Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography

Cancer therapy has shown terrific progress leading to important reduction of morbidity and mortality of several kinds of cancer. The therapeutic management of oncologic patients includes combinations of drugs, radiation therapy and surgery. Many of these therapies produce adverse cardiovascular complications which may negatively affect both the quality of life and the prognosis. For several years the most common noninvasive method of monitoring cardiotoxicity has been represented by radionuclide ventriculography while other tests as effort EKG and stress myocardial perfusion imaging may detect ischemic complications, and 24-hour Holter monitoring unmask suspected arrhythmias. Also biomarkers such as troponine I and T and B-type natriuretic peptide may be useful for early detection of cardiotoxicity. Today, the widely used non-invasive method of monitoring cardiotoxicity of cancer therapy is, however, represented by Doppler-echocardiography which allows to identify the main forms of cardiac complications of cancer therapy: left ventricular (systolic and diastolic) dysfunction, valve heart disease, pericarditis and pericardial effusion, carotid artery lesions. Advanced ultrasound tools, as Integrated Backscatter and Tissue Doppler, but also simple ultrasound detection of "lung comet" on the anterior and lateral chest can be helpful for early, subclinical diagnosis of cardiac involvement. Serial Doppler echocardiographic evaluation has to be encouraged in the oncologic patients, before, during and even late after therapy completion. This is crucial when using anthracyclines, which have early but, most importantly, late, cumulative cardiac toxicity. The echocardiographic monitoring appears even indispensable after radiation therapy, whose detrimental effects may appear several years after the end of irradiation

MRI-guided focused ultrasound surgery in musculoskeletal diseases: the hot topics

MRI-guided focused ultrasound surgery (MRgFUS) is a minimally invasive treatment guided by the most sophisticated imaging tool available in today's clinical practice. Both the imaging and therapeutic sides of the equipment are based on non-ionizing energy. This technique is a very promising option as potential treatment for several pathologies, including musculoskeletal (MSK) disorders. Apart from clinical applications, MRgFUS technology is the result of long, heavy and cumulative efforts exploring the effects of ultrasound on biological tissues and function, the generation of focused ultrasound and treatment monitoring by MRI. The aim of this article is to give an updated overview on a "new" interventional technique and on its applications for MSK and allied sciences

ULTRASOUND OSTEOTOMY: EVOLUTION OF SURGICAL TECHNIQUE IN ONCOLOGICAL SPINAL NEUROSURGERY

Background. I tumori spinali (SCT) possono essere classificati in: tumori extradurali-extramidollari (60%), tumori intradurali-extramidollari (30%, come neurinomi e meningiomi) e tumori intradurali-intramidollari (10%, come astrocitomi ed ependimomi). La chirurgia è il gold standard di trattamento, eseguita con l’aiuto del monitoraggio neurofisiologico intra operatorio. Istologia (secondo la classificazione WHO 2016), la regione coinvolta, grado di resezione, età del paziente sono i fattori che determinano la prognosi. L’evoluzione della chirurgia spinale è relativamente opaca, solo negli ultimi anni il numero di pazienti candidati alla chirurgia vertebrale mininvasiva e con strumenti di alta qualità è aumentato in modo significativo. Sonopet® è sicuro per la dura madre, nervi e vasi e consiste in un manipolo e in una console con tre funzioni distinte, vibrazione longitudinale, irrigazione e aspirazione. Scopo dello studio. Il nostro studio prende in considerazione lo sviluppo della tecnica chirurgica in oncologia spinale nel corso degli anni fino alla moderna Neurochirurgia. Descriviamo come il dispositivo Aspiratore Osseo ad Ultrasuoni (Sonopet®) approccia i tumori spinali. Inoltre, esaminiamo retrospettivamente i pazienti sottoposti a intervento chirurgico per tumori spinali presso la Neurochirurgia Universitaria, Dipartimento di Neuroscienze DNS, presso l’Università di Padova negli ultimi anni, concentrandoci sulla rilevanza di questa moderna tecnica chirurgica. Materiali e metodi. Presentiamo una serie monocentrica di pazienti in cui abbiamo usato l’osteotomo ad ultrasuoni per eseguire laminotomie con scarsa morbidità, in modo meno invasivo, maneggevole e accurato, evitando lesioni durali, minimizzando le perdite ematiche e migliorando la qualità dell’intervento. I tumori del midollo spinale da C2 a S1, gli istotipi della popolazione adulta e pediatrica sono criteri di inclusione; le lesioni cerebrali e disordini degenerativi spinali sono stati esclusi. Abbiamo identificato 39 pazienti, per un totale di 42 interventi, raccogliendo dati su età, sesso, tempi operatori, strumenti, perdite ematiche, insorgenza dei sintomi, status neurologico, RMN cerebrali e CT con e senza contrasto alla dimissione e a 30 giorni, tecniche chirurgiche (laminotomie, laminectomie). Abbiamo valutato le complicanze post-operatorie, il follow up neurologico e neuroradiologico tramite RX della colonna a 30 giorni e una RMN spinale a 6 mesi. Il follow-up riportava un range 6-48 mesi e media 34 mesi. Risultati. La popolazione considerata aveva un’ età media di 46 anni, il rapporto M:F era 1.4:1, il 23.8% di un’ età compresa tra 50 e 60 anni, il 31% delle operazioni riguardava il distretto toracico e il 23.8% quello lombare, il 38.1% registrava il coinvolgimento di due vertebre e il 23.8% di una. I neurinomi e le lesioni espansive intramidollari (ciascuno 28.6%) erano le diagnosi più frequenti. Le laminotomie eseguite sono state 14 (33.3%), coinvolgendo il Sonopet® in 9 interventi (64.3%). Il tempo medio con l’osteotomo ad ultrasuoni è stato di 278 minuti per le laminotomie e 228 min per le laminectomie. Le perdite ematiche hanno mostrato valori di Hb inferiori in entrambi gli approcci, ma più nelle laminectomie (110 g/L vs 118 g/L nelle laminotomie). Nel 50% delle procedure (n=21) si sono verificate delle complicanze minori (parestesie), che si sono risolte spontaneamente dopo alcune settimane. Solo in 8 casi dei 21 che hanno presentato complicanze era stato eseguito l’approccio chirurgico con Sonopet®. In questa popolazione non si sono riscontrate fistole liquorali. Conclusioni. Ulteriori studi sono necessari, l’uso dell’aspiratore ad ultrasuoni Sonopet® è utile in interventi di chirurgia spinale e dovrebbe essere incoraggiato.Background. Spinal cord tumors (SCTs) can be classified into extradural- extramedullary tumors (60%), intradural-extramedullary tumors (30%, as neurinomas and meningiomas) and intradural-intramedullary tumors (10%, as astrocytomas and ependymomas). Surgical treatment is the gold standard, with the help of intraoperative neurophysiological monitoring (IONM). Histology sec. the WHO 2016 classification, region involved, degree of resection, age of patient are the factors that determine the prognosis. Evolution of spine surgery is relatively opaque, only in recent years the number of patients candidates for minimally invasive spine surgery and with high quality tools has expanded significantly. Sonopet® is safe for dura mater, nerves and vessels and consists of an handpiece and a console with three function, longitudinally vibration, irrigation and suction. Aims. Our study takes under attention the development of surgical technique in spinal oncology over the years up to modern Neurosurgery. We describe how the Ultrasound Bone Aspirator device (Sonopet®) approach spinal tumors. Furthermore, we retrospectively review patients undergone surgery for spinal tumors at the Academic Neurosurgery, Department of Neuroscience DNS, University of Padua in recent years focusing on the relevance of this modern surgical nuance. Materials and methods. We present a single-center series of patients, using ultrasound osteotome to perform laminotomy with poor morbidity. Sonopet® is a modern surgical tool, less invasive, manageable and allow to avoid incidental dural injury respect to laminectomy, minimizing blood losses and enhancing surgical quality. Spinal cord tumors from C2 to S1, histotypes of lesion adult and pediatrics population were inclusion criteria; cerebral lesions were excluded, as degenerative spinal disorders. We identified 39 patients, for a total of 42 procedures, collecting data on age, sex, operating time, instruments, blood loss, onset of symptoms, pre and post-operative neurological status at discharge and at 30 days, spinal MRI and CT scans with/without contrast, surgical techniques (laminotomies, laminectomies). We evaluated post-operative complications, neurological and neuroradiological follow up with spine RX at 30 days and with a 6 months spinal MRI. Follow up was with a range of 6-48 months with an average of 34 months. Results. Population had a mean age of 46 years, radio M:F was 1.4:1, 23.8% aged between 50 – 60, 31% of procedures were strictly thoracic and 23.8% lumbar, 38.1% had an involvement of two vertebrae and 23.8% of one. Neurinoma and intramedullary expansive lesions (28.6% each) were the most frequent lesions in our series. Laminotomies performed were 14 (33.3%), Sonopet® was involved in 9 procedures (64.3%). Average time with Sonopet® was 278 min for laminotomy and 228 min for laminectomy. Blood losses collected showed lower Hb values in both surgical techniques, but more in laminectomies (110g/L vs 118g/L of laminotomies). Minor complications (minor sensitive impairment) occurred in 50% of procedures (n=21), resolved spontaneously in several weeks. In 8 cases with complication was used Sonopet® to perform surgical approach. In this series, zero in incidental dural injuries were encountered. Conclusions. Further studies are suggested, use of Ultrasonic Bone Aspirator Sonopet® is useful in oncological spine procedures and should be encouraged

A clinical audit of laparoscopic surgery for recto-vaginal endometriosis at a tertiary referral centre in KwaZulu-Natal.

Masters Degree. University of KwaZulu-Natal, Durban.Aim: The aim of the study was to evaluate the operative and post-operative complications, and outcomes of laparoscopic surgery using the Harmonic scalpel in patients with recto-vaginal endometriosis (RVE). Furthermore, pre-operative work up and referral patterns were evaluated. Design: Retrospective chart review. Method: Following ethical (BREC No. BE O42/11) and hospital regulatory approvals, a retrospective chart review of the hospital case records of all patients who underwent laparoscopic surgery for RVE using the Harmonic scalpel from January 2004 to December 2010 was performed. All relevant clinical information was captured on structured data sheets which were kept confidential and used strictly for the purposes of the audit. Results: The case records of 105 women who had laparoscopic surgery for endometriosis between January 2004 to December 2010 were identified Thirty-three (31.4%) patients with RVE were treated using the Harmonic scalpel as the main energy source. From this cohort of patients, there was one case which required conversion to laparotomy for rectal injury which was successfully repaired; one case required re-laparoscopy for suspected intra-operative bleeding and another required cystoscopy and double J stenting due to anuria of 21 hours post- surgery. The mean hospital stay was 4 days. 76% of women had improvement of pain after surgical intervention and concomitant adjuvant medical therapy was used in 30.3%. Conclusion: The usage of Harmonic scalpel as the energy source in the management of RVE appears to be safe and the morbidity is comparable to other energy sources reported in literature

Patterns of injury and violence in Yaoundé Cameroon: an analysis of hospital data.

BackgroundInjuries are quickly becoming a leading cause of death globally, disproportionately affecting sub-Saharan Africa, where reports on the epidemiology of injuries are extremely limited. Reports on the patterns and frequency of injuries are available from Cameroon are also scarce. This study explores the patterns of trauma seen at the emergency ward of the busiest trauma center in Cameroon's capital city.Materials and methodsAdministrative records from January 1, 2007, through December 31, 2007, were retrospectively reviewed; information on age, gender, mechanism of injury, and outcome was abstracted for all trauma patients presenting to the emergency ward. Univariate analysis was performed to assess patterns of injuries in terms of mechanism, date, age, and gender. Bivariate analysis was used to explore potential relationships between demographic variables and mechanism of injury.ResultsA total of 6,234 injured people were seen at the Central Hospital of Yaoundé's emergency ward during the year 2007. Males comprised 71% of those injured, and the mean age of injured patients was 29 years (SD = 14.9). Nearly 60% of the injuries were due to road traffic accidents, 46% of which involved a pedestrian. Intentional injuries were the second most common mechanism of injury (22.5%), 55% of which involved unarmed assault. Patients injured in falls were more likely to be admitted to the hospital (p < 0.001), whereas patients suffering intentional injuries and bites were less likely to be hospitalized (p < 0.001). Males were significantly more likely to be admitted than females (p < 0.001)DiscussionPatterns in terms of age, gender, and mechanism of injury are similar to reports from other countries from the same geographic region, but the magnitude of cases reported is high for a single institution in an African city the size of Yaoundé. As the burden of disease is predicted to increase dramatically in sub-Saharan Africa, immediate efforts in prevention and treatment in Cameroon are strongly warranted

Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: an EFSUMB position statement

The use of contrast-enhanced ultrasound (CEUS) in adults is well established in many different areas, with a number of current applications deemed off-label, but the use supported by clinical experience and evidence. Paediatric CEUS is also an off-label application until recently with approval specifically for assessment of focal liver lesions. Nevertheless there is mounting evidence of the usefulness of CEUS in children in many areas, primarily as an imaging technique that reduces exposure to radiation, iodinated contrast medium and the patient-friendly circumstances of ultrasonography. This position statement of the European Federation of Societies in Ultrasound and Medicine (EFSUMB) assesses the current status of CEUS applications in children and makes suggestions for further development of this technique

Developmental delays and subcellular stress as downstream effects of sonoporation

Posters: no. 2Control ID: 1672434OBJECTIVES: The biological impact of sonoporation has often been overlooked. Here we seek to obtain insight into the cytotoxic impact of sonoporation by gaining new perspectives on anti-proliferative characteristics that may emerge within sonoporated cells. We particularly focused on investigating the cell-cycle progression kinetics of sonoporated cells and identifying organelles that may be stressed in the recovery process. METHODS: In line with recommendations on exposure hardware design, an immersion-based ultrasound platform has been developed. It delivers 1 MHz ultrasound pulses (100 cycles; 1 kHz PRF; 60 s total duration) with 0.45 MPa peak negative pressure to a cell chamber that housed HL-60 leukemia cells and lipid-shelled microbubbles at a 10:1 cell-tobubble ratio (for 1e6/ml cell density). Calcein was used to facilitate tracking of sonoporated cells with enhanced uptake of exogenous molecules. The developmental trend of sonoporated cells was quantitatively analyzed using BrdU/DNA flow cytometry that monitors the cell population’s DNA synthesis kinetics. This allowed us to measure the temporal progression of DNA synthesis of sonoporated cells. To investigate whether sonoporation would upset subcellular homeostasis, post-exposure cell samples were also assayed for various proteins using Western blot analysis. Analysis focus was placed on the endoplasmic reticulum (ER): an important organelle with multi-faceted role in cellular functioning. The post-exposure observation time spanned between 0-24 h. RESULTS: Despite maintaining viability, sonoporated cells were found to exhibit delays in cell-cycle progression. Specifically, their DNA synthesis time was lengthened substantially (for HL-60 cells: 8.7 h for control vs 13.4 h for the sonoporated group). This indicates that sonoporated cells were under stress: a phenomenon that is supported by our Western blot assays showing upregulation of ER-resident enzymes (PDI, Ero1), ER stress sensors (PERK, IRE1), and ER-triggered pro-apoptotic signals (CHOP, JNK). CONCLUSIONS: Sonoporation, whilst being able to facilitate internalization of exogenous molecules, may inadvertently elicit a cellular stress response. These findings seem to echo recent calls for reconsideration of efficiency issues in sonoporation-mediated drug delivery. Further efforts would be necessary to improve the efficiency of sonoporation-based biomedical applications where cell death is not desirable.postprin

A study on the change in plasma membrane potential during sonoporation

Posters: no. 4Control ID: 1680329OBJECTIVES: There has been validated that the correlation of sonoporation with calcium transients is generated by ultrasound-mediated microbubbles activity. Besides calcium, other ionic flows are likely involved in sonoporation. Our hypothesis is the cell electrophysiological properties are related to the intracellular delivery by ultrasound and microbubbles. In this study, a real-time live cell imaging platform is used to determine whether plasma membrane potential change is related to the sonoporation process at the cellular level. METHODS: Hela cells were cultured in DMEM supplemented with 10% FBS in Opticell Chamber at 37 °C and 5% CO2, and reached 80% confluency before experiments. The Calcein Blue-AM, DiBAC4(3) loaded cells in the Opticell chamber filled with PI solution and Sonovue microbubbles were immerged in a water tank on a inverted fluorescence microscope. Pulsed ultrasound (1MHz freq., 20 cycles, 20Hz PRF, 0.2-0.5MPa PNP) was irradiated at the angle of 45° to the region of interest for 1s.The real-time fluorescence imaging for different probes was acquired by a cooled CCD camera every 20s for 10min. The time-lapse fluorescence images were quantitatively analyzed to evaluate the correlation of cell viability, intracellular delivery with plasma membrane potential change. RESULTS: Our preliminary data showed that the PI fluorescence, which indicated intracellular delivery, was immediately accumulated in cells adjacent to microbubbles after exposure, suggesting that their membranes were damaged by ultrasound-activated microbubbles. However, the fluorescence reached its highest level within 4 to 6 minutes and was unchanged thereafter, indicating the membrane was gradually repaired within this period. Furthermore, using DIBAC4(3), which detected the change in the cell membrane potential, we found that the loss of membrane potential might be associated with intracellular delivery, because the PI fluorescence accumulation was usually accompanied with the change in DIBAC4 (3) fluorescence. CONCLUSIONS: Our study suggests that there may be a linkage between the cell membrane potential change and intracellular delivery mediated by ultrasound and microbubbles. We also suggest that other ionic flows or ion channels may be involved in the cell membrane potential change in sonoporation. Further efforts to explore the cellular mechanism of this phenomenon will improve our understanding of sonoporation.postprin

How sonoporation disrupts cellular structural integrity: morphological and cytoskeletal observations

Posters: no. 1Control ID: 1672429OBJECTIVES: In considering sonoporation for drug delivery applications, it is essential to understand how living cells respond to this puncturing force. Here we seek to investigate the effects of sonoporation on cellular structural integrity. We hypothesize that the membrane morphology and cytoskeletal behavior of sonoporated cells under recovery would inherently differ from that of normal viable cells. METHODS: A customized and calibrated exposure platform was developed for this work, and the ZR-75-30 breast carcinoma cells were used as the cell model. The cells were exposed to either single or multiple pulses of 1 MHz ultrasound (pulse length: 30 or 100 cycles; PRF: 1kHz; duration: up to 60s) with 0.45 MPa spatial-averaged peak negative pressure and in the presence of lipid-shelled microbubbles. Confocal microscopy was used to examine insitu the structural integrity of sonoporated cells (identified as ones with exogenous fluorescent marker internalization). For investigations on membrane morphology, FM 4-64 was used as the membrane dye (red), and calcein was used as the sonoporation marker (green); for studies on cytoskeletal behavior, CellLight (green) and propidium iodide (red) were used to respectively label actin filaments and sonoporated cells. Observation started from before exposure to up to 2 h after exposure, and confocal images were acquired at real-time frame rates. Cellular structural features and their temporal kinetics were quantitatively analyzed to assess the consistency of trends amongst a group of cells. RESULTS: Sonoporated cells exhibited membrane shrinkage (decreased by 61% in a cell’s cross-sectional area) and intracellular lipid accumulation (381% increase compared to control) over a 2 h period. The morphological repression of sonoporated cells was also found to correspond with post-sonoporation cytoskeletal processes: actin depolymerization was observed as soon as pores were induced on the membrane. These results show that cellular structural integrity is indeed disrupted over the course of sonoporation. CONCLUSIONS: Our investigation shows that the biophysical impact of sonoporation is by no means limited to the induction of membrane pores: e.g. structural integrity is concomitantly affected in the process. This prompts the need for further fundamental studies to unravel the complex sequence of biological events involved in sonoporation.postprin

Contrast-enhanced imaging in the biological and functional assessment of breast cancer

Contrast-enhanced MRI and ultrasound have emerged as additional imaging modalities in the management of breast cancer. This thesis examines the role these modalities currently play in the surgical management of breast cancer. Ways in which MRI may contribute to staging, diagnosis, treatment and prognosis are investigated. It was demonstrated that small additional enhancing foci on MRI, away from the primary tumour, represent in-situ or invasive cancer foci. Although their resection may result in extended wide local excisions or even unnecessary mastectomies, it was demonstrated that MRI findings do not currently influence the amount of tissue removed during breast conservation surgery. Volumetric analysis of breast MRI was proposed as an accurate objective assessment of the extent of surgery required for a particular tumour. Breast MRI was shown to be useful in the assessment of extent of residual disease during primary medical therapy but not in the detection of axillary lymph node metastases. In the second section of this thesis, the clinical application of pre-operative MRI in providing prognostic as well as diagnostic information was evaluated. Contrast- enhancement with both MRI and ultrasound is believed to depend on tumour angiogenesis but only a weak correlation was demonstrated between contrast- enhancement intensity and tumour angiogenesis. The detection of angiogenesis was applied to Doppler ultrasound using a novel microbubble ultrasound contrast agent (Levovist). Within a multicentre prospective study, Doppler ultrasound was shown to be a powerful discriminator of malignancy in suspected local recurrence. A strong correlation was found between MRI and histological assessment of tumour size but there was no correlation between enhancement intensity and other pathological prognostic variables. This thesis has shown that breast MRI is useful in pre-operative planning of surgery and provides diagnostic as well as limited prognostic information. Future proposed studies to determine the effect of MRI on patient management and patient outcome in breast cancer are considered