Test, evidence, transition projects in Scotland: developing the evidence needed for transition of effective interventions in cancer care from innovation into mainstream practice.

BACKGROUND: A robust evidence base is required to assist healthcare commissioners and providers in selecting effective and sustainable approaches to improve cancer diagnosis and treatment. Such evidence can be difficult to build, given the fast-paced and highly pressured nature of healthcare delivery, the absence of incentives, and the presence of barriers in conducting pragmatic yet robust research evaluations. Cancer Research UK (CRUK) has played an active part in building the evidence base through its funding of programmes to identify, evaluate and scale-up innovative approaches across the UK. The aim of this paper is to describe and explain the research design and intended approach and activities for two cancer services improvement projects in Scotland funded by CRUK. METHODS: A hybrid effectiveness-implementation study design will assess both the efficiency of the new pathways and their implementation strategies, with the aim of generating knowledge for scale-up. A range of implementation, service and clinical outcomes will be assessed as determined by the projects' Theories of Change (ToCs). A naturalistic case study approach will enable in-depth exploration of context and process, and the collection and synthesis of data from multiple sources including routine datasets, patient and staff surveys, in-depth interviews and observational and other data. The evaluations are informed throughout by a patient/public representatives' group, and by small group discussions with volunteer cancer patients. DISCUSSION: Our approach has been designed to provide a holistic understanding of how (well) the improvement projects work (in relation to their anticipated outcomes), and how they interact with their wider contexts. The evaluations will help identify barriers, facilitators, and unanticipated consequences that can impact scalability, sustainability and spread. By opting for a pragmatic, participatory evaluation research design, we hope to inform strategies for scaling up successful innovations while addressing challenges in a targeted manner.

Nipple-Sparing Mastectomy versus Skin-Sparing Mastectomy: Does Saving the Nipple Impact Short- and Long-Term Patient Satisfaction?

BACKGROUND: Nipple-sparing mastectomy (NSM) is an oncologically safe alternative to skin-sparing mastectomy (SSM). This study evaluated whether NSM patients were more satisfied than SSM patients in short- and long-term follow-up. METHODS: Women who underwent NSM or SSM between 2009 and 2019 completed a postoperative BREAST-Q survey at least 1 year after surgery and patient characteristics were compared. Patient satisfaction at 1-5 years and 6-10 years after NSM and SSM were analyzed. RESULTS: Overall, 431 patients were included; 247 had NSM and 184 had SSM 1-10 years prior to BREAST-Q survey completion. SSM patients were older, had higher body mass index (BMI), larger breast weight, and more hypertension than NSM patients, but oncologic treatments were similar between groups. BREAST-Q Psychosocial Well-Being and Sexual Well-Being scores were significantly higher in NSM patients compared with SSM patients in the 1-5 years cohort; however, scores attenuated in the 6-10 years cohort. Satisfaction with breasts was nearly significantly higher in NSM patients compared with SSM patients in the 1-5 years cohort (p = 0.056), but no different in the 6-10 years cohort. Receipt of adjuvant chemotherapy, receipt of postmastectomy radiation therapy, and BMI ≥30 were independent risk factors for dissatisfaction with breasts. CONCLUSIONS: Women who are not candidates for NSM should be reassured that long-term qualify of life is not significantly different between SSM and NSM. Dissatisfaction with reconstructed breasts is linked with other factors (besides the nipple), which patients should be made aware of at the time of surgical decision making.

Performance of a novel protease-activated fluorescent imaging system for intraoperative detection of residual breast cancer during breast conserving surgery.

PURPOSE: Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20-40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. METHODS: We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. RESULTS: Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81-5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. CONCLUSIONS: Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery.

BACKGROUND: Obtaining tumor-free margins is critical to prevent recurrence after lumpectomy for breast cancer. Unfortunately, current approaches leave positive margins that require second surgeries in 20-40% of patients. We assessed the LUM Imaging System for real-time, intraoperative detection of residual tumor. METHODS: Breast lumpectomy cavity walls and excised specimens were assessed with the LUM Imaging System after 1 mg/kg intravenous LUM015, a protease-activatable fluorescent agent. Fluorescence at potential sites of residual tumor in lumpectomy cavity walls was evaluated intraoperatively with a sterile hand-held probe, with real-time predictive results displayed on a monitor intraoperatively, and later correlated with histopathology. RESULTS: In vivo lumpectomy cavities and excised specimens were imaged after LUM015 injection in 45 women undergoing breast cancer surgery. Invasive ductal and lobular cancers and intraductal cancer (DCIS) were included. A total of 570 cavity margin surfaces in 40 patients were used for algorithm development. Image analysis and display took approximately 1 s per 2.6-cm-diameter circular margin surface. All breast cancer subtypes could be distinguished from adjacent normal tissue. For all imaged cavity surfaces, sensitivity for tumor detection was 84%. Among 8 patients with positive margins after standard surgery, sensitivity for residual tumor detection was 100%; 2 of 8 were spared second surgeries because additional tissue was excised at sites of LUM015 signal. Specificity was 73%, with some benign tissues showing elevated fluorescent signal. CONCLUSIONS: The LUM015 agent and LUM Imaging System allow rapid identification of residual tumor in the lumpectomy cavity of breast cancer patients and may reduce rates of positive margins.

Correction to: Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery.

The article Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery, written by Barbara L. Smith et al., was originally published electronically on the publisher's internet portal on January 2, 2020, without open access.

Enhanced Recovery Minimizes Opioid Use and Hospital Stay for Patients Undergoing Mastectomy with Reconstruction.

BACKGROUND: This study examined the effects of an enhanced recovery program on inpatient opioid requirements and hospital length of stay (LOS) for mastectomy patients undergoing immediate reconstruction. METHODS: An enhanced recovery program for patients undergoing mastectomy with immediate tissue expander (TE) or implant reconstruction was evaluated by comparing a contemporary cohort of 611 patients in 2016-2018 with a historical cohort of 188 patients in 2010. Opioid use and LOS were compared over time and stratified by laterality, mastectomy type, axillary procedure, and reconstruction. Associations were assessed by uni- and multivariate analyses. RESULTS: In 2010, 95.2% of patients required intravenous (IV) opioids, with a last dose 15.5 h after completion of surgery, compared with 68.7% of patients in 2016-2018, with a last dose 1.8 h after surgery (p < 0.001). Patients prescribed gabapentin postoperatively were less likely to require inpatient IV or oral opioids (p < 0.001). The mean LOS decreased from 37 h in 2010 to 27.5 h in 2016-2018 without an increase in the readmission rate (6.9% vs. 4.1%; p = 0.112). Patients were more likely to stay more than one night if they were older (p = 0.012), had undergone bilateral mastectomies (p < 0.001) or TE reconstruction (p = 0.012), and had surgery in 2010 compared with 2016-2018 (p < 0.001). Even after adjustment for LOS, IV opioid use remained significantly associated with year of surgery (p < 0.001). CONCLUSIONS: Compared with 2010, patients undergoing mastectomy with TE or implant reconstruction in 2016-2018 required less inpatient opioids and had decreased LOS. The authors attribute this to an enhanced recovery program focused on preoperative counseling, non-opioid analgesics, and improved surgical efficiencies.

Synthesis and structure-activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS).

The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1µM.

Long-Term Outcomes of Multiple-Wire Localizations for More Extensive Breast Cancer: Multiple-Wire Excision Does Not Increase Recurrence, Unplanned Imaging, or Biopsies.

BACKGROUND: We previously reported that breast conservation was feasible for women with large or irregularly shaped breast cancers when tumor resection was guided by multiple localizing wires. We now report long-term outcomes of multiple-wire versus single-wire localized lumpectomies for breast cancer. PATIENTS AND METHODS: We retrospectively reviewed wire-localized lumpectomies at our institution from May 2000 to November 2006. Rates of ipsilateral in-breast tumor recurrence, metastasis, and subsequent unplanned diagnostic imaging and biopsy were compared between multiple-wire and single-wire cohorts. RESULTS: We identified 112 multiple-wire and 160 single-wire breast cancer lumpectomies that achieved clear margins. Median age was 64 years in the multiple-wire cohort and 57 years in the single-wire cohort. Mean lumpectomy volume was 75 mL in multiple-wire patients and 49 mL in single-wire patients (P = .003). Invasive tumor size, axillary node status, and use of radiation and systemic therapy were similar, but the multiple-wire group had more patients with ductal carcinoma-in-situ only (38% vs. 28%). At 108 months' median follow-up, there was no significant difference in local or distant recurrence rates between multiple-wire and single-wire cohorts. Six (5%) multiple-wire patients and 6 (4%) single-wire patients had local recurrences and 3 (3%) multiple-wire and 5 (3%) single-wire patients developed metastatic disease. Unplanned diagnostic imaging was required for 53 (47%) multiple-wire and 65 (41%) single-wire patients. Subsequent ipsilateral biopsy occurred in 15 (13%) multiple-wire and 19 (12%) single-wire patients. CONCLUSION: Breast-conserving surgery with multiple localizing wires is a safe alternative to mastectomy for breast cancer patients with large mammographic lesions.

Nipple Discharge After Nipple-Sparing Mastectomy With and Without Associated Pregnancy.

BACKGROUND: Nipple-sparing mastectomies (NSMs) preserve the intact nipple, including nipple duct orifices. Retained orifices might remain patent and communicate with the underlying reconstruction. We report the incidence and outcomes of nipple discharge after NSM in pregnant and nonpregnant women. PATIENTS AND METHODS: Retrospective review of all NSMs at our institution from June 2007 to June 2018 was performed. Subsequent pregnancies and nipple discharge were documented. Patient demographic, operative, histopathology, and cancer treatment data were collected. Descriptive analysis was performed for patients who developed nipple discharge. RESULTS: From June 2007 to June 2018, 2778 NSM procedures were performed in 1620 patients, with a mean age of 48 (range, 20-80) years. Fifteen hundred sixty-eight NSMs were therapeutic and 1210 were for risk reduction. Thirty-three subsequent pregnancies were observed in 27 patients, with a mean age of 33 (range, 26-42) years at NSM. Bilateral or unilateral discharge occurred in 6 of 27 (22%) postpartum patients and resolved spontaneously. At 54 months mean follow-up after NSM (range, 16-98 months) and 23 (range, 1-61) months after delivery, no local-regional recurrences were observed. In 1593 patients without subsequent pregnancy, there were 4 patients (0.25%) treated with bilateral NSM with subsequent unilateral watery nipple discharge. There was no evidence of associated malignancy on physical exam, imaging, or cytology, and with 55 to 110 months follow-up, no new or recurrent cancers have been observed. CONCLUSION: Despite extensive removal of nipple and subareolar duct tissue during NSM, milky nipple discharge is possible postpartum. Watery, acellular discharge occurs rarely in nonpregnant patients. To date, no patient with discharge has developed a local recurrence or new breast cancer.