Integration of multiomics data shows down regulation of mismatch repair and tubulin pathways in triple-negative chemotherapy-resistant breast tumors.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). The response to NAC is prognostic, with reductions in overall survival and disease-free survival rates in those patients who do not achieve a pathological complete response (pCR). Based on this premise, we hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence. METHODS AND RESULTS: We investigated 24 samples from 12 non-LAR TNBC patients with paired pre- and post-NAC data, including four patients with recurrence shortly after surgery (< 24 months) and eight who remained recurrence-free (> 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and nonrecurrent TNBC tumors; however, post-NAC samples demonstrated significant alterations in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the 9 paired non-LAR samples available in the NAC I-SPY1 trial confirmed 56 gene sets. Within these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n = 392) breast cancer dataset with relapse-free survival (RFS) data was used to refine our gene list to a 17-gene signature. A threefold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine-learning models. Due to the limited number of studies with pre- and post-NAC TNBC tumor data, further validation of the signature is needed. CONCLUSION: Analysis of multiomics data from post-NAC TNBC chemoresistant tumors showed down regulation of mismatch repair and tubulin pathways. Additionally, we identified a 17-gene signature in TNBC associated with post-NAC recurrence enriched with down-regulated immune genes.

Postoperative Opioid Utilization and Patient Satisfaction in General Surgery Procedures: A Prospective Observational Study.

BACKGROUND: Wide variation of opioid prescribing persists despite attempts to quantify number of opioids utilized postoperatively. We aim to prospectively determine number of opioids used after common surgery procedures to guide future prescribing. METHODS: A prospective observational trial was performed of opioids prescribed and used postoperatively. Patients filled out pre- and postoperative surveys, and number of opioids utilized was captured at postoperative visit. RESULTS: One-hundred-and-thirteen patients met inclusion. Median opioids prescribed exceeded number of opioids taken for all procedures. Median number of opioids taken postoperatively was fewer than 10 for all categories of procedures: simple skin/soft tissue 2 (IQR 1-4), complex skin/soft tissue 1.5 (IQR 0-14), simple laparoscopy 1 (IQR 0-20) and complex laparoscopy 4 (IQR 0-20), laparotomy 0 (IQR 0-26), and open inguinal hernia 2 (IQR 0-2). Nearly 80% of patients had leftover opioids, and 31% planned to keep them. There was little difference between preoperative and postoperative level of satisfaction with a pain control regimen. DISCUSSION: Postoperatively, patients utilize opioids less frequently than prescribed and often keep leftover pills. Patient pain control satisfaction is unrelated to number of opioids prescribed and taken postoperatively.

Characterizing Occult Nodal Disease Within a Clinically Node-Negative, Neoadjuvant Breast Cancer Population.

BACKGROUND: Neoadjuvant therapy aims to preoperatively downstage breast cancer patients. We evaluated nodal upstaging in clinically node-negative (cN0) patients receiving neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET). METHODS: cN0 patients undergoing neoadjuvant therapy from 2009 to 2018 were reviewed. Univariate and multivariate analyses evaluated rates of nodal upstaging. RESULTS: A total of 228 cN0 patients with a mean age of 55 years underwent neoadjuvant therapy for Stage I-III invasive carcinoma. Subtypes included ER+/HER2- = 93 (40%), HER2+ = 61 (27%), and triple negative (TNBC) = 74 (33%). Among ER+/HER2- patients, 65 (70%) underwent NET. Overall, 49 patients (21%) were upstaged due to occult nodal disease. Factors associated with higher rates of occult nodal disease included advanced stage on initial presentation (P = .008), larger presenting tumor size (P = .009), low/intermediate tumor grade (P = .025), and ER+/HER2- subtype (P < .001); incidence of occult nodal disease by subtype included: ER+/HER2- = 37%, HER2+ = 15%, TNBC = 8%. Patients experiencing a breast pCR had a significantly lower rate of nodal upstaging compared to those with residual tumor (4% vs. 96%, P < .001). On multivariate analysis, ER+/HER- patients exhibited higher risk of occult nodal disease when compared to patients with HER2+ (odds ratio [OR] = 3.4, 95% CI, 1.2-9.8, P = .003) and TNBC (OR = 5.7, 95% CI, 1.7-19.6, P = .003). Comparing NAC vs. NET in ER+/HER2- patients showed no difference in rates of occult nodal disease (39% vs. 35%, P = .13). CONCLUSIONS: ER+/HER2- subtype carries higher risk for occult nodal disease after neoadjuvant therapy; NAC versus NET in these patients does not affect nodal upstaging.

Patient-Derived Xenograft Engraftment and Breast Cancer Outcomes in a Prospective Neoadjuvant Study (BEAUTY).

PURPOSE: Patient-derived xenografts (PDX) are a research tool for studying cancer biology and drug response phenotypes. While engraftment rates are higher for tumors with more aggressive characteristics, it is uncertain whether engraftment is prognostic for cancer recurrence. PATIENTS AND METHODS: In a prospective study of patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with taxane ± trastuzumab followed by anthracycline-based chemotherapy, we report the association between breast cancer events and PDX engraftment using tumors derived from treatment naïve (pre-NAC biopsies from 113 patients) and treatment resistant (post-NAC at surgery from 34 patients). Gray test was used to assess whether the cumulative incidence of a breast cancer event differs with respect to either pre-NAC PDX engraftment or post-NAC PDX engraftment. RESULTS: With a median follow-up of 5.7 years, the cumulative incidence of breast cancer relapse did not differ significantly according to pre-NAC PDX engraftment (5-year rate: 13.6% vs. 13.4%; P = 0.89). However, the incidence of a breast event was greater for patients with post-NAC PDX engraftment (5-year rate: 50.0% vs. 19.6%), but this did not achieve significance (P = 0.11). CONCLUSIONS: In treatment-naïve breast cancer receiving standard NAC, PDX engraftment was not prognostic for breast cancer recurrence. Further study is needed to establish whether PDX engraftment in the treatment-resistant setting is prognostic for cancer recurrence.

Prevalence of SARS-CoV-2 Antibodies in a Multistate Academic Medical Center.

OBJECTIVE: To estimate the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in health care personnel. METHODS: The Mayo Clinic Serology Screening Program was created to provide a voluntary, two-stage testing program for SARS-CoV-2 antibodies to health care personnel. The first stage used a dried blood spot screening test initiated on June 15, 2020. Those participants identified as reactive were advised to have confirmatory testing via a venipuncture. Venipuncture results through August 8, 2020, were considered. Consent and authorization for testing was required to participate in the screening program. This report, which was conducted under an institutional review board-approved protocol, only includes employees who have further authorized their records for use in research. RESULTS: A total of 81,113 health care personnel were eligible for the program, and of these 29,606 participated in the screening program. A total of 4284 (14.5%) of the dried blood spot test results were "reactive" and warranted confirmatory testing. Confirmatory testing was completed on 4094 (95.6%) of the screen reactive with an overall seroprevalence rate of 0.60% (95% CI, 0.52% to 0.69%). Significant variation in seroprevalence was observed by region of the country and age group. CONCLUSION: The seroprevalence for SARS-CoV-2 antibodies through August 8, 2020, was found to be lower than previously reported in other health care organizations. There was an observation that seroprevalence may be associated with community disease burden.

Lymph node positivity and association with long-term survival for different histologies of appendiceal cancer.

BACKGROUND: Appendiceal cancers represent a diverse group of malignancies with varying biological behavior. The significance of lymph node metastases in relation to long-term survival and chemotherapy response is poorly defined. METHODS: The National Cancer Database was queried to find patients diagnosed with appendiceal cancer from 1998 to 2012. Kaplan-Meier curves and multivariable Cox regression analyses were used to study the association between lymph node status and overall survival. Stage IV patients were excluded. RESULTS: The rate of nodal positivity of the 9841 patients with known node status was: signet ring 47.4%, carcinoid 42.3%, nonmucinous adenocarcinoma 28.8%, goblet cell 21.9%, and mucinous adenocarcinoma 20.4%. Node-positive patients had worse long-term survival for all subtypes with the exception of carcinoid tumors (p < 0.001). The strongest association was for signet cell and goblet cell. Adjuvant chemotherapy in node-positive patients improved survival for mucinous, nonmucinous, and signet ring cell histology (p < 0.01), but not for goblet cell. CONCLUSIONS: Nodal involvement in patients with appendiceal cancer varies in incidence, association with adverse survival, and response to systemic therapy. Individualized treatment algorithms for the management of the subtypes of appendiceal cancer are needed.

Unplanned implant removal in locally advanced breast cancer.

Study conducted to determine frequency and timing of unplanned breast implant removal after mastectomy, reconstruction, and postmastectomy radiation (PMRT). From 2010-2017, 52 patients underwent mastectomy, reconstruction, and PMRT. With median follow-up of 3.1 years, 23 patients (44%) experienced implant removal. Implant removal occurred in 9 (17%) patients before starting PMRT and 14 (27%) patients after starting PMRT. Implant removal rates were similar for hypofractionated PMRT compared with standard fractionation and for proton compared with photon PMRT. Implant removal is common for women undergoing mastectomy and reconstruction followed by PMRT. The risk is clinically significant even before starting radiation.

Association between subthreshold depression and self-care behaviours in adults with type 2 diabetes: A protocol for a cross-sectional study.

AIMS AND OBJECTIVES: To examine the association between subthreshold depression and self-care behaviours in adults with type 2 diabetes (T2D) attending a tertiary healthcare service. BACKGROUND: Diabetes is a global public health problem. Self-care behaviours are a fundamental element in managing diabetes as adherence to self-care activities is associated with improved glycaemic control. Depression in T2D is associated with decreased adherence to self-care behaviours. Adults with subthreshold depression in diabetes may have difficulties in achieving metabolic control. Further, people with subthreshold depression have an increased risk of developing major depression. Few studies have examined the association between subthreshold depression and self-care behaviours. DESIGN: A cross-sectional study. METHODS: The study will be conducted among 384 adults diagnosed with T2D for at least a year attending their routine outpatient appointment at Tribhuvan University Teaching Hospital in Nepal. Convenience sampling will be used to recruit study participants. Data will be collected via face-to-face interviews and a medical record review. Self-care behaviours will be assessed using the Summary of Diabetes Self-care activities and subthreshold depression will be determined using the Patient Health Questionnaire- 9. Covariates in the study include sociodemographic and clinical factors, diabetes knowledge, perceived social support and self-efficacy. This paper complies with the STROBE reporting guideline for cross-sectional studies. RESULTS: We will use multiple linear regression to examine the association between subthreshold depression and each self-care behaviours (i.e. diet, physical activity, foot care, blood glucose testing and medication) and total self-care behaviour. CONCLUSIONS: Effective management of diabetes requires adherence to self-care behaviours. The findings of the study will help in identifying an effective way to improve diabetes self-care. RELEVANCE TO CLINICAL PRACTICE: Our observations will inform nursing research and practice by providing evidence about how subthreshold depression may influence self-care behaviours.

Comparative Effectiveness of Pylorus-Preserving Versus Standard Pancreaticoduodenectomy in Clinical Practice.

OBJECTIVES: We compared risk-adjusted short- and long-term outcomes between standard pancreaticoduodenectomy (SPD) and a pylorus-preserving pancreaticoduodenectomy (PPPD). METHODS: The National Cancer Database was queried for the years 2004 to 2014 to identify patients with adenocarcinoma of the pancreatic head undergoing SPD and PPD. Margin status, lymph node yield, length of stay (LOS), 30- and 90-day mortality, and overall survival were compared. RESULTS: A total of 11,172 patients were identified, of whom 9332 (83.5%) underwent SPD and 1840 (16.5%) PPPD. There was no difference in patient age, sex, stage, tumor grade, radiation treatment, and chemotherapy treatment between the 2 groups. Total number of regional lymph nodes was examined, and surgical margin status and overall survival were also comparable. However, patients undergoing PPPD had a shorter LOS (11.3 vs 12.3 days, P < 0.001), lower 30-day mortality (2.5% vs 3.7%, P = 0.02), and 90-day mortality (5.5% vs 6.9%, P = 0.03). On multivariate analyses, patients undergoing SPD were at higher risk for 30-day mortality compared with PPPD (odds ratio, 1.51; 95% confidence interval, 1.07-2.13). CONCLUSIONS: Standard pancreaticoduodenectomy and PPPD are oncologically equivalent, yet PPPD is associated with a reduction in postoperative mortality and shorter LOS.

Implementation of an Enhanced Recovery After Surgery (ERAS) Program is Associated with Improved Outcomes in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with increased postoperative complications and a prolonged length of stay (LOS). We report on our experience following implementation of an Enhanced Recovery After Surgery (ERAS) program for CRS and HIPEC. METHODS: Patients were divided into pre- and post-ERAS groups. Modifications in the ERAS group included routine use of transversus abdominis plane blocks, intra- and postoperative fluid restriction, and minimizing the use of narcotics, drains, and nasogastric tubes. RESULTS: Of a total of 130 procedures, 49 (38%) were in the pre-ERAS group and 81 (62%) were in the ERAS group. Mean LOS was reduced from 10.3 ± 8.9 days to 6.9 ± 5.0 days (p = 0.007) and the rate of grade III/IV complications was reduced from 24 to 15% (p = 0.243) following ERAS implementation. The ERAS group received less intravenous fluid during hospitalization (19.2 ± 18.7 L vs. 32.8 ± 32.5 L, p = 0.003) and used less opioids than the pre-ERAS group (median of 159.7 mg of oral morphine equivalents vs. 272.6 mg). There were no significant changes in the rates of 30-day readmission or acute kidney injury between the two groups (p = non-significant). On multivariable analyses, ERAS was significantly associated with a reduction in LOS (- 2.89 days, 95% CI - 4.84 to - 0.94) and complication rates (odds ratio 0.22, 95% CI 0.08-0.57). CONCLUSIONS: Implementation of an ERAS program for CRS and HIPEC is associated with a reduction in overall intravenous fluids, postoperative narcotic use, complication rates, and LOS.

Depomedroxyprogesterone acetate therapy for hot flashes in survivors of breast cancer: no unfavorable impact on recurrence and survival.

PURPOSE: Survivors of estrogen receptor-expressing breast cancer generally do not receive estrogen-based therapy for menopausal symptoms due to concern for provoking recurrence of disease. Single-dose depomedroxyprogesterone acetate has been shown to be among the most effective non-estrogen strategies for treatment of menopausal hot flashes, but long-term evidence for safety in survivors is lacking. METHODS: We conducted an institutional review board approved, retrospective, case-control cohort study at a tertiary, academic referral center. Patients with estrogen receptor-expressing early-stage operable breast cancer who received depomedroxyprogesterone acetate for hot flashes between January 2005 and December 2012 were identified. We confirmed 75 patients who met strict inclusion criteria who were matched 1:1 with controls for age, stage of disease, HER2 status, and year of diagnosis. Overall survival, loco-regional recurrence-free survival, and progression-free survival assessments for cases were compared with controls. RESULTS: Median follow-up duration was 68.4 months in cases and 57.6 months in controls. Estimated local-regional recurrence-free survival at 10 years was 97% (95% CI, 92-100%) in cases and 98% (95% CI, 95-100%) in controls. Estimated progression-free survival at 10 years was 89% (95% CI, 80-100%) in cases and 83% (95% CI, 73-95) in controls. The majority (75%) of case patients experienced satisfactory relief of hot flashes from depomedroxyprogesterone injection. DISCUSSION: In this retrospective case-control study, we were unable to identify a detrimental effect of depomedroxyprogesterone acetate therapy for hot flashes in survivors of estrogen receptor-expressing breast cancer. Depomedroxyprogesterone acetate may be acceptable for management of hot flashes in this population.

The effects of body mass index on operative time and outcomes in nipple-sparing mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) use is increasing. We investigated the relationships between body mass index (BMI), operative time (OT), and ischemic complications. METHODS: A single center, retrospective review was performed of NSMs from 2006 to 2018. Analysis included descriptive statistics, Wilcoxon rank-sum test and logistic regression. RESULTS: Among 294 patients, 510 breast reconstructions were performed (216 bilateral). Median OTs in the prosthetic-based (266 patients, 90.5%) and autologous tissue groups (28 patients, 9.5%) were 266 and 529 min, respectively. Median OTs ranged from 236 to 358 min for those with BMI <20 and ≥ 40, respectively. Increasing BMI correlated with OT (r = 0.33, p < 0.001) and was associated with slightly higher odds of major NAC ischemic complications (OR = 1.09, p = 0.02). CONCLUSION: Higher BMI is associated with up to 50% longer OT, but is not a contraindication to NSM with reconstruction. Surgeons should recognize increased time and resource utilization.

Making an informed choice: Which breast reconstruction type has the lowest complication rate?

INTRODUCTION: The aim of this study was to investigate long-term breast reconstruction outcomes at a single institution in order to offer data-driven counseling for patients. METHODS: A retrospective review was performed of 399 patients who underwent mastectomy with 1-stage implant-based breast reconstruction (IBBR), 2-stage IBBR, or autologous tissue reconstruction (ATR) for invasive breast cancer or ductal carcinoma in situ at our institution from 2010 to 2017. Complications were classified as major for any unplanned return to the operating room (OR). RESULTS: Overall complication rates were similar among 1-stage IBBR (59%), 2-stage IBBR (60%), and ATR (52%, p = 0.54). Factors independently associated with major complications were diabetes (OR = 25.4 95% CI: 3.2-202.4; p = 0.002), and 1-stage IBBR vs. ATR (1-stage: OR = 2.0 95% CI: 1.0-4.0; p = 0.04). Bilateral procedures were also at increased risk of major complications on univariate analysis (OR = 1.59 95% CI: 1.0-2.5; p = 0.04). CONCLUSIONS: Long-term breast reconstruction complication rates are higher than previously anticipated. Patients should be counseled that IBBR is associated with higher rates of complications, including unplanned return to the OR, compared to ATR.

Pain and opioid prescriptions vary by procedure after breast surgery.

BACKGROUND: With the opioid epidemic in the United States, evaluating opioid prescribing patterns is essential. We evaluated opioids prescribed at discharge following breast surgery and their association with patient factors and pain scores. METHODS: We retrospectively identified adult patients who underwent a mastectomy for cancer at Mayo Clinic sites from January 2010 to December 2016. Pain scores and prescription data were compared across operations and patient factors by univariate and multivariable analyses. RESULTS: Of 4021 patients, 3782 (94.1%) received an opioid prescription. Median oral milligram morphine equivalents (MME) were similar across all site-specific procedure groups (medians ranging from 225 to 375) while pain scores ranged from 1 to 4. Patients undergoing bilateral mastectomy (BM) and immediate breast reconstruction (IBR) reported the greatest pain scores. Pain scores did not vary with age or diagnosis for patients undergoing unilateral mastectomy or BM with lymph node surgery and IBR procedures. On multivariable analysis, variables associated with a MME discharge prescription >Q4 values included age, body mass index, site, year, inpatient status, and pain before discharge >3. CONCLUSION: Patient-reported pain following breast surgery varied by procedure, while MMEs prescribed remained similar. This suggests current opioid prescribing does not reflect intensity of pain and requires further research to optimize discharge opioid prescribing practices.

Cognitive profile and determinants of poor cognition in people without dementia in Parkinson's disease.

Background: The Montreal Cognitive Assessment (MoCA) has been recommended as a cognitive screening tool for clinical practice and research in Parkinson's disease (PD), yet no normative data have been published for MoCA in PD without dementia. Methods: We undertook a pooled secondary analysis of data from two studies (one cross-sectional design and one clinical trial) conducted in the East of England region. All participants were aged 18 years or over, met UK Brain Bank criteria for PD and did not have clinical dementia. Cognitive status was assessed using MoCA at baseline in both studies. The influences of age, gender, disease duration, medication load (LEDD) and mood (HADS) on cognition were examined using regression analysis. Results: Data from 101 people with PD without dementia were available (mean age 71 years, 66% men). Median (IQR) MoCA was 25(22, 27). Age was found as the only predictor of MoCA in this sample. People aged over 71 had poorer MoCA (Beta=0.6 (95%CI 0.44, 0.82)) and an increased odds of MoCA <26 (Beta=0.29 (95%CI 0.12, 0.70)) as well as poorer scores on several MoCA sub-domains. Conclusion: We present the normative data for MoCA in people with PD without clinical dementia. Age appeared to be the only associated factor for lower level of cognition, suggestive of Mild cognitive impairment in PD (PD-MCI) in PD without clinical diagnosis of dementia.

The diagnostic value of splenectomy in patients without a definitive preoperative diagnosis.

BACKGROUND: The purpose of this study was to describe the diagnostic value and therapeutic benefit of diagnostic splenectomy. METHODS: Retrospective review was performed of patients undergoing splenectomy with an unknown diagnosis (UD), a hematologic malignancy (HM) or idiopathic thrombocytopenic purpura. Surgical indications and postoperative outcomes were evaluated. RESULTS: 113 splenectomy patients were identified. Of the UD patients undergoing splenectomy, 46% (n = 16) received a definitive diagnosis postoperatively. A change in diagnosis occurred in 12% (n = 4) of HM patients. Complete symptom relief was observed more often in UD patients who received a definitive diagnosis after splenectomy 69% (n = 11), compared to the 47% (n = 9) who did not receive definitive diagnosis postoperatively. CONCLUSIONS: The diagnostic ability of splenectomy was 46% when the diagnosis was unknown preoperatively. Additionally, a majority of patients experienced relief of symptoms postoperatively. Splenectomy may be a useful diagnostic and therapeutic tool in select UD and HM patients.

The Opioid Crisis and Surgeons: National Survey of Prescribing Patterns and the Influence of Motivators, Experience, and Gender.

BACKGROUND: Surgeons are the fifth largest prescribers of opioids in the US. Few studies exist to describe surgeon prescribing practices. METHODS: A survey was conducted of surgical providers at all ACGME-accredited surgical residency programs. Statistical comparisons between groups were made. RESULTS: A total of 114 providers from 21 states responded; 58% male, 57% residents. Only 8% reported being told they were over-prescribing opioids. Oxycodone ± acetaminophen was most commonly prescribed (49%). Median opioids prescribed exceeded guidelines for acute pain management for every procedure except laparoscopic appendectomy/cholecystectomy, lumpectomy and laparoscopic inguinal hernia repair. Attending surgeons more often gave no opioids after laparoscopic appendectomy/cholecystectomy (9% vs 0%; p=0.012), more likely reported patient attempts to return opioids to them (33% vs 16%; p=0.04), and less likely considered patients giving their opioids to someone else (39% vs. 74%; p<0.001). PGY 1-2 residents prescribe fewer opioids than advanced residents for simple mastectomy (p=0.04), exploratory laparotomy (p=0.05), and thoracotomy (p=0.03). CONCLUSIONS: Surgeons vary significantly in their opioid prescriptions, even for the same operation. There are few differences by gender but some important differences by experience.