Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Long-term outcomes of SBRT for PSMA PET detected oligometastatic prostate cancer.

BACKGROUND: Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach. METHODS: A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET. RESULTS: 103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures. CONCLUSION: PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.

Resistance to local anaesthetics administered via epidural, intrathecal and pudendal injections.

A primigravida presented to our institution in established labour. Her past medical history included joint hypermobility, postural orthostatic tachycardia syndrome, Raynaud's syndrome, fibromyalgia and gastroparesis. Two technically uneventful lumbar epidurals with bupivacaine and fentanyl provided no analgesia. The spinal element of a planned combined spinal and epidural was also ineffective, so alternative analgesia was offered. While this was being prepared, the obstetric team recommended an instrumental delivery. An attempted pudendal nerve block with lidocaine had no effect, and general anaesthesia was therefore provided for a lower segment caesarean delivery. We believe this is the first report of local anaesthetic resistance via three distinct routes of administration in a single patient. Resistance to local anaesthetics is unusual and is more common in patients with hypermobility spectrum disorders. This case demonstrates the unique experience of a patient with a hypermobility condition who had failed epidural, spinal and pudendal local anaesthetic. We suggest that patients with a hypermobility condition should be specifically assessed for local anaesthetic resistance as part of anaesthetic pre-assessment, to enable early planning.

The challenges and opportunities for implementing group antenatal care ('Pregnancy Circles') as part of standard NHS maternity care: A co-designed qualitative study.

OBJECTIVE: To identify the challenges and opportunities for rolling out a bespoke model of group antenatal care called Pregnancy Circles (PC) within the National Health Service: what kind of support and training is needed and what adaptations are appropriate, including during a pandemic when face-to-face interaction is limited. DESIGN: Exploratory qualitative study (online focus group). Study co-designed with midwives. Data analysed thematically using an ecological model to synthesise. SETTING: Five maternity services within the National Health Service. PARTICIPANTS: Seven midwives who facilitated PCs. Three senior midwives with implementation experience participated in the co-design process. FINDINGS: Three themes operating across the ecological model were identified: 'Implementing innovation', 'Philosophy of care' and 'Resource management'. Tensions were identified between group care's focus on relationships and professional autonomy, and concepts of efficiency within the NHS's market model of care. Midwives found protected time, training and ongoing support essential for developing the skills and confidence needed to deliver this innovative model of care. Integrating Pregnancy Circles with continuity of carer models was seen as the most promising opportunity for long-term implementation. Midwives perceived continuity and peer support as the most effective elements of the model and there was some evidence that the model may be robust enough to withstand adaptation to online delivery. KEY CONCLUSIONS: Midwives facilitating group care enjoyed the relationships, autonomy and professional development the model offered. Harnessing this personal (micro-level) satisfaction is key to wider implementation. Group care is well aligned with current maternity policy but the challenges midwives face (temporal, practical and cultural) must be anticipated and addressed at macro and meso level for wider implementation to be sustainable. The PC model may be flexible enough to adapt to online delivery and extend continuity of care but further research is needed in these areas. IMPLICATIONS FOR PRACTICE: Implementation of group care in the NHS requires senior leadership and expertise in change management, protected time for training and delivery of the model, and funding for equipment. Training and ongoing support, are vital for sustainability and quality control. There is potential for online delivery and integrating group care with continuity models.

FDG-PET to predict long-term outcome from anti-PD-1 therapy in metastatic melanoma.

BACKGROUND: We have previously shown that 75% of patients treated with programmed cell death protein 1 (PD-1) with or without CTLA4 who have not progressed by 1 year have complete metabolic response (CMR), including two-thirds of patients with partial response (PR). We now report 5-year outcomes. PATIENTS AND METHODS: Retrospective analysis of 104 patients with baseline and 1-year positron emission tomography (PET) and computed tomography (CT). The 1-year response was determined using RECIST for CT and European Organisation for Research and Treatment of Cancer (EORTC) criteria for PET. Progression-free survival (PFS) and overall survival (OS) were determined from the 1-year landmark. RESULTS: At the median follow-up of 61 months (range 58-64 months) from 1-year PET, 94% remained alive and all but one had discontinued treatment after a median treatment duration of 23 months (range 1-59 months). Disease progression occurred in 19 patients (18%): 10 (53%) while on treatment and 12 (63%) in solitary sites for which 8 (67%) received local treatment. RECIST PFS rate at 5 years after PET was higher in complete response (CR) compared with PR/stable disease (SD) (93% versus 76%, respectively) and CMR compared with non-CMR (90% versus 54%, respectively). In patients with PR, 5-year PFS rate was superior in CMR (88% and 59%). A total of 35 (34%) patients (14/29 in CR, 31/78 in CMR) discontinued treatment within 12 months, largely due to toxicity, with no impact on PFS rate compared with those that continued (84% versus 78%). Despite progression events, OS rate at 5 years was excellent and similar in patients with CR and PR/SD (100% versus 91%, respectively) as well as in those with CMR and non-CMR (96% versus 87%, respectively). CONCLUSIONS: Five years after the 1-year PET, sustained responses are observed in the majority of patients, particularly in those with CMR. PET continues to predict progression better than CT, particularly in those with residual disease on CT. In the minority that progress, often in solitary sites and managed locally, OS rate remains excellent. PET is effective in evaluating residual lesions on CT and can predict long-term benefit.

How long are mechanically ventilated patients fasted prior to surgery? An exploratory study examining preoperative fasting practices across trauma centres.

For mechanically ventilated patients undergoing surgery, interrupting enteral feeding to prevent pulmonary aspiration is common; however, there are no published preoperative fasting guidelines for these patients, resulting in fasting practices that often vary greatly between hospitals. This retrospective study described fasting practices and surgical outcomes of mechanically ventilated patients across five trauma centres. The primary exposure was hours nil per os before surgery and was stratified into short (<6h) and moderate (≥6h) fasting duration. Shared frailty models assessed the relationship between time to perioperative complication and nil per os category. Three of the five hospitals had preoperative fasting guidelines, and those most compliant required patients to be fed up until surgery. Most patients were fasted ≥6h prior to surgery and no increased risk of complication was found for patients who were fasted <6h. Future studies are needed to establish appropriate preoperative fasting thresholds for mechanically ventilated patients.

FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma.

Background: Immune checkpoint inhibitor therapy has resulted in impressive and durable clinical activity for many cancers including melanoma; however, there remain few reliable predictors for long-term response. This study investigated whether [18F]2-fluoro-2-deoxy-D-glucose (FDG-PET) imaging may better predict long-term outcomes compared with standard computed tomography (CT) response criteria. Patients and methods: Retrospective analysis of metastatic melanoma patients treated with anti-PD-1-based immunotherapy with baseline and 1-year FDG-PET and CT imaging at Melanoma Institute Australia. One-year response was determined using RECIST for CT and EORTC criteria for PET, coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD). Progression-free survival (PFS) was determined from the 1-year landmark. Results: Patients (n = 104) were evaluated with median follow-up 30.1 months and 98% remain alive. Most received anti-PD-1 as monotherapy (67%) or combined with ipilimumab (31%). At 1 year, 28% had CR, 66% had PR and 6% had SD on CT, while 75% had CMR, 16% PMR and 9% SMD/PMD on PET. CMR was observed in 68% of patients with PR on CT. RECIST PFS post 1-year landmark was similar in patients with CR versus PR/SD, but improved in patients with CMR versus non-CMR {median not reached [NR] versus 12.8 month; hazard ratio [HR] 0.06 [95% confidence interval (CI) 0.02-0.23]; P < 0.01}. In patients with PR on CT, PFS was improved in patients with PR + CMR versus PR + non-CMR (median NR versus 12.8 months; HR 0.07 [95% CI 0.02-0.27]; P < 0.01). In the 78 CMR patients, 78% had discontinued treatment and 96% had ongoing response. Conclusions: Whilst only a small proportion of patients have a CR at 1 year, most patients with a PR have CMR on PET. Almost all patients with CMR at 1 year have ongoing response to therapy thereafter. PET may have utility in predicting long-term benefit and help guide discontinuation of therapy.

Melanoma patient imaging in the era of effective systemic therapies.

Imaging plays a critical role in the current multi-disciplinary management of patients with melanoma. It is used for primary disease staging, surgical planning, and surveillance in high-risk patients, and for monitoring the effects of systemic or loco-regional therapies. Several different imaging modalities have been utilised in the past. Contemporary imaging practises vary geographically depending on clinical guidelines, physician preferences, availability and cost. Targeted therapies and immunotherapies have revolutionised the treatment of patients with metastatic melanoma over the last few years. With this have come new patterns of disease that were not observed after conventional therapies, and new criteria to assess therapeutic responses. In this article we review the role of imaging for patients with melanoma in the era of effective systemic therapies and discuss likely future developments.

Lutetium-177-labelled anti-prostate-specific membrane antigen antibody and ligands for the treatment of metastatic castrate-resistant prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Promising therapeutic results of the prostate-specific membrane antigen (PSMA) ligand have been shown when labelling with lutetium-177 (177Lu). We performed a systematic review and meta-analysis to assess the therapeutic response of 177Lu-PSMA in the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A systematic review was conducted using electronic databases up to December 2016. Two reviewers independently extracted data and assessed methodological quality. The main outcome of interest was antitumour biochemical response of 177Lu-PSMA, analysing two measures: 'any PSA decline' and '>50% decline' from baseline. A random-effects meta-analysis was used to calculate the pooled proportion across studies. The I2 statistic was calculated in each case to investigate the extent of heterogeneity across the studies. A sensitivity analysis was conducted removing two studies, which were presented as abstracts and proportions were summarised by chemical type (177Lu-J591/DKZ/I&T). All analyses were conducted using Stata v14. RESULTS: A total of 10 studies were included in the analysis giving a total sample size of 369, 220 (of 334 analysable) experienced any PSA decline. The pooled proportion of patients with any PSA decline was 68% (95% confidence interval (CI): 61-74). The I2 statistic was 39.1% (P=0.11) suggesting minor heterogeneity between results. The pooled proportion of patients with >50% PSA decline was 37% (95% CI: 22-52). The I2 statistic was 91.0% (P<0.001) suggesting substantial heterogeneity between results. On subgroup analysis, a higher proportion of patients in the 177Lu-DKZ/I&T subgroup had a PSA decline >50%, however, it can be seen that the 177Lu-DKZ/I&T subgroup had a substantial amount of heterogeneity across studies. CONCLUSIONS: This review suggests promising early results for the treatment of mCRPC, especially from patients treated with the more recently developed radioligands. Overall, our meta-analysis showed that approximately two-thirds of patients had a biochemical response. Randomised-controlled trials would be necessary to verify its effectiveness against current systemic therapies and create an ideal treatment protocol.

Snake constriction rapidly induces circulatory arrest in rats.

As legless predators, snakes are unique in their ability to immobilize and kill their prey through the process of constriction, and yet how this pressure incapacitates and ultimately kills the prey remains unknown. In this study, we examined the cardiovascular function of anesthetized rats before, during and after being constricted by boas (Boa constrictor) to examine the effect of constriction on the prey's circulatory function. The results demonstrate that within 6 s of being constricted, peripheral arterial blood pressure (PBP) at the femoral artery dropped to 1/2 of baseline values while central venous pressure (CVP) increased 6-fold from baseline during the same time. Electrocardiographic recordings from the anesthetized rat's heart revealed profound bradycardia as heart rate (fH) dropped to nearly half of baseline within 60 s of being constricted, and QRS duration nearly doubled over the same time period. By the end of constriction (mean 6.5±1 min), rat PBP dropped 2.9-fold, fH dropped 3.9-fold, systemic perfusion pressure (SPP=PBP-CVP) dropped 5.7-fold, and 91% of rats (10 of 11) had evidence of cardiac electrical dysfunction. Blood drawn immediately after constriction revealed that, relative to baseline, rats were hyperkalemic (serum potassium levels nearly doubled) and acidotic (blood pH dropped from 7.4 to 7.0). These results are the first to document the physiological response of prey to constriction and support the hypothesis that snake constriction induces rapid prey death due to circulatory arrest.

Recent outbreaks of infectious syphilis, United Kingdom, January 2012 to April 2014.

Six outbreaks of infectious syphilis in the United Kingdom, ongoing since 2012, have been investigated among men who have sex with men (MSM) and heterosexual men and women aged under 25 years. Interventions included case finding and raising awareness among healthcare professionals and the public. Targeting at-risk populations was complicated as many sexual encounters involved anonymous partners. Outbreaks among MSM were influenced by the use of geospatial real-time networking applications that allow users to locate other MSM within close proximity.

Investigation of a cluster of syphilis among heterosexuals in an English town.

A cluster of five (3 primary and 2 early latent) cases of syphilis were identified in young heterosexuals in the east of England. Three were symptomatic at presentation. No further cases linked to this cluster have been diagnosed since June 2010. Effective partner notification is key to the identification and treatment of infected contacts.

Surveillance of community genital Chlamydia trachomatis testing in the East of England, 2008-2010.

BACKGROUND: Widespread testing for chlamydia is expected to result in a reduction in prevalence. In 2008, coverage indicators introduced by the Department of Health (DH) required collection and submission of all tests performed outside of genitourinary medicine clinics. No mechanism existed to collect community-based tests conducted outside of the National Chlamydia Screening Programme. The Health Protection Agency Regional Epidemiology Unit in the East of England (EoE) set up a new system to routinely collect and submit these tests on behalf of the regional Primary Care Organizations (PCOs). METHODS: Testing data were requested from all laboratories commissioned to undertake chlamydia testing by EoE PCOs. Data were imported into a bespoke Structured Query Language server database and automated data processing routines were run. Data fulfilling national criteria were submitted for inclusion in the DH indicators. RESULTS: High-quality data were submitted to set deadlines with minimum impact on laboratories. Completeness of data variables varied by laboratory and by variable type. After complex data processing, 96% of laboratory reported tests in the 15-24 year age range were eligible for submission. CONCLUSIONS: This centralized method of data collection provides high-quality data, allowing for further analysis, which can be used to inform improvements in health care. These methods could be transferred to any of the hundreds of organisms for which similar laboratory data exist.

Lung perfusion and chest wall configuration is altered by glossopharyngeal breathing.

Glossopharyngeal insufflation is used by competitive breath-hold divers to increase lung gas content above baseline total lung capacity (TLC) in order improve performance. Whilst glossopharyngeal insufflation is known to induce hypotension and tachycardia, little is known about the effects on the pulmonary circulation and structural integrity of the thorax. Six male breath-hold divers were studied. Exhaled lung volumes were measured before and after glossopharyngeal insufflation. On two study days, subjects were studied in the supine position at baseline TLC and after maximal glossopharyngeal insufflation above TLC. Tc 99(m) labelled macro-aggregated albumin was injected and a computed tomography (CT) scan of the thorax was performed during breath-hold. Single photon emission CT images determined flow and regional deposition. Registered CT images determined change in the volume of the thorax. CT and perfusion comparisons were possible in four subjects. Lung perfusion was markedly diminished in areas of expanded lung. 69% of the increase in expired lung volume was via thoracic expansion with a caudal displacement of the diaphragm. One subject who was not proficient at glossopharyngeal insufflation had no change in CT appearance or lung perfusion. We have demonstrated areas of hyperexpanded, under perfused lung created by glossopharyngeal insufflation above TLC.

Epizootiology and management of feline leukemia virus in the Florida puma.

Feline leukemia virus (FeLV) was not detected in Florida pumas (Puma concolor coryi) in almost 20 yr of surveillance; however, the finding of two FeLV antigen-positive pumas during the 2002-2003 capture season led to an investigation of FeLV in the population. Between January 1990 and April 2007, the proportion of pumas testing FeLV antibody positive increased, with antibody-positive pumas concentrated in the northern portion of puma range. Five of 131 (4%) pumas sampled between July 2000 and April 2007 were viremic, with all cases clustered in Okaloacoochee Slough (OKS). Clinical signs and clinical pathology at capture were absent or included lymphadenopathy, moderate-to-severe anemia, and lymphopenia. All viremic pumas died; causes of death were septicemia (n=2), intraspecific aggression (n=2), and anemia/dehydration (n=1). Outcome after FeLV exposure in pumas was similar to that in domestic cats, with evidence of regressive, latent, and persistent infections. Management of the epizootic included vaccination, and as of April 2007, 52 free-ranging pumas had received one or more inoculations. Vaccinations were concentrated in OKS and in a band between OKS and the remainder of the puma population. There have been no new cases since July 2004; however, the potential for reintroduction of the virus remains.

Platelet activation in acute pulmonary embolism.

BACKGROUND: Platelet activation is implicated in thrombotic disorders, but has not been described in acute clinical pulmonary embolism (PE). OBJECTIVES: To investigate the natural history of platelet activation in PE and associated markers of inflammation, thrombosis and cardiac dysfunction. METHODS: Thirty-five consecutive patients (age 62 +/-17 years) with acute PE were prospectively enrolled and followed for 6 months. Platelet activation was assessed by flow cytometry [measuring expression of platelet P-selectin, conformational activation of glycoprotein IIb/IIIa complex (PAC-1) and formation of platelet-leukocyte complexes] and by plasma soluble P-selectin. Platelet activation, right ventricular (RV) function (assessed as RV ejection area by transthoracic echocardiography), D-dimer and high-sensitivity C-reactive protein (hs-CRP) were measured at presentation and repeated over 6 months follow-up. RESULTS: Soluble P-selectin (56 +/-19 ng mL(-1), anovaP < 0.0001) and PAC-1 (1.5 +/- 1.8%, anovaP = 0.005) were mildly but significantly increased in patients with acute PE relative to healthy young men (soluble P-selectin 33 +/- 13 ng mL(-1), P < 0.001; PAC-1 binding 0.5 +/- 0.6%, P < 0.01) and age-matched controls (soluble P-selectin 31 +/- 9 ng mL(-1), P < 0.001; PAC-1 binding 0.4 +/-0.4%, P < 0.05). Platelet P-selectin expression and platelet-leukocyte complexes were not increased during acute PE. Echocardiographic RV ejection area correlated inversely with soluble P-selectin (r = -0.47, P = 0.007) and positively with platelet P-selectin (r = 0.49, P = 0.0007), suggesting P-selectin is shed from activated platelets in proportion to the severity of RV dysfunction. Elevated soluble P-selectin, D-dimer and hs-CRP demonstrated a time-dependent return to normal during 6 months follow-up. CONCLUSION: Platelet activation is evident after acute PE. Platelet activation correlates with the severity of RV dysfunction, and can persist for several months after acute PE.