Catching and monitoring clinical innovation through performance indicators. The case of the breast-conserving surgery indicator.

Background: The evolution in the surgical and diagnostic procedures, the attention to women’s preferences, the case mix, and di erences in professional practices may lead to a variability in the quality of breast cancer clinical pathway. To catch and manage this variability it is important to use valid measures. The aim of this paper is to examine the concurrent validity of the breast-conserving surgery (BCS) indicator and to provide evidence to guide the quality improvement process. Methods: The BCS indicator was calculated using hospital discharge records (HDRs) and was validated against surgi- cal registry (SR) data in a random sample of 336 women undergoing breast cancer surgery in 2012 in two Tuscan teaching hospitals. The concurrent validity of BCS was examined by cross-tabulating patients using the ICD-9 CM codes for breast surgery obtained from the two data sources. Results: The analysis, carried out involving breast cancer professionals, highlighted that the large majority of inter- ventions coded as “mastectomies” in HDRs are in fact reconstructing procedures, including nipple-sparing, skin- sparing and skin-reducing mastectomies in SR. These results led us to re ne the old algorithm, that calculates the proportion of breast-conserving surgery over the total number of breast interventions, and reclassify breast cancer surgical procedures into three categories: conservative, reconstructive and traditional mastectomy. Based on this new classi cation algorithm, the percentages of (I) reconstructive interventions were 16% at Florence TH and 38.3% at Pisa TH; (II) breast-conserving interventions were respectively 72.8 and 52.1%; and (III) mastectomies 11.2 and 9.6%. After adjusting for age in a logistic regression model, the percentages of reconstructive interventions at Florence and Pisa were respectively 22 and 34% and those of breast-conserving interventions 63 and 53%. Conclusions: Our results indicate that breast cancer care indicators should be re ned by distinguishing reconstruc- tive procedures (nipple/skin-sparing surgery with implant or breast tissue expander insertion) from traditional mas- tectomy. The involvement of breast care professionals in the choice of indicators proved to be crucial to capture the up-to-date breast cancer surgical practice and inform the quality improvement process. Keywords: Performance indicators, Breast cancer, Breast conserving surgery, Healthcare quality, Professional involvemen

Systematic and continuous collection of patient-reported outcomes and experience in women with cancer undergoing mastectomy and immediate breast reconstruction: a study protocol for the Tuscany Region (Italy)

Introduction: Monitoring how patients feel and what they experience during the care process gives health professionals data to improve the quality of care, and gives health systems information to better design and implement care pathways. To gain new insights about specific gaps and/or strengths in breast cancer care, we measure patient-reported outcomes (PROs) and patient-reported experiences (PREs) for women receiving immediate breast reconstruction (iBR). Methods and analysis: Prospective, multicentre, cohort study with continuous and systematic web-based data collection from women diagnosed with breast cancer, who have an indication for iBR after mastectomy treated at any Breast Unit (BU) in Tuscany Region (Italy). Patients are classified into one of two groups under conditions of routine clinical practice, based on the type of iBR planned (implant and autologous reconstruction). Patient-reported information are obtained prior to and after surgery (at 3-month and 12-month follow-up). We estimate that there are around 700 annual eligible patients.Descriptive analyses are used to assess trends in PROs over time and differences between types of iBR in PROs and PREs. Additionally, econometric models are used to analyse patient and BU characteristics associated with outcomes and experiences. PREs are evaluated to assess aspects of integrated care along the care pathway. Ethics and dissemination: The study has been reviewed and obtained a nihil obstat from the Tuscan Ethics Committees of the three Area Vasta in 2017. Dissemination of results will be via periodic report, journal articles and conference presentations

Segmental Liver Transplantation From Living Donors Report of the Technique and Preliminary Results in Dogs

A technique of orthotopic liver transplantation using a segmental graft from living donors was developed in the dog. Male mongrel dogs weighing 25–30 kg were used as donors and 10–15 kg as recipients. The donor operation consists of harvesting the left lobe of the liver (left medial and left lateral segments) with the left branches of the portal vein, hepatic artery and bile duct, and the left hepatic vein. The grafts are perfused in situ through the left portal branch to prevent warm ischemia. The recipient operation consists of two phases: 1total hepatectomy with preservation of the inferior vena cava using total vascular exclusion of the liver and veno-venous bypass, 2implantation of the graft in the orthotopic position with anastomosis of the left hepatic vein to the inferior vena cava and portal, arterial and biliary reconstruction. Preliminary experiments consisted of four autologous left lobe transplants and nine non survival allogenic left lobe transplants. Ten survival experiments were conducted. There were no intraoperative deaths in the donors and none required transfusions. One donor died of sepsis, but all the other donor dogs survived without complication. Among the 10 grafts harvested, one was not used because of insufficient bile duct and artery. Two recipients died intraoperatively of air embolus and cardiac arrest at the time of reperfusion. Three dogs survived, two for 24 hours and one for 48 hours. They were awake and alert a few hours after surgery, but eventually died of pulmonary edema in 2 cases and of an unknown reason in the other. Four dogs died 2–12 hours postoperatively as a result of hemorrhage for the graft's transected surface. An outflow block after reperfusion was deemed to be the cause of hemorrhage in these cases. On histologic examination of the grafts, there were no signs of ischemic necrosis or preservation damage

The role of clinicopathologic and molecular prognostic factors in the post-mastectomy radiotherapy (PMRT): a retrospective analysis of 912 patients

OBJECTIVE: To assess the association of clinicopathologic and molecular features with loco-regional recurrence (LRR) in post-mastectomy breast cancer patients with or without adjuvant radiotherapy (PMRT). PATIENTS AND METHODS: We retrospectively reviewed data of patients undergone to mastectomy followed or not by PMRT between January 2004 and June 2013. The patients were divided according to clinicopathologic and molecular sub-classification features. LRR and Cancer Specific Survival (CSS) were calculated using the Kaplan-Meier method; the prognostic factors were compared using long-rank tests and Cox regression model. RESULTS: A total of 912 patients underwent to mastectomy of whom 269 (29.5%) followed by PMRT and 643 (70.5%) not; among the PMRT group, 77 underwent to the chest wall (CW) and 202 to the chest wall and lymphatic drainage (CWLD) irradiation. The median follow-up was 54 months (range, 3-118). No significant difference in terms of LRR and CSS was found between non-PMRT and PMRT group (p=0.175; and p=0.628). The multivariate analysis of LRR for patients who did not undergo PMRT showed a significant correlation with the presence of extracapsular extension (ECE) (p=0.049), Ki-67>30% (p=0.048) and triple negative status (p=0.001). In the PMRT group, triple negative status resulted as the only variable significantly correlated to LRR (p=0.006) at the multivariate analysis and T-stage also showed a trend to significance (p=0.073). Finally, no difference in LRR control was shown between CW and CWLD-PMRT (p=0.078). CONCLUSIONS: After mastectomy ECE, a cut off of Ki-67>30% and triple negative status werestrictly correlated with LRR regardless of clinicopathologic stage. PMRT has a positive impact in decreasing LRR in patients with this molecular profile. Besides, CW might represent a valid option for patients with one to three positive nodes

Human saliva as route of inter-human infection for mouse mammary tumor virus

Etiology of human breast cancer is unknown, whereas the Mouse Mammary Tumor Virus (MMTV) is recognized as the etiologic agent of mouse mammary carcinoma. Moreover, this experimental model contributed substantially to our understanding of many biological aspects of the human disease. Several data strongly suggest a causative role of MMTV in humans, such as the presence of viral sequences in a high percentage of infiltrating breast carcinoma and in its preinvasive lesions, the production of viral particles in primary cultures of breast cancer, the ability of the virus to infect cells in culture. This paper demonstrates that MMTV is present in human saliva and salivary glands. MMTV presence was investigated by fluorescent PCR, RT-PCR, FISH, immunohistochemistry, and whole transcriptome analysis. Saliva was obtained from newborns, children, adults, and breast cancer patients. The saliva of newborns is MMTV-free, whereas MMTV is present in saliva of children (26.66%), healthy adults (10.60%), and breast cancer patients (57.14% as DNA and 33.9% as RNA). MMTV is also present in 8.10% of salivary glands. RNA-seq analysis performed on saliva of a breast cancer patient demonstrates a high expression of MMTV RNA in comparison to negative controls. The possibility of a contamination by murine DNA was excluded by murine mtDNA and IAP LTR PCR. These findings confirm the presence of MMTV in humans, strongly suggest saliva as route in inter-human infection, and support the hypothesis of a viral origin for human breast carcinoma

ANKRd44 gene silencing: a putative role in trastuzumab resistance in HER2-like breast cancer

Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance

Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

In this study, we determined if BRCA1 partners involved in DNA double-strand break (DSB) and mismatch repair (MMR) may contribute to breast and ovarian cancer development. Taking advantage the functional conservation of DNA repair pathways between yeast and human, we expressed several BRCA1 missense variants in DNA repair yeast mutants to identify functional interaction between BRCA1 and DNA repair in BRCA1-induced genome instability. The pathogenic p.C61G, pA1708E, p.M775R, and p.I1766S, and the neutral pS1512I BRCA1 variants increased intra-chromosomal recombination in the DNA-repair proficient strain RSY6. In the mre11, rad50, rad51, and msh6 deletion strains, the BRCA1 variants p.C61G, pA1708E, p.M775R, p.I1766S, and pS1215I did not increase intra-chromosomal recombination suggesting that a functional DNA repair pathway is necessary for BRCA1 variants to determine genome instability. The pathogenic p.C61G and p.I1766S and the neutral p.N132K, p.Y179C, and p.N550H variants induced a significant increase of reversion in the msh2Δ strain; the neutral p.Y179C and the pathogenic p.I1766S variant induced gene reversion also, in the msh6Δ strain. These results imply a functional interaction between MMR and BRCA1 in modulating genome instability. We also performed a somatic mutational screening of MSH6, RAD50, MRE11A, and RAD51 genes in tumor samples from 34 patients and identified eight pathogenic or predicted pathogenic rare missense variants: four in MSH6, one in RAD50, one in MRE11A, and two in RAD51. Although we found no correlation between BRCA1 status and these somatic DNA repair variants, this study suggests that somatic missense variants in DNA repair genes may contribute to breast and ovarian tumor development

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Radioguided occult lesion localization technical procedures and clinical applications

Purpose: Regarding radioguided surgery, the concept of “radioguided occult lesion localization” (ROLL) is based on both preoperative interventional imaging and intraoperative radioguided detection of a clinically occult neoplastic lesion. Methods: This methodology consists in the direct administration into the lesion of99mTc–macroaggregated human albumin formed by relatively large particles retained at the injection site, which direct radioguided excisional biopsy. Results: This modality has expanded from the classic application of ROLL for nonpalpable breast lesions to other tumors, such as solitary pulmonary nodules or recurrences from differentiated thyroid carcinoma. In 2011, in order to improve the classification of different radioguided surgical procedures, ROLL applications were included in the more complete concept of GOSTT (Guided intraOperative Scintigraphic Tumor Targeting). This concept was introduced to include the entire range of basic and advanced radioguided procedures necessary to supply a “road map” for the surgeon. Conclusions: The terms ROLL and GOSTT have further developed by incorporating novel modalities such as hybrid tracers for simultaneous fluorescence and radioactive signal detection and innovative navigation systems based on mixed-reality protocols