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Background: His bundle (HB) potentials vary in amplitude and duration in patients with and without slow pathways. The aim of this study was to determine the characteristics of HB potentials and to elucidate whether they can provide clues for identification of slow pathway (SP). Methods: The present research prospectively studied the electrophysiological findings of 162 patients with symptomatic atrioventricular nodal reentrant tachycardia (AVNRT) due to slow-fast or fast-slow type and atrioventricular reentrant tachycardia (AVRT). Maximal HB potential (HBmax, HB with the highest amplitude) among HB cloud was recorded in both groups. For AVNRT patients, the following were measured: (1) AH interval at the “jump” during programmed atrial stimulation (A2H2, taken as a reflection of SP conduction time); (2) Distance from HBmax to the successful SP ablation site (HBmax-ABL) and from HBmax to the ostium of coronary sinus (HBmax-CSO). Results : HBmax was 0.29 ± 0.10 mV in AVNRT patients, whereas it was 0.17 ± 0.05 mV in AVRT group (p < 0.0001). Likewise, the HBmax duration was 22 ± 5 ms in AVNRT group and 16 ± 3 ms in AVRT group (p < 0.0001). The area under the ROC curve of HBmax amplitude in AVNRT patients was 0.86 and the optimal HBmax cut-off to predict AVNRT was ≥ 0.22 mV with a sensitivity of 0.78 and specificity of 0.84. HBmax-CSO was positively correlated with HBmax-ABL, and HBmax-ABL was positively correlated with A2H2. Conclusions : HBmax amplitudes were higher and durations longer in patients with AVNRT, as compared to those with AVRT. Moreover, the distance between HBmax and successful ablation site was positively correlated with the SP conduction time and with the distance from HBmax to the CS ostium.

Non-immune hydrops fetalis is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities. The prevalence of non-immune hydrops fetalis is unknown. Currently, about 90% of cases of hydrops fetalis are non-immune hydrops fetalis. Non-immune hydrops fetalis causes are multi-factorial. The pathophysiological mechanism of non-immunologic hydrops fetalis is related to ab-normal fluid transportation between plasma and tissues. This is due to the increase in hydrostatic capillary pressure and capillary permeability and a reduction of the plasma osmotic pressure or lymphatic flow.A variety of viral infection agents have been associated with non-immune hydrops fetalis like parvovirus B19, herpes simplex virus, cytomegalovirus, Toxoplasma gondii, Treponema pallidum, but even other viruses that attack the maternal and fetus during pregnancy cannot be excluded as possible causes of non-immune hydrops fetalis. We present one case of non-immune hydrops fetalis who was diagnosed intra-uterine, three weeks after recovery from Coronavirus disease (COVID-19). After much investigation, we could not find any known factor that may be the cause of non-immunologic hydrops fetalis. Therefore, we predisposed a possible causal connection between non-immunologic hydrops fetalis and Coronavirus disease (COVID-19).

Introduction: Large and consistent evidence supports the use of eribulin mesylate in clinical practice in third or later line treatment of metastatic triple negative breast cancer (mTNBC). Conversely, there is paucity of data on eribulin efficacy in second line treatment. Methods: We investigated outcomes of 44 mTNBC patients treated from 2013 through 2019 with second line eribulin mesylate in a multicentre retrospective study involving 14 Italian oncologic centres. Results: Median age was 51 years, with 11.4% of these patients being metastatic at diagnosis. Median overall survival (OS) and progression free survival (PFS) from eribulin starting were 11.9 (95%CI: 8.4-15.5) and 3.5 months (95%CI: 1.7-5.3), respectively. We observed 8 (18.2%) partial responses and 10 (22.7%) patients had stable disease as best response. A longer PFS on previous first line treatment predicted a better OS (HR=0.87, 95%CI: 0.77-0.99, p= 0.038) and a longer PFS on eribulin treatment (HR=0.92, 95%CI: 0.85-0.98, p=0.018). Progression free survival to eribulin was also favorably influenced by prior adjuvant chemotherapy (HR=0.44, 95%CI: 0.22-0.88, p=0.02). Eribulin was generally well tolerated, with grade 3-4 adverse events being recorded in 15.9% of patients. Conclusions: The outcomes described for our cohort are consistent with those reported in the pivotal Study301 and subsequent observational studies. Further data from adequately-sized, ad hoc trials on eribulin use in second line for mTNBC are warranted to confirm our findings.

Background In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. Methods We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). Results In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions. Conclusions Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.

Aim: To investigate the association between maternal post-traumatic stress disorder (PTSD) during pregnancy and offspring DNA methylation and cortisol levels. Materials & methods: Blood genome-wide DNA methylation and cortisol was measured in the youngest child of 117 women who experienced sexual violence/torture during the Kosovo war. Results: Seventy-two percent of women had PTSD symptoms during pregnancy. Their children had higher cortisol levels and differential methylation at candidate genes ( NR3C1, HTR3A and BNDF) . No methylation differences reached epigenome-wide corrected significance levels. Conclusion: Identifying the biological processes whereby the negative effects of trauma are passed across generations and defining groups at high risk is a key step to breaking the intergenerational transmission of the effects of mental disorders.

SMARCA4-deficient thoracic sarcoma is a newly described entity of thoracic sarcomas with a poor prognosis, defined by poorly differentiated epithelioid to rhabdoid histomorphology and SMARCA4 gene inactivation. We present a case of a SMARCA4-deficient thoracic sarcoma in a 41-year-old male with a smoking history who presented with an upper anterior mediastinal mass, after seeking medical evaluation for increasing thoracic pain, odynophagia, and dizziness. The biopsy confirmed a large cell tumor with an epithelioid to rhabdoid histomorphology, positive for EMA, CD99, vimentin, TLE1, INI1, PAS-positive cytoplasmic granules, and PD-L1 (100% of tumor cells). High TMB and HRD scores were displayed in the tumor. The histology and immunophenotype of the mass were in line with the diagnosis of SMARCA4-deficient thoracic sarcoma. In the course of his treatment, the patient showcased a partial response to pembrolizumab and the combination of pembrolizumab and ipilimumab. This case report highlights the importance of recognizing SMARCA4-deficient thoracic sarcoma as an individual entity and supports the importance of checkpoint inhibition therapy for SMARCA4-deficient thoracic sarcomas, particularly in cases with a high TMB and PD-L1 expression.

Background This study describes the long-term survival, risk of reoperation and clinical outcomes of patients undergoing solitary surgical aortic valve replacement (SAVR) with a Carpentier-Edwards Perimount (CE-P) bioprosthetic in Western Denmark. The renewed interest in SAVR is based on the questioning regarding the long-term survival since new aortic replacement technique such as transcatheter aortic-valve replacement (TAVR) probably have shorter durability, why assessment of long-term survival could be a key issue for patients. Methods From November 1999 to November 2013 a cohort of a total of 1604 patients with a median age of 73 years (IQR: 69–78) undergoing solitary SAVR with CE-P in Western Denmark was obtained November 2018 from the Western Danish Heart Registry (WDHR). The primary endpoint was long-term survival from all-cause mortality. Secondary endpoints were survival free from major adverse cardiovascular and cerebral events (MACCE), risk of reoperation, cause of late death, patient-prothesis mismatch, risk of AMI, stroke, pacemaker or ICD implantation and postoperative atrial fibrillation (POAF). Time-to-event analysis was performed with Kaplan-Meier curve, cumulative incidence function was performed with Nelson-Aalen cumulative hazard estimates. Cox regression was applied to detect risk factors for death and reoperation. Results In-hospital mortality was 2.7% and 30-day mortality at 3.4%. The 5-, 10- and 15-year survival from all-cause mortality was 77, 52 and 24%, respectively. Survival without MACCE was 80% after 10 years. Significant risk factors of mortality were small valves, smoking and EuroSCORE II ≥4%. The risk of reoperation was Conclusions Patients undergoing aortic valve replacement with a Carpentier-Edwards Perimount valve shows a very satisfying long-term survival. Future research should aim to investigate biological valves long-term durability for comparison of different SAVR to different TAVR in long perspective.

Breast cancer (BC) heterogeneity is composite in nature, with a wide variety of factors concurring to define several pathological entities, which differ by clinical presentation, pathologic features, therapy administered, and inherent outcomes1. Additional sources of breast cancer heterogeneity may raise during the disease course. In BC patients whose disease was initially diagnosed in the early stage and subsequently progressed with metastatic involvement of one single or multiple site/s, the molecular characteristics of metastatic lesions do not necessary mimic those of the disease initially diagnosed. A well-depicted molecular landscape is crucial for subtype definition, prognostic evaluation and appropriate therapeutic decisions. Accordingly, current guidelines suggest repeating the immunohistochemical (IHC) assessment in patients with metastatic spread and at least one secondary lesion amenable to biopsy2. Discordance in human epidermal growth factor receptor 2 (HER2) status between the tumor and metastatic lesions is widely acknowledged, and not yet completely unraveled in their biologic meaning and prognostic relevance3–11. The overexpression of HER2 or amplification of the related gene is extensively recognized as a feature associated with more aggressive biological behavior12,13. However, the extent to which changes in HER2 status may affect patients’ prognosis is still a matter of debate14. We herein propose an observational study of HER2-positive metastatic breast cancer (mBC) patients treated with the anti-HER2 targeted agents pertuzumab and/or trastuzumab emtansine (T-DM1). Our research question is whether relevant differences exist in long-term outcomes of patients with concordant HER2 status between the primary tumor and its secondary lesion/s compared to patients whose disease revealed HER2-positivity gain at the IHC assessment of metastatic lesions. In our historical cohorts, we also sought to identify factors associated with HER2-positivity gain at the IHC reassessment, for which an impact on prognosis may be foreseen.

Substantial changes in the management of cancer patients have been required worldwide in response to the COVID‐19 pandemic. Beyond the due details on the primitive cancer site and setting at diagnosis, these latter adaptions are most commonly exemplified by a significant reduction in the screening of asymptomatic subjects, delays in elective surgery and radiotherapy for primary tumors, and dose reductions and/or delays in systemic therapy administration. Advanced breast cancer patients with hormonal receptor positive, HER2 negative tumors are usually treated with endocrine therapy combined with CDK 4/6 inhibitors as first‐ and second‐line treatment. During the pandemic, experts’ recommendations have suggested the omission or delay of CDK 4/6 inhibitors delivery, or a careful evaluation of their real need due to the hypothesized increased risk of SARS‐Cov‐2 infection and disease possibly related to neutropenia. The inherent literature is sparse and inconsistent. We herein present data on the use of CDK 4/6 inhibitors during the pandemic. The evidence reported punctually reflects the experience matured at our Institution, a comprehensive cancer centre, on the topic of interest.

Background and Purpose: Measures taken to prevent COVID-19 infections, aside from causing disruptions in many facets of our daily life, have impeded education, including the higher education process, as never seen before on a global scale. Recent studies have indicated the potential negative impact of the COVID-19 pandemic on the mental health trajectory of university students. Anxiety and depression can seriously hamper students’ quality of life and educational achievement. This study explored anxiety and depression among university students in Kosovo during the lockdown as a result of COVID-19 pandemics. The study was implemented during the initial phase of the pandemic. This study also explored the impact of selected determinants on the reported mental health of students. Methods: In total, 904 university students from the largest public university in Kosovo were enrolled in a web-based cross-sectional study during the early phase of the national lockdown due to the COVID-19 pandemic. Results: The first and second hierarchical regression models indicated that the anxiety and depression scores of students were predicted by gender, knowing someone who was infected with COVID-19, concerns about the potential financial impact of measures taken by governments to respond to the COVID-19 pandemic and excessive information seeking about COVID-19. The third model improved significantly when the variables concerns about family members’ health, concerns about being lonely, problems with online lectures and requests for help from the university related to online lectures were added to the model. Overall, the findings indicated that situational variables associated with measures taken to respond to the COVID-19 pandemic appeared to predict anxiety and depression among students. Conclusion: These findings indicate that universities and public health institutions need to support students, especially the more vulnerable students, in enhancing their skills to cope with mental health problems and distress related to the pandemic and the shift to online learning.

Among children who sustain mild traumatic brain injury (mTBI), 10-30% develop a cluster of cognitive, physical, and emotional symptoms commonly referred to as post-concussion syndrome (PCS). Symptoms typically resolve within 7-10 days, but a minority of patients report symptoms that persist for months or even years. The aim of our study was to identify a neurobiochemical marker after mTBI that can predict the presence of post-concussion syndrome three months after head injury in paediatric patients.Children between 7 and 16 years of age who had head trauma and no other complaints were included. Three months after the initial visit, participants or parents/guardians were interviewed in person about the children's PCS symptoms using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ).The mean value of S100B protein in serum in 38 patients without signs of PCS was 0.266 μg LOur prospective study showed that S100B protein is a useful neurobiomarker for detecting paediatric patients at risk for post-concussion syndrome. We found that the biomarker S100B correlated with the severity of traumatic brain injury (number of lesions on CT) and the presence of post-concussion syndrome.

BackgroundHER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.MethodsThe biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.ResultsWe herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients.Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).ConclusionsOur data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Brugada syndrome is an arrhythmogenic disease with often fatal outcome in otherwise healthy and young individuals. Anamnesis and ECG are cornerstones in a syncope workup. In our case, a 27-year-old male presented to the emergency department due to recurrent syncope. Repeated 12‑lead-ECGs revealed a type 2 Brugada pattern. A positive drug challenge suggested a Brugada syndrome and electrophysiological testing reproducibly induced monomorphic ventricular tachycardia. Consequently, an ICD was implanted for secondary prevention. On 2-year follow-up, the patient remained free from other arrhythmic events or ICD interventions.

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65–10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25–15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

The main aim of the present study was to investigate the moderating role of aggressive driving of others on the relationship between self-reported aggressive driving behaviors committed by driver himself/herself and drivers’ aberrant and positive driver behaviors (i.e. errors, violations, and positive driver behaviors) among drivers from Estonia, Greece, Kosovo, Russia, and Turkey as the total sample in order to understand the grand pattern. The other aim was to examine the same moderating role of aggressive driving for each country separately. It was hypothesized that the combination of self-reported of aggressive driving behaviors committed by the driver himself/herself and perceiving aggressive acts of other drivers against them associates with more errors and violations for each country and the total sample. On the other hand, this combination was expected to associate with less positive driver behaviors. Surveys were completed by 743 participants from five countries (i.e., Estonia, Greece, Kosovo, Russia, and Turkey). The Driver Anger Indicators Scale (DAIS) and the short version of the Driver Behavior Questionnaire (DBQ) with items of Positive Driver Behavior Scale were used as measurement tools. Moderation analyses were conducted for the total sample and each country separately. The results of the moderation analyses indicated that there was a moderating role of perceiving other drivers as engaging in aggressive behaviors on the relationship between aggressive behaviors of the driver himself/herself and their errors or violations in the total sample and every country except for Russia. However, the significant interaction between aggressive behaviors committed by the driver himself/herself and other drivers' aggressive acts in traffic was related to more positive driver behaviors for Kosovar drivers and less positive driver behaviors for Russian drivers and the total sample. It could be discussed that the way of understanding aggressive behaviors for self and other related to aberrant and positive driver behaviors in traffic may be important to manage aggression for individual level and country level.

Emergency medical care in palliative patients during the COVID-19 pandemic, it is important to provide a consistent treatment for stable patients that should be consistent with the goals and benefits, the perspective of these patients, but avoiding palliative patients with a poor prognosis that is unlikely to survive. Cancer is the second leading cause of death in the world around 8.8 million deaths a year. Worldwide, about 7-10 million patients are diagnosed with cancer each year, recently there has been a significant increase in the number of cases diagnosed with cancer. About 70% of cancer deaths are in low- and middle-income countries. The goals of emergency medical care based on the criteria of BLS and ACLS, that is should be done “Do not do resuscitation, do not intubate but continue medical treatment excluding endotracheal intubation without prospects for the patient, but offering BLS only treatment concentrated symptomatic. ED is often the only place that can provide the necessary medical interventions (e.g., intravenous fluids or pain management medications. Medications as well as immediate access to advanced diagnostic tests when needed such as CT, RM and other diagnostic and treatment procedures.

Highlights • Hydatid disease is a parasitic infestation by a tapeworm of the genus Echinococcosis of which 50%–75% of hydatid cysts occur in the liver. • In approximately one-fourth of the cases, hepatic hydatid cyst ruptures into the biliary tree producing obstructive jaundice. • Moreover, primary hydatid cysts of the biliary tract have been reported in English literature. • This is an interesting and intriguing case of obstructive jaundice caused by hydatid cyst in extrahepatic ducts 13 years after liver hydatid endocystectomy. • ERCP represent an important management strategy for patients with hydatid cysts in extra-hepatic ducts even primary or complications of liver hydatid cyst., Introduction Hydatid disease affects most commonly the liver, and complications with the rupture into the biliary tree develop in approximately one-fourth of the cases. Moreover, primary hydatid cysts of the biliary tract have been reported. Presentation of case We report an extremely rare case of obstructive jaundice caused by hydatid cyst in extrahepatic ducts 13 years after liver hydatid endocystectomy treated by Endoscopic retrograde cholangiopancreatography (ERCP). A 28-year-old male patient who had undergone surgical treatment – removal of liver hydatid cyst 13 years earlier, presented with signs of obstructed jaundice, confirmed with blood tests results and magnetic resonance cholangiopancreatography (MRCP). Actually, there were no pathological changes detected in the hepatic parenchyma, but the intrahepatic and extrahepatic bile ducts were dilated. ERCP was performed and the entire hydatid material was evacuated and washed out into the gastrointestinal tract. In addition, after laparoscopic cholecystectomy, hydatid cysts were also confirmed in the gallbladder. Discussion Generally, the obstructive jaundice caused by hydatid cyst in the extrahepatic ducts can also be caused by the rupture of the liver hydatid cyst in the biliary tract, or by primary hydatid cyst in the biliary tract. The ERCP plays a key role in the diagnosis and the treatment of this pathology. Conclusion The ERCP, has now become an important diagnostic and therapeutic procedure in management of primary extrahepatic hydatid cysts and of complicated liver hydatid cysts.

Medical plants, including Vitex agnus-castus L., Lamiaceae, were used in folk medicine for a long time; however, V. agnus-castus mechanisms of actions on trachea are not known. This study was attempted to give evidence for medicinal use of V. agnus-castus as a relaxant and to identify its underlying mechanisms. To this end, V. agnus-castus extract was extracted with ethanol and tested in rabbit tracheal smooth muscle using isolated organ baths. The V. agnus-castus extract (0.15–60 mg/ml) relaxed against acetylcholine-induced constriction in isolated rabbit tracheal smooth muscle, in vitro. Further, V. agnus-castus extract (0.15–75 mg/ml) shown relaxing effects in carbachol and high K-induced contraction of rabbit tracheal smooth muscle, implying antimuscarinic and calcium channel blocking activities. The addition (preincubation) of L-NAME (inhibitor of nitric oxide synthases), as well as indomethacin (cyclooxygenase inhibitor), inhibited (102%, 95% respectively) relaxing effects induced by V. agnus-castus extract precontracted with carbachol. On the other hand, bradykinin (stimulator of nitric oxide synthases) and zaprinast (phosphodiesterase inhibitor) further potentiated (40%, 41%, respectively) relaxing-induced effects by the V. agnus-castus extract. Our data suggest that V. agnus-castus extract airway-relaxing properties have muscarinic antagonism, are dependent on calcium blockade, and are at least partly mediated by the nitric oxide/cyclic guanosine monophosphate- and cyclooxygenase-1-prostaglandin E2-dependent mechanisms. These effects justify V. agnus-castus extract use in various respiratory disorders.

This event reflects the author's involvement in internationally recognized education and training models, as ATLS, ETC, and DSTC, and UEMS Boards of Emergency SurgeryDo different countries need very different things? I don’t think so, for the simple reason that in Europe and about the challenges we face, with regard to trauma and other medical and surgical emergencies, similarities are much greater than differences.• We all agree on the need for a trauma system “to assure that patients (…) seamlessly receive the proper care, in the proper locations, with proper interventions and, if necessary, transfer to a hospital able to provide the best and most appropriate care” (www.aast.org).• We all agree that teamwork is necessary for prehospital care, transportation, emergency room care, intensive care, surgery, and in/post-hospital rehabilitation.• We all agree on the need for trauma registries with, as much as possible, global follow-up of patient's course.• And finally, we all agree that it is necessary to educate, how to prevent and how to treat.This is also apparent from the recommendations of the European Trauma Course Organization (ETCO) about equipment and facilities: complete trauma team, trauma admission bay close to the ambulance entrance, enough space and adequate lighting, the adjacent operating room to allow emergency procedures, standardequipment for the initial management of major trauma, immediate availability of additional equipment as difficult airway equipment, X-ray, ultrasound machine, surgical instruments, readily available bloodproducts and massive transfusion equipment, co-located CT scanner to allow immediately imaging and access to angiography and interventional radiology, 24 hours a day within 30-60 minutes of request.

Radioimmunotherapy (RIT) aims to deliver a high radiation dose to cancer cells, while minimizing the exposure of normal cells. Typically, monoclonal antibodies are used to target the radionuclides to cancer cell surface antigens. However, antibodies face limitations due to their poor tumor penetration and suboptimal pharmacokinetics, while the expression of their target on the cancer cell surface may be gradually lost. In addition, most antigens are expressed in a limited number of tumor types. To circumvent these problems, we developed a Nanobody (Nb)-based RIT against a prominent stromal cell (stromal-targeting radioimmunotherapy or STRIT) present in nearly all tumors, the tumor-associated macrophage (TAM). Macrophage Mannose Receptor (MMR) functions as a stable molecular target on TAM residing in hypoxic areas, further allowing the delivery of a high radiation dose to the more radioresistant hypoxic tumor regions. Since MMR expression is not restricted to TAM, we first optimized a strategy to block extra-tumoral MMR to prevent therapy-induced toxicity. A 100-fold molar excess of unlabeled bivalent Nb largely blocks extra-tumoral binding of Lu-177-labeled anti-MMR Nb and prevents toxicity, while still allowing the intra-tumoral binding of the monovalent Nb. Interestingly, three doses of Lu-177-labeled anti-MMR Nb resulted in a significantly retarded tumor growth, thereby outcompeting the effects of antiPD1, anti-VEGFR2, doxorubicin and paclitaxel in the TS/A mammary carcinoma model. Together, these data propose anti-MMR STRIT as a valid new approach for cancer treatment.

Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells. In this study, we developed and characterized single-domain antibodies (sdAbs) against the MM-antigen CS1 and evaluated its therapeutic potential in MM using TRNT. We first validated CS1 as potential target for TRNT. CS1 is expressed in normal and malignant plasma cells in different disease stages including progression and relapse. It is expressed in dormant as well as proliferating MM cells, while low expression could be observed in environmental cells. Biodistribution studies demonstrated the specific uptake of anti-CS1 sdAbs in tissues of 5TMM cell infiltration including bone, spleen and liver. TRNT using anti-CS1 sdAbs labeled with actinium-225 significantly prolonged survival of syngeneic, immunocompetent 5T33MM mice. In addition, we observed an increase in CD8+ T-cells and more overall PD-L1 expression on immune and non-immune cells, implying an interferon gamma signature using actinium-225 labeled CS1-directed sdAbs. In this proof-of-principle study, we highlight, for the first time, the therapeutic potential and immunomodulating effects of anti-CS1 radionuclide therapy to target residual MM cells.