Surgical creation of multiple drainage holes versus local injection of corticosteroids for treatment of aural hematomas in dogs: 51 dogs with 71 aural hematomas (2000–2017)

OBJECTIVE To investigate the outcome of surgical creation of multiple drainage holes (MDHs) versus local corticosteroid injection (LCI) for treatment of aural hematomas (AHs) in dogs and identify risk factors for recurrence and development of new AHs. ANIMALS 51 dogs with 71 AHs. PROCEDURES Medical records were reviewed, and information on signalment, clinical findings, and outcome was recorded. Recurrence was defined as development of an AH at the primary site after the first month of treatment. Development of a new AH was defined as an AH occurring at a site different from the treated site. RESULTS The recurrence rate after the first month of treatment was significantly higher following the LCI procedure (17/48 AHs [33%]) than after the MDH procedure (1/24 AHs [4%]). The odds of recurrence increased as the numbers of LCI in the first month increased (OR, 2.414). Recurrent AHs after LCI resolved with additional LCIs; only 1 AH (2%) required a change to MDHs. No recurrence was observed after the eighth month, and the cosmetic results were good. Sixteen of 51 (31%) dogs had multiple or new AHs. The risk of new AHs was higher in Golden Retrievers and Labrador Retrievers and in dogs with allergic dermatitis. CONCLUSIONS AND CLINICAL RELEVANCE Long-term outcomes suggested that both creation of MDHs and LCI can be therapeutic options for dogs with AHs. However, the risk of new AH development should be considered, especially in retriever breeds and dogs with allergic dermatitis.

Combined Microwave Ablation and Osteosynthesis for Long Bone Metastases

Background and Objectives: The purpose of this study was to evaluate the feasibility, safety and efficacy of microwave ablation (MWA) in combination with open surgery nail positioning for the treatment of fractures or impending fractures of long bone metastases. Material and Methods: Eleven patients (four men, seven women) with painful bone metastases of the humerus, femur or tibia with non-displaced fractures (one case) or impending fractures (10 cases) underwent open MWA in combination with osteosynthesis by locked nail positioning. Pain intensity was measured using a VAS score before and after treatment. CT or MRI were acquired at one month before and 1, 3, 6, 12 and 18 months after treatment. Results: All procedures were successfully completed without major complications. The level of pain was significantly reduced one month after treatment. For the patients with humerus metastases, the complete recovery of arm use took 8 weeks, while for the patients with femoral metastases the complete recovery of walking capacity took 11 weeks. The VAS score ranged from 7 (4–9) before treatment to 1.5 (0–2.5) after treatment. During a mid-term follow-up of 18 months (range 4–29 months), none of the patients showed tumor relapse or new fractures in the treated site. Two patients died due to tumor disease progression. Conclusion: Results of this preliminary study suggest that combined MWA and surgical osteosynthesis with locked nails is a safe and effective treatment for pathological fractures or malignant impending fractures of long bone metastases of the humerus, femur and tibia. Further analyses with larger cohorts are warranted to confirm these findings.

Radiofrequency ablation for palliative treatment of osseous metastases results in rapid, significant, and durable improvements in pain relief and quality of life: Results from the OPuS One trial.

12086 Background: Patients with bone metastases may experience pain and decreased quality of life. Standard of care therapies such as radiation therapy could take weeks for pain relief and carry a risk of radiation induced fracture. Minimally invasive percutaneous radiofrequency ablation (RFA) have been shown in small observational studies to be an alternative treatment for bone metastases. We report the results of the OPuS One trial evaluating RFA for the palliative treatment of patients with painful bone metastases. Methods: OPuS One (NCT03249584) was a multicenter prospective trial. 218 subjects with painful bone metastases (≥ 4/10 worst pain scores, Brief Pain Inventory [BPI], at target treated site) were enrolled from 15 sites. RFA was performed under image guidance at one or two locations. Vertebral augmentation was followed based on physician’s discretion. Subjects’ pain (BPI) and quality of life (EQ-5D) scores were calculated in subjects at three days, one week, and one, three, six, and 12 months post RFA. Rate of complete (0 pain score at treated site with no concomitant analgesic increase) and partial responders (≥ 2 pain score reduction without analgesic increase or analgesic reduction of ≥ 25% from baseline) were calculated. Device-, procedure-, and/or therapy-related adverse events (AEs) were collected. Results: 206 subjects, 113 (55%) female and 93 (45%) males (mean age was 63.7 years) were treated with RFA. Most common primary cancers were breast (23%), lung (23%), and kidney (10%). 184 (89%) subjects were treated for metastatic lesions involving the thoracolumbar spine and 22 (11%) subjects were treated for iliac crest, periacetabulum, sacrum or mixed vertebral and pelvic location. 99% (262/264) of RFA procedures were technically successful and 97% were followed by vertebral augmentation. Subjects reported significant improvement in worst pain from baseline at 7.8 to 5.5, 4.7, 3.6, 3.2, 2.4, and 2.6 at three days, one week and one, three, six, and 12 months post RFA, respectively (p < 0.0001 for all visits). Significant improvements were also seen in average pain (p < 0.0001 for all visits), pain interference (p < 0.0001 for all visits), and quality of life scores (p < 0.0001 for all visits). Overall response rates were 53%, 58%, 61%, 63%, 70%, and 75% at three days, one week, one month, three months, six months, and twelve months post RFA, respectively. Six AEs were reported with three as serious: intra-abdominal fluid collection, pneumonia and respiratory failure. 82 deaths were reported during the study, none were related to the device, therapy, and/or procedure. No skeletal related events were reported. Conclusions: In a large prospective multicenter trial, OPuS One, RFA provided rapid, significant, and durable improvements in pain relief and quality of life up to 12 months. Clinical trial information: NCT03249584.

Direct Aquatic Application of Crushed Dolomite Reduces CO2 Evasion in an Acidified River

&lt;p&gt;Acidified rivers may have increased CO&lt;sub&gt;2&lt;/sub&gt; emissions because their low pH transforms inorganic carbon in the form of bicarbonate anions to CO&lt;sub&gt;2&lt;/sub&gt;, which can evade to the atmosphere, thus interrupting the delivery inorganic carbon to the oceans, a key flux in the long-term carbonate silicate cycle. Enhanced weathering (EW) is a carbon dioxide removal (CDR) strategy aiming to increase drawdown of atmospheric CO&lt;sub&gt;2&lt;/sub&gt; through accelerated carbonation weathering of crushed minerals with targeted carbonate sequestration in oceanic stores. To date, EW research has been focused on terrestrial application of crushed minerals, and the CDR capability of enhancing weathering via addition of crushed minerals to rivers from lime dosers is essentially unexplored. Lime dosers have been used for decades to directly deposit crushed carbonate rock to rivers as a function of river flow in Norway and Nova Scotia, Canada, yet their potential as a CDR tool has yet to be verified in the field. In this study, we adapt CO&lt;sub&gt;2&lt;/sub&gt; flux sensors (eosFD) designed for soils to be deployed in rivers. We conducted field trials on the Killag River, Nova Scotia, upstream and downstream of a lime doser over a period of six weeks in the autumn of 2020. Preliminary analysis shows elevated CO&lt;sub&gt;2&lt;/sub&gt; evasion rates upstream of the lime doser and decreased evasion rates downstream. Aside from flood waves, CO&lt;sub&gt;2&lt;/sub&gt; evasion at the downstream (treated) site is reduced to almost zero for extended periods of time. Next steps are to identify whether the reduced CO&lt;sub&gt;2&lt;/sub&gt; evasion is due to CO&lt;sub&gt;2&lt;/sub&gt; drawdown via increased carbonation weathering of the crushed dolomite or through reduced CO&lt;sub&gt;2&lt;/sub&gt; evasion due to increased pH, or from a combination of the two processes. The results of this study may have implications for carbon credit programs for acidification mitigation and may encourage more widespread use of enhanced weathering as a CDR tool in rivers.&lt;/p&gt;

Perceptual correlates of homosynaptic long-term potentiation in human nociceptive pathways: a replication study

Animal studies have shown that high-frequency stimulation (HFS) of peripheral C-fibres induces long-term potentiation (LTP) within spinal nociceptive pathways. The aim of this replication study was to assess if a perceptual correlate of LTP can be observed in humans. In 20 healthy volunteers, we applied HFS to the left or right volar forearm. Before and after applying HFS, we delivered single electrical test stimuli through the HFS electrode while a second electrode at the contra-lateral arm served as a control condition. Moreover, to test the efficacy of the HFS protocol, we quantified changes in mechanical pinprick sensitivity before and after HFS of the skin surrounding both electrodes. The perceived intensity was collected for both electrical and mechanical stimuli. After HFS, the perceived pain intensity elicited by the mechanical pinprick stimuli applied on the skin surrounding the HFS-treated site was significantly higher compared to control site (heterotopic effect). Furthermore, we found a higher perceived pain intensity for single electrical stimuli delivered to the HFS-treated site compared to the control site (homotopic effect). Whether the homotopic effect reflects a perceptual correlate of homosynaptic LTP remains to be elucidated.

Identification of the geographical extent of an area benefiting from a transportation project: A generalized synthetic control

In evaluating the benefits of an infrastructure project, it is essential to consider who is benefiting from the project and where benefits are located. However, there is no established way to accurately determine the latter. To fill this methodological gap, this study proposes an approach for the ex-post identification of the geographical extent of an area benefiting from a transportation project based on a generalized synthetic control method. Specifically, it allows comparing multiple treatment units with their counterfactuals in a single run—changes in land prices (actual outcome) at each treated site are compared to the counterfactual outcome, and the individual (i.e., unit-level) treatment effect on the treated site is then estimated. This approach is empirically applied to a large-scale Japanese heavy railway, the Tsukuba Express line project. Our approach enables the detection of 1) the complicated spatial shape of benefit incidence; 2) negative spillovers; and 3) the increase in options (train routes), typically not considered in a benefit evaluation system based on the hedonic approach, but which can be capitalized into land prices.

Sickle Cell Pain: Intervention with Capsaicin Exposure (SPICE)

Background Pain is a common and debilitating complication of sickle cell disease (SCD) often requiring high doses of opioids for relief. The stigma associated with pain and opioid use has made it difficult for those with SCD to obtain needed treatment for pain, which can be acute or chronic, and nociceptive or neuropathic in nature. Given these difficulties, coupled with the inconsistency of opioids in successfully treating chronic and neuropathic pain, there is a need for non-opioid alternatives to treat this increasingly recognized subset of patients with SCD. Topical capsaicin for neuropathic pain has been studied extensively in adults with comparable efficacy to gabapentinoids, but it has not been investigated for SCD-related pain. We investigated the safety and feasibility of high dose (8%) topical capsaicin for treatment of neuropathic pain in children with SCD. The primary objective was to assess drug safety. Secondary objectives were to assess the feasibility and optimal utilization strategy of various measures of neuropathic and chronic pain states, and to obtain preliminary efficacy data. Prior to this study there has been very little published data regarding quantitative sensory testing as a trended datapoint to assess therapeutic effect on neuropathic pain. Methods Patients between ages 14-21 years with SCD and reported symptoms of neuropathic pain were included. During each of 7 visits scheduled at 6 week intervals, mechanical quantitative sensory testing (QST) was conducted using an electronic von Frey instrument (Bioseb) at a control site (thenar eminence) and the two most common sites of vaso-occlusive pain as reported at enrollment. Participants also completed the PainDETECT® questionnaire (Pfizer) for neuropathic pain assessment. During visits 1, 3, and 5 an 8% capsaicin patch was applied to the previously established most common site of pain. Safety was evaluated via CTCAE based analysis of adverse events in real time and at study completion. Efficacy was primarily evaluated by improvement in mechanical pain threshold at the site of most frequent pain (treated with capsaicin) relative to the 2nd most common site of pain (not treated). Trends in PainDetect scores also contributed to a preliminary understanding of capsaicin efficacy. Results 10 out of 13 patients approached (5 male, 5 female) were enrolled as planned within 8 weeks. 9 participants completed visits 1-5, and 7 completed visit 6 prior to study suspension due to COVID restrictions. There were no CTCAE grade 3 adverse events attributable to capsaicin. There were no vaso-occlusive pain crises triggered by a patch application. One participant requested that the second patch be removed early due to intolerance of the burning sensation associated with the patch. She subsequently did not have the third patch applied at visit 5. All participants were informed at enrollment of the likelihood of this side effect, which was nearly universal among participants but generally well tolerated. The other 9 participants completed all possible study activities and felt the second patch application was more tolerable than the first. 6 participants felt after 2 treatments the treated area was no longer their most common site of pain. These subjective reports were supported by more objective measures. The average difference in pain threshold as measured by QST between the two painful sites (QSTTreated - QSTuntreated) was used to evaluate a beneficial effect of capsaicin. This difference from visit 1 to visit 5 changed from -31.94g to +11.51g over the first 5 visits for an average improvement in pain threshold at the treated site relative to the untreated site of +43.45g (p=0.02) (Fig. 1), indicating that by visit 5 the threshold was higher at the treated site than the untreated site, a reversal from visit 1. Statistical analysis could not be completed for subsequent visits due to incomplete datasets. Conclusion Our pilot study indicates 8% topical capsaicin is safe and feasible for children with SCD. The data indicates this therapy may be efficacious in ameliorating neuropathic pain for this population and warrants further investigation in a follow-up efficacy study to be initiated in the coming months. The initial negative difference in QST values and subsequent trends between the two sites coincided with patient reported relative pain severity and supports the potential of QST as a tool in trending medication effect on peripheral hypersensitivity. Disclosures Callaghan: Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Sancillio: Other; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Alnylum: Current equity holder in publicly-traded company; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Other, Speakers Bureau. Zaidi:Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Emmaus Life Sciences: Consultancy, Honoraria. OffLabel Disclosure: High dose (8%) topical capsaicin (Qutenza) is approved for the treatment of neuropathic pain associated with either postherpetic neuralgia or diabetic peripheral neuropathy.

Management of recurrent or progressive spinal metastases: reirradiation techniques and surgical principles

With the growing incidence of new cases and the increasing prevalence of patients living longer with spine metastasis, a methodological approach to the management of patients with recurrent or progressive disease is increasing in relevance and importance in clinical practice. As a result, disease management has evolved in these patients using advanced surgical and radiotherapy technologies. Five key goals in the management of patients with spine metastases include providing pain relief, controlling metastatic disease at the treated site, improving neurologic deficits, maintaining or improving functional status, and minimizing further mechanical instability. The focus of this review is on advanced reirradiation techniques, given that the majority of patients will be treated with upfront conventional radiotherapy and further treatment on progression is often limited by the cumulative tolerance of nearby organs at risk. This review will also discuss novel surgical approaches such as separation surgery, minimally invasive percutaneous instrumentation, and laser interstitial thermal therapy, which is increasingly being coupled with spine reirradiation to maximize outcomes in this patient population. Lastly, given the complexities of managing recurrent spinal disease, this review emphasizes the importance of multidisciplinary care from neurosurgery, radiation oncology, medical oncology, neuro-oncology, rehabilitation medicine, and palliative care.

Preclinical and Clinical Evidence of Immune Responses Triggered in Oncologic Photodynamic Therapy: Clinical Recommendations

Photodynamic therapy (PDT) is an anticancer strategy utilizing light-mediated activation of a photosensitizer (PS) which has accumulated in tumor and/or surrounding vasculature. Upon activation, the PS mediates tumor destruction through the generation of reactive oxygen species and tumor-associated vasculature damage, generally resulting in high tumor cure rates. In addition, a PDT-induced immune response against the tumor has been documented in several studies. However, some contradictory results have been reported as well. With the aim of improving the understanding and awareness of the immunological events triggered by PDT, this review focuses on the immunological effects post-PDT, described in preclinical and clinical studies. The reviewed preclinical evidence indicates that PDT is able to elicit a local inflammatory response in the treated site, which can develop into systemic antitumor immunity, providing long-term tumor growth control. Nevertheless, this aspect of PDT has barely been explored in clinical studies. It is clear that further understanding of these events can impact the design of more potent PDT treatments. Based on the available preclinical knowledge, recommendations are given to guide future clinical research to gain valuable information on the immune response induced by PDT. Such insights directly obtained from cancer patients can only improve the success of PDT treatment, either alone or in combination with immunomodulatory approaches.

Anti-Metastatic Benefits Produced by Hyperthermia and a CCL3 Derivative

Significant numbers of malignant tumor cells that have spread to surrounding tissues and other distant organs are often too small to be picked up in a diagnostic test, and prevention of even such small metastases should improve patient outcomes. Using a mouse model, we show in this article that intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia not only induces tumor growth inhibition at the treated site but also inhibits metastasis. Colon26 adenocarcinoma cells (1 × 105 cells/mouse) were grafted subcutaneously into the right hind leg of syngeneic BALB/c mice and after nine days, when tumor size reached ~11 mm in diameter, the local tumor mass was exposed to high-frequency waves, by which intratumoral temperature was maintained at 42 °C for 30 min. Mice received the CCL3 variant named eMIP (2 μg/mouse/day) intravenously for five consecutive days starting one day after heat treatment. We found that tumor growth in eMIP recipients after hyperthermia was inhibited markedly but no effect was seen in animals treated with either hyperthermia or eMIP alone. Furthermore, the number of lung metastases evaluated after 18 days was dramatically reduced in animals receiving the combination therapy compared with all other controls. These results encourage future clinical application of this combination therapy.