Comparing long-term local recurrence rates of surgical and non-surgical management of close anterior margins in breast conserving surgery.

PURPOSE: While it is known that histologically involved margins lead to a higher local recurrence rate, re-excision of anterior margins is less common than that of radial margins. However, there are minimal long-term data on the oncological safety of non-surgical management of anterior margins. PATIENTS AND METHODS: A retrospective study was performed of all patients who underwent breast conserving surgery for breast cancer between 2000 and 2008 at two tertiary referral centres. A close margin was defined as disease within two mm of the resection margin (including disease at the margin). RESULTS: 6922 patients underwent surgery for invasive or in situ breast cancer of whom 277 patients had a close anterior margin alone after breast conserving surgery. Two hundred and twenty patients had non-surgical management of their margins, while 57 had re-excision surgery. Overall, there were 4/57 local recurrences in the surgical management group and 12/220 in the non-surgical management group. The local recurrence-free survival rate at 5 years was 98.2% (1 recurrence, 95% CI 87.8-99.7) in the surgical management group and 97.2% (6 recurrences, 95% CI 93.8-98.7) in the non-surgical management group. At 10 years, the rates were 92.2% (4 recurrences, 95% CI 80.3-97.0) in the surgical management group and 93.9% (12 recurrences, 95% CI 89.4-96.5) in the non-surgical management group. There was no significant difference found in the local recurrence rate between management groups (HR 1.24, 95% CI 0.40, 3.85; p = 0.71). CONCLUSIONS: Local recurrence rates are acceptable and similar in both the surgically and non-surgically managed groups. Non-surgical management of close anterior margins appears oncologically safe when combined with appropriate adjuvant therapy.

Ex vivo study of human visceral nociceptors.

OBJECTIVE: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation. DESIGN: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses. RESULTS: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity. CONCLUSIONS: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.

P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.

Human visceral afferent recordings: preliminary report.

BACKGROUND: Conditions characterised by chronic visceral pain represent a significant healthcare burden with limited treatment options. While animal models have provided insights into potential mechanisms of visceral nociception and identified candidate drug targets, these have not translated into successful treatments in humans. OBJECTIVE: To develop an in vitro afferent nerve preparation using surgically excised freshly isolated human colon and vermiform appendix-mesentery tissues. METHODS: Non-inflamed appendix (n=18) and colon (n=9) were collected from patients undergoing right and left hemicolectomy. Electrophysiological recordings were made from mesenteric nerves and the tissue stimulated chemically and mechanically. RESULTS: Ongoing neuronal activity was sparse and where units occurred peak firing rates were: colon (2.0±0.4 spikes/s, n=4) and appendix (2.4±0.6 spikes/s, n=9). Afferent nerves innervating the appendix responded with a significant increase in activity following stimulation with inflammatory mediators (73±10.6 vs 3.0±0.3 spikes/s, n=6, p<0.001, inflammatory mediator vs baseline) and capsaicin (63±15.8 vs 2±0.3 spikes/s, n=3, p<0.001, capsaicin vs buffer). Afferent nerves innervating the colon responded with increased activity to blunt probing of the serosal surface. CONCLUSIONS: This first-in-human study demonstrates afferent nerve recordings from human gut tissue ex vivo and shows that tissue may be stimulated both chemically and mechanically to study neuronal responses. Collectively, the results provide preliminary evidence to validate this in vitro human tissue model as one that may aid future disease mechanistic studies and candidate drug testing.

Patient and public priorities for breast cancer research: a qualitative study in the UK.

OBJECTIVE: Internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals have published breast cancer research gaps that are informing research funding priorities in the UK and worldwide. We aimed to determine the breast cancer research priorities of the public to compare with those identified by clinicians and scientists. DESIGN: We conducted a qualitative study and thematic analysis using 'listening events' where patients with breast cancer and public representatives used a patient's breast cancer journey to identify research themes. PARTICIPANTS AND SETTING: Female participants were recruited from attendees at participating hospitals and support groups in the northwest of England, including patients, their family and friends as well as staff at a local retail centre. INTERVENTION: A framework approach was used to analyse transcribed discussions until thematic saturation was reached. MAIN OUTCOME MEASURES: Breast cancer research priorities were identified from participant discussions and compared with the published gaps identified by scientists and healthcare professionals. RESULTS: Thematic saturation was reached after 27 female participants participated in listening events. Our participants consistently focused on improved methods of dissemination of information and improving education on the signs and symptoms of breast cancer. This was not highlighted by scientists or healthcare professionals. There was strong emphasis on quality of life-related issues such as side effects of treatment. There was some agreement between the priorities deduced by our study and those of the professionals in the areas of screening, prevention and breast reconstruction. CONCLUSION: Our study identified some research themes that were not identified by scientists and healthcare professionals in two earlier landmark studies. This highlights the importance of including patients and public representatives when setting research priorities. The results should be used to guide investigators when planning future studies and for funding bodies in allocating resources for future projects.

Negative Pressure Wound Therapy Reduces Wound Breakdown and Implant Loss in Prepectoral Breast Reconstruction.

BACKGROUND: Single-use negative pressure wound therapy (NPWT) has been shown to encourage wound healing. It is often used when patient factors impair wound healing, or in more complex wounds, such as in implant-based breast reconstruction. We report the findings of a prospective cohort study comparing the use of NPWT with standard dressings in prepectoral breast reconstruction. METHODS: A prospective database of implant-based reconstruction from a single institution was mined to identify patients who underwent prepectoral reconstruction. Patient demographics, operative data, surgical complications, and 90-day outcomes were compared between patients who had NPWT and those who had standard dressings. RESULTS: Prepectoral implant-based breast reconstruction was performed on 307 breasts. NPWT dressings were used in 126 cases, with standard dressings used in 181 cases. Wound breakdown occurred in 10 cases after standard dressings versus 1 where NPWT was utilized. Of the standard dressing cases, only 3 implants were salvaged, while 7 cases led to implant loss. The 1 case of wound breakdown in the NPWT cohort settled with conservative measures. The cost of a reconstructive failure was £14,902, and the use of NPWT resulted in a cost savings of £426 per patient. CONCLUSIONS: The utilization of single-use NPWT reduces the rate of wound breakdown and implant loss in prepectoral implant-based reconstruction. In addition to the significant clinical benefits, this approach is cost-saving compared with standard dressings. These data suggest that prepectoral implant reconstruction should be considered as an indication for the use of NPWT.

Knowledge of oral cancer, distress and screening intentions: longer term effects of a patient information leaflet.

Study aim was to determine the influence of a patient information leaflet (PIL) on mouth cancer to improve knowledge, reduce distress and increase intention to accept a mouth screen over a 2-month period. The design was a randomised controlled trial. Two dental practices in the northwest of England participated. Standardised multi-item scales of the three outcome measures were employed. The PIL was given to a randomised intervention group of patients in waiting room. Single sheet questionnaire was completed by both groups of patients at baseline in waiting room (immediately following leaflet administration in intervention arm of study). Repeat questionnaire completion at 8 weeks by all patients through postal system. Mann-Whitney U-tests comparing outcome variables between patients with and without access to the leaflet at baseline and 8 weeks were performed. Multiple logistic regression was used to predict re-reading of the leaflet at home. Useable replies were received from 317 patients (60% response rate). All measures showed some benefit of immediate exposure to the leaflet at follow up. Older patients, less initial knowledge, and self-reported smoking positively predicted the re-reading of the leaflet. The introduction of a mouth cancer PIL into dental practice may help to inform patients about oral cancer, moderate distress and encourage acceptance of an oral health screen.

Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli.

Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9(-/-) mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in NaV1.9(-/-) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9(-/-) mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.