Local anaesthetics and chemotherapeutic agents: a systematic review of preclinical evidence of interactions and cancer biology.

Background: Local anaesthetics are widely used for their analgesic and anaesthetic properties in the perioperative setting, including surgical procedures to excise malignant tumours. Simultaneously, chemotherapeutic agents remain a cornerstone of cancer treatment, targeting rapidly dividing cancer cells to inhibit tumour growth. The potential interactions between these two drug classes have drawn increasing attention and there are oncological surgical contexts where their combined use could be considered. This review examines existing evidence regarding the interactions between local anaesthetics and chemotherapeutic agents, including biological mechanisms and clinical implications. Methods: A systematic search of electronic databases was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Selection criteria were designed to capture in vitro, in vivo, and clinical studies assessing interactions between local anaesthetics and a wide variety of chemotherapeutic agents. Screening and data extraction were performed independently by two reviewers. The data were synthesised using a narrative approach because of the anticipated heterogeneity of included studies. Results: Initial searches yielded 1225 relevant articles for screening, of which 43 met the inclusion criteria. The interactions between local anaesthetics and chemotherapeutic agents were diverse and multifaceted. In vitro studies frequently demonstrated altered cytotoxicity profiles when these agents were combined, with variations depending on the specific drug combination and cancer cell type. Mechanistically, some interactions were attributed to modifications in efflux pump activity, tumour suppressor gene expression, or alterations in cellular signalling pathways associated with tumour promotion. A large majority of in vitro studies report potentially beneficial effects of local anaesthetics in terms of enhancing the antineoplastic activity of chemotherapeutic agents. In animal models, the combined administration of local anaesthetics and chemotherapeutic agents showed largely beneficial effects on tumour growth, metastasis, and overall survival. Notably, no clinical study examining the possible interactions of local anaesthetics and chemotherapy on cancer outcomes has been reported. Conclusions: Reported preclinical interactions between local anaesthetics and chemotherapeutic agents are complex and encompass a spectrum of effects which are largely, although not uniformly, additive or synergistic. The clinical implications of these interactions remain unclear because of the lack of prospective trials. Nonetheless, the modulation of chemotherapy effects by local anaesthetics warrants further clinical investigation in the context of cancer surgery where they could be used together. Clinical trial registration: Open Science Framework (OSF, project link: https://osf.io/r2u4z).

Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

A near-infrared laser dispersion spectrometer with phase modulation for open-path methane sensing.

A laser-based open-path dispersion spectrometer for measuring atmospheric methane has been developed with the goal of achieving a very simple architecture, yet enabling molecular dispersion measurements immune to optical power variation. Well-mature, near-infrared photonics components were retained to demonstrate a compact, cost-effective, and low-power consumption dispersion spectrometer. In particular, measurements immune to received optical power variations are demonstrated despite the use of only phase modulation and are supported by the development of the corresponding physical model. The instrument has been validated under laboratory conditions, finding a precision of 2.6 ppb 100 m for a 2 s measurement, and demonstrated through atmospheric measurements performed continuously over six days with an 86 m path length.

Preoperative initiation of peripheral veno-arterial extracorporeal membrane oxygenation for a complex case of cardiac tamponade.

In this case report, we present an alternative approach to the anaesthetic management of patients presenting with delayed postoperative cardiac tamponade physiology. Given that pericardiocentesis was deemed unsafe, and a protracted surgical dissection was anticipated, peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was established prior to induction of anaesthesia to prevent catastrophic circulatory failure. To the best of our knowledge, this is the first reported case of planned preoperative commencement of peripheral VA-ECMO in a complex case of cardiac tamponade. We discuss the challenges associated with this case and the process for selecting this strategy. We also describe the role of transoesophageal echocardiography in planning the surgical approach. This report is completed by a discussion on the topic of delayed postoperative pericardial effusion and tamponade.

Anaesthesia and cancer recurrence: the influence of perioperative anaesthetic technique on cancer recurrence after surgery.

PURPOSE OF REVIEW: Cancer is a leading cause of death worldwide, and incidence is increasing. Excisional surgery is essential in approximately 70% of solid organ tumours. Emerging research in onco-anaesthesiology suggests that perioperative anaesthetic and analgesic techniques might influence long-term oncologic outcomes. RECENT FINDINGS: Prospective, randomized control trials (RCTs) demonstrate that perioperative regional and neuraxial anaesthetic techniques do not affect cancer recurrence. Ongoing trials are investigating the potential outcome benefits of systemic lidocaine. Retrospective studies indicate improved postoperative oncologic outcomes for certain types of breast cancer with higher intraoperative opioid dosage, nuancing available evidence on the effect of opioids. RCT evidence suggests that propofol has no beneficial effect compared with volatiles on breast cancer recurrence, although it remains unclear whether this applies to other cancer types. SUMMARY: Although regional anaesthesia definitively does not affect cancer recurrence, ongoing prospective RCTs with oncological outcomes as primary endpoints are awaited to establish if other anaesthetic or analgesic techniques influence cancer recurrence. Until such trials conclusively identify a causal relationship, insufficient evidence exists to recommend specific anaesthetic or analgesic techniques for tumour resection surgery based on altering the patient's risk of recurrence.

Impact of the COVID-19 pandemic on anaesthesia specialty training: a single-centre quantitative analysis.

Background: The COVID-19 pandemic disrupted healthcare services worldwide, with a consequent impact on the delivery of medical education and training in all acute care specialties. Anaesthesia training has been challenged by a combination of reduced elective theatre activity, redeployment of trainees to critical care units, and changes in standard anaesthetic practices. Methods: The aim of this study was to quantify the impact of COVID-19 on specialist anaesthesia training at a tertiary level teaching hospital in Ireland via a retrospective analysis of data captured by electronic anaesthesia records. The anaesthetic caseloads of trainees in periods before and during the pandemic were analysed along with airway management practices, core procedural skills performed, and critical care rostering. Data relating to 145 anaesthesia trainees were captured during the study periods: pre-pandemic (January 2018 to January 2020) and pandemic (January 2020 to January 2022). Results: The mean number of theatre cases logged per trainee in a 6-month period reduced from 156.8 pre-pandemic to 119.2 during the pandemic (23.9% reduction; P<0.0001). Although theatre caseload was reduced, trainees gained additional critical care experience with a significant increase in overall days spent staffing critical care wards. In the theatre setting, the number of arterial lines, central lines, neuraxial blocks, and peripheral nerve blocks performed were significantly reduced during the pandemic. Conclusions: Although the COVID-19 pandemic significantly reduced anaesthesia training exposure and increased critical care exposure over an extended period, the overall long-term significance of this alteration in the anaesthesia training experience remains uncertain.

Fast custom wavelet analysis technique for single molecule detection and identification.

Many sensors operate by detecting and identifying individual events in a time-dependent signal which is challenging if signals are weak and background noise is present. We introduce a powerful, fast, and robust signal analysis technique based on a massively parallel continuous wavelet transform (CWT) algorithm. The superiority of this approach is demonstrated with fluorescence signals from a chip-based, optofluidic single particle sensor. The technique is more accurate than simple peak-finding algorithms and several orders of magnitude faster than existing CWT methods, allowing for real-time data analysis during sensing for the first time. Performance is further increased by applying a custom wavelet to multi-peak signals as demonstrated using amplification-free detection of single bacterial DNAs. A 4x increase in detection rate, a 6x improved error rate, and the ability for extraction of experimental parameters are demonstrated. This cluster-based CWT analysis will enable high-performance, real-time sensing when signal-to-noise is hardware limited, for instance with low-cost sensors in point of care environments.

Perioperative Intravenous Lidocaine and Metastatic Cancer Recurrence - A Narrative Review.

Cancer is a major global health problem and the second leading cause of death worldwide. When detected early, surgery provides a potentially curative intervention for many solid organ tumours. Unfortunately, cancer frequently recurs postoperatively. Evidence from laboratory and retrospective clinical studies suggests that the choice of anaesthetic and analgesic agents used perioperatively may influence the activity of residual cancer cells and thus affect subsequent recurrence risk. The amide local anaesthetic lidocaine has a well-established role in perioperative therapeutics, whether used systemically as an analgesic agent or in the provision of regional anaesthesia. Under laboratory conditions, lidocaine has been shown to inhibit cancer cell behaviour and exerts beneficial effects on components of the inflammatory and immune responses which are known to affect cancer biology. These findings raise the possibility that lidocaine administered perioperatively as a safe and inexpensive intravenous infusion may provide significant benefits in terms of long term cancer outcomes. However, despite the volume of promising laboratory data, robust prospective clinical evidence supporting beneficial anti-cancer effects of perioperative lidocaine treatment is lacking, although trials are planned to address this. This review provides a state of the art summary of the current knowledge base and recent advances regarding perioperative lidocaine therapy, its biological effects and influence on postoperative cancer outcomes.

The Effect of Lidocaine and Bosutinib on 4T1 Murine Breast Cancer Cell Behaviour In Vitro.

BACKGROUND/AIM: Systemic lidocaine has recently emerged as a promising agent possessing numerous potentially anti-neoplastic effects. In vitro studies suggest that lidocaine may prevent metastasis by acting on the tyrosine kinase enzyme Src. Intravenous lidocaine has been reported to reduce pulmonary metastasis in vivo in a murine breast cancer model, however the beneficial effect is abolished by the Src inhibitor bosutinib. In this study we examined whether lidocaine and/or bosutinib affects 4T1 breast cancer cell activity in vitro and whether any drug interactions similar to that seen in murine models occur. MATERIALS AND METHODS: 4T1 murine breast cancer cells were exposed to lidocaine and/or bosutinib. Cell viability after 1 h of exposure was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell migration after 24 h of exposure was measured using the Oris™ migration assay. RESULTS: Lidocaine and bosutinib alone or combined inhibited 4T1 cell viability and migration, but only at supratherapeutic concentrations. Bosutinib did not modulate lidocaine's effect on viability or migration at any concentration tested. CONCLUSION: Although lidocaine may inhibit 4T1 metastasis in vivo, a direct effect on 4T1 cells is not detectable in vitro at non-toxic concentrations and unlike murine model testing, no unusual interaction with bosutinib was detected. Lidocaine's anti-metastatic properties are likely to be complex and multifactorial and difficult to replicate outside of a biological host.

Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery.

Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative pulmonary metastases. We investigated whether the additional administration of bosutinib (a known Src inhibitor) influences lidocaine's observed beneficial effect in this in vivo model. Female BALB/c mice (n = 95) were inoculated with 25,000 4T1 cells into the mammary fad pad and after 7 days the resulting tumours were excised under sevoflurane anaesthesia. Experimental animals were randomized to one of four treatments administered intravenously prior to excision: lidocaine, bosutinib, both lidocaine and bosutinib in combination, or saline. Animals were euthanized 14 days post-surgery and lung and liver metastatic colonies were evaluated. Post-mortem serum was analysed for MMP-2 and MMP-9, pro-metastatic enzymes whose expression is influenced by the Src pathway. Lidocaine reduced lung, but not liver metastatic colonies versus sevoflurane alone (p = 0.041), but bosutinib alone had no metastasis-inhibiting effect. When combined with lidocaine, bosutinib reversed the anti-metastatic effect observed with lidocaine on sevoflurane anaesthesia. Only lidocaine alone reduced MMP-2 versus sevoflurane (p = 0.044). Both bosutinib (p = 0.001) and bosutinib/lidocaine combined (p = 0.001) reduced MMP-9 versus sevoflurane, whereas lidocaine alone did not. In a murine surgical breast cancer model, the anti-metastatic effects of lidocaine under sevoflurane anaesthesia are abolished by the Src inhibitor bosutinib, and lidocaine reduces serum MMP-2. These results suggest that lidocaine may act, at least partly, via an inhibitory effect on MMP-2 expression to reduce pulmonary metastasis, but whether this is due to an effect on Src or via another pathway remains unclear.

Hypnosis: A Psychodynamic Perspective.

The relationship between hypnosis and psychoanalysis has always been complex, and often acrimonious. When Freud abandoned hypnosis as both the foundation of his theory building and his clinical intervention of choice, the two approaches and the theories associated with them have often seemed separated by enormous rifts, theoretical, clinical, and political. Yet throughout their considerable estrangement for over more than a century, each has much to offer to the other. In this contribution, I briefly review efforts by psychoanalysts to conceptualize and understand hypnosis, offer an introduction to the relatively new post-modern intersubjective approach to psychoanalysis, and demonstrates how the relational concepts associated with that perspective can be of significant help in preparing patients for hypnosis, and in crafting interventions geared to the dynamics of the individual patient, which enhance the likelihood of clinical success. Key relational elements are illustrated with clinical vignettes.

Mitigating Water Absorption in Waveguides Made From Unannealed PECVD SiO2.

Water absorption was studied in two types of waveguides made from unannealed plasma enhanced chemical vapor deposition (PECVD) SiO2. Standard rib anti-resonant reflecting optical waveguides (ARROWs) were fabricated with thin films of different intrinsic stress and indices of refraction. Buried ARROWs (bARROWs) with low and high refractive index differences between the core and cladding regions were also fabricated from the same types of PECVD films. All waveguides were subjected to a heated, high humidity environment and their optical throughput was tested over time. Due to water absorption in the SiO2 films, the optical throughput of all of the ARROWs decreased with time spent in the wet environment. The ARROWs with the lowest stress SiO2 had the slowest rate of throughput change. High index difference bARROWs showed no decrease in optical throughput after 40 days in the wet environment and are presented as a solution for environmentally stable waveguides made from unannealed PECVD SiO2.

Optofluidic Lab-on-a-Chip Fluorescence Sensor Using Integrated Buried ARROW (bARROW) Waveguides.

Optofluidic, lab-on-a-chip fluorescence sensors were fabricated using buried anti-resonant reflecting optical waveguides (bARROWs). The bARROWs are impervious to the negative water absorption effects that typically occur in waveguides made using hygroscopic, plasma-enhanced chemical vapor deposition (PECVD) oxides. These sensors were used to detect fluorescent microbeads and had an average signal-to-noise ratio (SNR) that was 81.3% higher than that of single-oxide ARROW fluorescence sensors. While the single-oxide ARROW sensors were annealed at 300 °C to drive moisture out of the waveguides, the bARROW sensors required no annealing process to obtain a high SNR.

Molecular Fountain.

The resolution of any spectroscopic or interferometric experiment is ultimately limited by the total time a particle is interrogated. Here we demonstrate the first molecular fountain, a development which permits hitherto unattainably long interrogation times with molecules. In our experiments, ammonia molecules are decelerated and cooled using electric fields, launched upwards with a velocity between 1.4 and 1.9 m/s and observed as they fall back under gravity. A combination of quadrupole lenses and bunching elements is used to shape the beam such that it has a large position spread and a small velocity spread (corresponding to a transverse temperature of <10 µK and a longitudinal temperature of <1 µK) when the molecules are in free fall, while being strongly focused at the detection region. The molecules are in free fall for up to 266 ms, making it possible, in principle, to perform sub-Hz measurements in molecular systems and paving the way for stringent tests of fundamental physics theories.

Signal-to-noise Enhancement in Optical Detection of Single Viruses with Multi-spot Excitation.

We present fluorescence detection of single H1N1 viruses with enhanced signal to noise ratio (SNR) achieved by multi-spot excitation in liquid-core anti-resonant reflecting optical waveguides (ARROWs). Solid-core Y-splitting ARROW waveguides are fabricated orthogonal to the liquid-core section of the chip, creating multiple excitation spots for the analyte. We derive expressions for the SNR increase after signal processing, and analyze its dependence on signal levels and spot number. Very good agreement between theoretical calculations and experimental results is found. SNR enhancements up to 5x104 are demonstrated.

Removing asthma triggers and improving children's health: The Asthma Partnership Demonstration project.

BACKGROUND: Studies have revealed the efficacy of home-based environmental interventions on reduction of asthma symptoms as a strategy for managing asthma in children. A focus on education and behavior change alone is generally too limited to reduce exposure to asthma triggers that exist because of adverse housing conditions. OBJECTIVE: To demonstrate that housing conditions as a focus of a health intervention should be considered more widely as an effective means of addressing serious health problems such as asthma. METHODS: Residences of 41 families of children identified with some of the highest rates of asthma-related hospital visits were assessed for the presence of asthma triggers. RESULTS: The intervention had a positive effect on lessening the effect of the child's asthma on the family's lives and activities. Reductions in frequency of negative effects of children's asthma on sleeping, job or work around the house, and family activity plans, fewer worries or concerns about children getting enough sleep and performing normal daily activities, and fewer adverse effects of children's asthma medications were reported. Reduced use of asthma medication, medication applications, and health visits were noted. Households with return visits had 50% lower hospital bills for childhood asthma treatment. CONCLUSION: Home environment conditions that lead to or exacerbate asthma may be reduced or eliminated by making minor repairs and introducing reasonable cleaning regimens that address sources of asthma triggers. This can produce greater awareness on the part of families about the presence of asthma triggers and motivate future action to address the conditions associated with these triggers.

Improved environmental stability for plasma enhanced chemical vapor deposition SiO2 waveguides using buried channel designs.

Ridge and buried channel waveguides (BCWs) made using plasma-enhanced chemical vapor deposition SiO2 were fabricated and tested after being subjected to long 85°C water baths. The water bath was used to investigate the effects of any water absorption in the ridge and BCWs. Optical mode spreading and power throughput were measured over a period of three weeks. The ridge waveguides quickly absorbed water within the critical guiding portion of the waveguide. This caused a nonuniformity in the refractive index profile, leading to poor modal confinement after only seven days. The BCWs possessed a low index top cladding layer of SiO2, which caused an increase in the longevity of the waveguides, and after 21 days, the BCW samples still maintained ~20% throughput, much higher than the ridge waveguides, which had a throughput under 5%.

Simple indicators for projecting short-term dental market fluctuations.

BACKGROUND: There have been fluctuations over time in dental care expenditures in the United States. This project aims to develop simple indicators that are easily available to people and that can be useful to predict short-term market fluctuations. METHODS: The authors analyzed data concerning 30 variables for the period of 1980 through 2012 for correlations with dental care expenditures during that period, looking for factors that historically moved in a highly correlated manner, either positively or negatively, with dental care expenditures. The authors lagged the factors to determine their potential predictive value for dental care expenditures. RESULTS: Personal consumption expenditures and gross domestic product emerged as valid leading indicators for predicting short-term dental market fluctuations. CONCLUSION: Two simple measures that are easily available to dentists and others can serve as indicators of short-term fluctuations in the dental marketplace. Their validity as indicators can, and should, be monitored regularly. PRACTICAL IMPLICATIONS: These indicators can be of significant value for practitioners in being alerted to potential market changes and planning to accommodate these changes. Combined, these factors can tell what changes are coming and when they have arrived.

Optofluidic wavelength division multiplexing for single-virus detection.

Optical waveguides simultaneously transport light at different colors, forming the basis of fiber-optic telecommunication networks that shuttle data in dozens of spectrally separated channels. Here, we reimagine this wavelength division multiplexing (WDM) paradigm in a novel context--the differentiated detection and identification of single influenza viruses on a chip. We use a single multimode interference (MMI) waveguide to create wavelength-dependent spot patterns across the entire visible spectrum and enable multiplexed single biomolecule detection on an optofluidic chip. Each target is identified by its time-dependent fluorescence signal without the need for spectral demultiplexing upon detection. We demonstrate detection of individual fluorescently labeled virus particles of three influenza A subtypes in two implementations: labeling of each virus using three different colors and two-color combinatorial labeling. By extending combinatorial multiplexing to three or more colors, MMI-based WDM provides the multiplexing power required for differentiated clinical tests and the growing field of personalized medicine.

Electro-optical detection of single λ-DNA.

Single λ-DNA molecules are detected on a nanopore-gated optofluidic chip electrically and optically. Statistical variations in the single particle trajectories are used to predict the intensity distribution of the fluorescence signals.