitabine/nab-paclitaxel seems to have a similar safety and efficacy profile as the original regimen.

Microcirculatory alterations during continuous renal replacement therapy in ICU: A novel view on the 'dialysis trauma' concept.

OBJECTIVE: The purpose of this study was to evaluate microcirculation over 24 h renal replacement therapy (CRRT) in critically ill patients. METHODS: We conducted a single-center, prospective, observational study, measuring microcirculation parameters, monitored by near infrared spectroscopy (NIRS) before hemodiafiltration onset (H0), and at six (H6) and 24 h (H24) during CRRT in critically ill patients. Serum Cystatin C (sCysC) and soluble (s)E-selectin levels were measured at the same time points. Twenty-eight patients [19 men (68%)] were included in the study. RESULTS: Tissue oxygen saturation (StO2, %) [76.5 ± 12.5 (H0) vs 75 ± 11 (H6) vs 70 ± 16 (H24), p = 0.04], reperfusion rate, indicating endothelial function (EF, %/sec) [2.25 ± 1.44 (H0) vs 2.1 ± 1.8 (H6) vs 1.6 ± 1.4 (H24), p = 0.02] and sCysC (mg/L) [2.7 ± 0.8 (H0) vs 2.2 ± 0.6 (H6) vs 1.8 ± 0.8 (H24), p < 0.0001] significantly decreased within the 24 h CRRT. Change of EF positively correlated with changes of sCysC within 24 h CRRT (r = 0.464, p = 0.013) while in patients with diabetes the change of StO2 correlated with dose (r = − 0.8, p = 0.01). No correlation existed between hemoglobin and temperature changes with the deteriorated microcirculation indices. sE-Selectin levels in serum were elevated; no difference was established over the 24 h CRRT period. A strong correlation existed between the sE-Selectin concentration change at H6 and H24 and the mean arterial pressure change in the same period (r = 0.77, p < 0.001). CONCLUSIONS: During the first 24 h of CRRT implementation in critically ill patients, deterioration of microcirculation parameters was noted. Microcirculatory alterations correlated with sCysC changes and with dose in patients with diabetes.

Comparison of resident performance in interpreting mammography results using a probabilistic or a natural frequency presentation: a multi-institutional randomized experimental study.

BACKGROUND: Residents are being increasingly challenged on how best to integrate diagnostic information in making decisions about patient care. The aim of this study is to assess the ability of residents to accurately integrate statistical data from a screening mammography test in order to estimate breast cancer probability and to investigate whether a simple alteration of the representation mode of probabilities into natural frequencies facilitates these computations. METHODS: A multi-institutional randomized controlled study of residents was performed in eight major hospitals in the city of Athens. Residents were asked to estimate the positive predictive value of the screening mammography test given its sensitivity and 1-specificity as well as the prevalence of breast cancer in the relevant population. One version of the scenario was presented in the single-event probability format that is commonly used in the medical literature, while the other used the natural frequency representation. The two questionnaire versions were randomly assigned to the participants. RESULTS: Out of 200 residents, 153 completed and returned the questionnaire (response rate 76.5%). Although more than one-third of the residents reported excellent or close to excellent familiarity with sensitivity and positive predictive value, the majority of responses (79.1%) were incorrect. However, a significantly higher proportion of residents in the natural frequency group (n = 88) selected the correct response compared with residents (n = 65) in the single-event probability group (28.4% vs 10.8%; 95% confidence intervals of the difference between the two proportions = 5.6-29.7%; P < 0.01). DISCUSSION: Residents more often correctly understand test performance accuracy when test characteristics are presented to them as natural frequency representations than the more common approach of presenting single event probabilities. Educators and journal editors should be aware of this facilitative effect.

Changes in skeletal muscle microcirculation after a hemodialysis session correlates with adequacy of dialysis.

BACKGROUND: Monitoring of the microcirculation may add additional information in terms of improving the adequacy of hemodialysis (HD) for patients. Withdrawal of liquid and complement activation during a HD session reduces the external pressure on the microcirculation and leads to an increased dilatation of the peripheral capillaries. The purposes of this study were to assess the effect of a single HD or hemodiafiltration session on the thenar microcirculation in patients with end-stage renal disease (ESRD) with or without diabetes, investigate the possible relationship between changes in the microcirculation and adequacy of dialysis (including Kt/V and parameters indicating secondary hyperparathyroidism), and compare microcirculation measurements obtained from patients with ESRD and those from healthy controls. METHODS: This pilot prospective observational study including eleven patients with ESRD on maintenance HD (nine men of mean age 73±10.5 years, ten [91%] with hypertension), nine patients with ESRD on maintenance hemodiafiltration (six men of mean age 65.5±13.2 years, five [55.5%] with diabetes and four [44.5%] with hypertension), and eight healthy volunteers. Two paired microcirculation assessments were recorded for each HD patient before and after a dialysis session. Near infrared spectroscopy and the vascular occlusion test were used to assess the microcirculation, and blood work samples were collected before and after dialysis when the pump slowed down. RESULTS: Patients with ESRD showed an increase in thenar cell metabolism at rest after a 4-hour HD session, and changes in cell metabolism correlated with the Kt/V of the session. Pre-dialysis tissue oxygen saturation over the 4-hour HD session correlated with pre-dialysis serum calcium and parathyroid hormones. Vascular reactivity was lower in ESRD patients receiving HD or hemodiafiltration than in healthy controls. CONCLUSION: Improvement in skeletal muscle microcirculation noted after a HD session was related to adequacy of dialysis. Evaluation of the microcirculation may provide additional information for management of patients on HD and identify novel targets for treatment. These preliminary findings need to be tested using a larger data set.

Assessment of cognitive biases and biostatistics knowledge of medical residents: a multicenter, cross-sectional questionnaire study.

PURPOSE: The aim of this study is to determine the perceived familiarity of medical residents with statistical concepts, assess their ability to integrate these concepts in clinical scenarios, and investigate their susceptibility to the gambler's fallacy and the conjunction fallacy. METHODS: A multi-institutional, cross-sectional survey of Greek medical residents was performed. Participants were asked to indicate their familiarity with basic statistical concepts and answer clinically oriented questions designed to assess their biostatistics knowledge and cognitive biases. Univariate, bivariate, and multivariate statistical models were used for the evaluation of data. RESULTS: Out of 153 respondents (76.5% response rate), only two participants (1.3%) were able to answer all seven biostatistics knowledge questions correctly while 29 residents (19%) gave incorrect answers to all questions. The proportion of correct answers to each biostatistics knowledge question ranged from 15 to 51.6%. Residents with greater self-reported familiarity were more likely to perform better on the respective knowledge question (all p<0.01). Multivariate analysis of the effect of individual resident characteristics on questionnaire performance showed that previous education outside Greece, primarily during medical school, was associated with lower biostatistics knowledge scores (p<0.001). A little more than half of the respondents (54.2%) answered the gambler's fallacy quiz correctly. Residents with higher performance on the biostatistics knowledge questions were less prone to the gambler's fallacy (odds ratio 1.38, 95% confidence intervals 1.12-1.70, p=0.003). Only 48 residents (31.4%) did not violate the conjunction rule. CONCLUSIONS: A large number of medical residents are unable to correctly interpret crucial statistical concepts that are commonly found in the medical literature. They are also especially prone to the gambler's fallacy bias, which may undermine clinical judgment and medical decision making. Formalized systematic teaching of biostatistics during residency will be required to de-bias residents and ensure that they are proficient in understanding and communicating statistical information.

Prediction of the renal replacement therapy requirement in mechanically ventilated critically ill patients by combining biomarkers for glomerular filtration and tubular damage.

PURPOSE: Mechanically ventilated critically ill patients with high severity score indices need a very cautious therapeutic approach. Considering that inappropriate decisions on renal replacement therapy (RRT) initiation may promote unwanted adverse effects, we evaluated whether a panel of novel and traditional renal markers is superior to conventional renal marker in predicting RRT requirements in this group of patients. METHODS: This was a prospective observational study, performed at the two distinct multidisciplinary intensive care units (ICUs) of a 1000-bed tertiary hospital. Of 310 consecutive patients, 106 patients fulfilled the inclusion criteria of the study. Urinary neutrophil gelatinase-associated lipocalin (uNGAL), serum creatinine (sCr) and serum cystatin C (sCysC) were determined on ICU admission. The predictive performance of all markers for first RRT was tested and compared based on the area under the receiver operating characteristic (ROC) curves. Time-dependent ROC curves were used to assess the earlier time point where the markers presented their maximum area under the curve (AUC). RESULTS: All studied biomarkers and acute physiology and chronic health evaluation (APACHE) II score, were significant independent predictors of RRT (uNGAL-AUC=0.73, sCysC-AUC=0.76, sCr-AUC=0.78, APACHE-AUC=0.73, P<0.0001). sCysC and sCr showed early maximum predictive ability within 10 days of ICU admission, while uNGAL and APACHE II score within 11 days of ICU admission. sCr combined with normalized (n)NGAL and sCysC combined with either nNGAL or uNGAL established best predictors for the RRT initiation (AUC-ROC=0.8). Distinguishing patients without acute kidney injury (AKI) on ICU entry, the combination of sCysC and APACHE II score proved best (AUC-ROC=0.78). CONCLUSIONS: Specific markers of kidney dysfunction and of kidney damage can be successfully combined to increase the prognostic capability for RRT initiation. The presence of AKI affects diagnostic performance. Without an established AKI on ICU admission, future RRT requirement was better predicted by the combination of illness severity with a marker of glomerular filtration rate. With AKI on ICU admission a combination of the marker of glomerular filtration rate with one of tubular injury proved best.

Myasthenia gravis and stroke in the setting of giant cell arteritis.

This case report concerns the diagnosis of two independent chronic diseases in a patient hospitalized for stroke, myasthenia gravis (MG) and giant cell arteritis (GCA). MG has been found to be associated with several diseases, but there are very few cases documenting its coexistence with GCA. We report the case of a 79-year-old woman initially hospitalized for stroke. Patient's concurrent symptoms of blepharoptosis, dysphagia, and proximal muscle weakness were strongly suggestive of myasthenia gravis. The persistent low-grade fever and elevated inflammatory markers in combination with the visual deterioration that developed also raised the suspicion of GCA. Histological examination confirmed GCA, while muscle acetylcholine receptor antibodies were also present. Even though in medicine one strives to interpret a patient's symptoms with one diagnosis, when one entity cannot fully interpret the clinical and laboratory findings, clinicians must consider the possibility of a second coexisting illness.

Microcirculation and macrocirculation in cardiac surgical patients.

Background. The aim of our study was to investigate the relationship between microcirculatory alterations after open cardiac surgery, macrohemodynamics, and global indices of organ perfusion. Methods. Patients' microcirculation was assessed with near-infrared spectroscopy (NIRS) and the vascular occlusion technique (VOT). Results. 23 patients undergoing open cardiac surgery (11 male/12 female, median age 68 (range 28-82) years, EuroSCORE 6 (1-12)) were enrolled in the study. For pooled data, CI correlated with the tissue oxygen consumption rate as well as the reperfusion rate (r = 0.56, P < 0.001 and r = 0.58, P < 0.001, resp.). In addition, both total oxygen delivery (DO(2), mL/min per m(2)) and total oxygen consumption (VO(2), mL/min per m(2)) also correlated with the tissue oxygen consumption rate and the reperfusion rate. The tissue oxygen saturation of the thenar postoperatively correlated with the peak lactate levels during the six hour monitoring period (r = 0.50, P < 0.05). The tissue oxygen consumption rate (%/min) and the reperfusion rate (%/min), as derived from the VOT, were higher in survivors compared to nonsurvivors for pooled data [23 (4-54) versus 20 (8-38) P < 0.05] and [424 (27-1215) versus 197 (57-632) P < 0.01], respectively. Conclusion. Microcirculatory alterations after open cardiac surgery are related to macrohemodynamics and global indices of organ perfusion.

Electrical muscle stimulation: an effective form of exercise and early mobilization to preserve muscle strength in critically ill patients.

Purpose. This is a secondary analysis of previously published data to investigate the effects of electrical muscle stimulation (EMS) on strength of various muscle groups in critically ill patients. Methods. One hundred forty-two consecutive patients, with APACHE II score ≥ 13, were randomly assigned to the EMS or the control group. EMS sessions were applied daily on vastus lateralis, vastus medialis, and peroneus longus of both lower extremities. Various muscle groups were evaluated with the Medical Research Council (MRC) scale for muscle strength. Handgrip strength assessment was also employed. Results. Twenty four patients in the EMS group and 28 patients in the control group were finally evaluated. EMS patients achieved higher MRC scores than controls (P ≤ 0.05) in wrist flexion, hip flexion, knee extension, and ankle dorsiflexion. Collectively, the EMS group performed higher (P < 0.01) in the legs and overall. Handgrip strength correlated (P ≤ 0.01) with the upper and lower extremities' muscle strength and the overall MRC scores. Conclusions. EMS has beneficial effects on the strength of critically ill patients mainly affecting muscle groups stimulated, while it may also affect muscle groups not involved presenting itself as a potential effective means of muscle strength preservation and early mobilization in this patient population.

The effort-reward imbalance questionnaire in Greek: translation, validation and psychometric properties in health professionals.

OBJECTIVES: The aim of the present study was to translate, adapt and validate the Effort-reward imbalance (ERI) questionnaire in a sample of Greek healthcare professionals. METHODS: An internationally recommended methodology was followed to perform translation of the ERI instrument into the Greek language. The questionnaire was then randomly administered to 600 Greek physicians, nurses, physiotherapists and laboratory staff, and 456 questionnaires with no missing data on the ERI items were returned (76% response rate). Tool validation included assessment of internal consistency, factorial structure, discriminant validity and presence of floor or ceiling effects. Criterion validity was demonstrated by investigating the association of theoretically relevant ERI summary measurements with respondents' self-rated health. RESULTS: The Greek version of the ERI questionnaire showed good psychometric properties. Cronbach's alpha values were 0.79, 0.72 and 0.75 for the three ERI scales of effort, reward and overcommitment respectively. Exploratory factor analysis yielded a 5-factor solution that closely reflected the original theoretical ERI model. Significant associations were found between respondents' age, gender and specific occupation with ERI scores. ERI ratio and "overcommitment" scores in the highest tertiles were associated with elevated odds ratios (OR) of below-average self-rated health (OR=5.38, 95% confidence intervals 1.77 to 16.38, p=0.003, and OR=3.41, 95% confidence intervals 1.39 to 8.38, p=0.007, respectively). CONCLUSIONS: The translated and adapted Greek version is comparable with the original ERI instrument in terms of validity and factorial structure and is suitable for assessment of the psychosocial work environment of Greek healthcare professionals.

Lung sonography and recruitment in patients with early acute respiratory distress syndrome: a pilot study.

INTRODUCTION: Bedside lung sonography is a useful imaging tool to assess lung aeration in critically ill patients. The purpose of this study was to evaluate the role of lung sonography in estimating the nonaerated area changes in the dependent lung regions during a positive end-expiratory pressure (PEEP) trial of patients with early acute respiratory distress syndrome (ARDS). METHODS: Ten patients (mean ± standard deviation (SD): age 64 ± 7 years, Acute Physiology and Chronic Health Evaluation II (APACHE II) score 21 ± 4) with early ARDS on mechanical ventilation were included in the study. Transthoracic sonography was performed in all patients to depict the nonaerated area in the dependent lung regions at different PEEP settings of 5, 10 and 15 cm H2O. Lung sonographic assessment of the nonaerated lung area and arterial blood gas analysis were performed simultaneously at the end of each period. A control group of five early ARDS patients matched for APACHE II score was also included in the study. RESULTS: The nonaerated areas in the dependent lung regions were significantly reduced during PEEP increases from 5 to 10 to 15 cm H2O (27 ± 31 cm2 to 20 ± 24 cm2 to 11 ± 12 cm2, respectively; P < 0.01). These changes were associated with a significant increase in arterial oxygen partial pressure (74 ± 15 mmHg to 90 ± 19 mmHg to 102 ± 26 mmHg; P < 0.001, respectively). No significant changes were observed in the nonaerated areas in the dependent lung regions in the control group. CONCLUSIONS: In this study, we show that transthoracic lung sonography can detect the nonaerated lung area changes during a PEEP trial of patients with early ARDS. Thus, transthoracic lung sonography might be considered as a useful clinical tool in the management of ARDS patients.