Search

Background: In humans, methane (CH4) is exclusively produced by the intestinal microbiota and has been implicated in several conditions including cardiovascular disease. After microbial production of CH4 in the gut, it steadily crosses into the systemic circulation and reaches the lungs where it can be detected in the exhaled breath, as a surrogate measure for intestinal CH4 production. Recent reports have shown an association between CH4 and vagal dysfunction as well as the inhibition of CH4 activity on ileal contractions with atropine, suggesting its action on the parasympathetic nervous system. Given these findings, we hypothesized that CH4 may be affecting resting heart rate (HR) based on the potential effect of CH4 on the vagus nerve. Objectives: Given its possible role in the parasympathetic nervous system, we aimed to study the relationship between breath CH4 and resting HR in humans. Additionally, we performed a longitudinal study analyzing the change in HR and its association with breath CH4 over time. Methods: First, we reviewed 1,126 subjects and compared HR in subjects with detectable and undetectable breath CH4. Second, we performed a post hoc analysis of a randomized control trial to compare the change in HR for those who had an increase in breath CH4 versus those that had a decrease in breath CH4 over 14 weeks. Last, we assessed whether a larger decrease in CH4 is associated with a larger increase in HR over time. Results: In the retrospective cohort, subjects with detectable CH4 had a lower HR compared to those with undetectable CH4 (73.0 ± 0.83 vs. 76.0 ± 0.44 beats/min, p = 0.01). In the post hoc analysis, a decrease in CH4 over time was associated with an increase in HR (median ∆ = 6.5 ± 8.32 beats/min, p = 0.0006). Last, we demonstrated a biological gradient whereby a larger drop in CH4 was associated with a greater increase in HR (R = −0.31, p = 0.03). Conclusion: Our findings suggest a potential role for the microbiome (and specifically CH4 from methanogens) to regulate HR. Considering these findings, mechanistic studies are warranted to further investigate this potential novel microbiome-neurocardiac axis.

Irritable bowel syndrome (IBS) includes diarrhea-predominant (IBS-D) and constipation-predominant (IBS-C) subtypes. We combined breath testing and stool microbiome sequencing to identify potential microbial drivers of IBS subtypes.IBS-C and IBS-D subjects from 2 randomized controlled trials (NCT03763175 and NCT04557215) were included. Baseline breath carbon dioxide, hydrogen (H 2 ), methane (CH 4 ), and hydrogen sulfide (H 2 S) levels were measured by gas chromatography, and baseline stool microbiome composition was analyzed by 16S rRNA sequencing. Microbial metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes collection databases.IBS-C subjects had higher breath CH 4 that correlated with higher gut microbial diversity and higher relative abundance (RA) of stool methanogens, predominantly Methanobrevibacter , as well as higher absolute abundance of Methanobrevibacter smithii in stool. IBS-D subjects had higher breath H 2 that correlated with lower microbial diversity and higher breath H 2 S that correlated with higher RA of H 2 S-producing bacteria, including Fusobacterium and Desulfovibrio spp. The predominant H 2 producers were different in these distinct microtypes, with higher RA of Ruminococcaceae and Christensenellaceae in IBS-C/CH 4 + (which correlated with Methanobacteriaceae RA) and higher Enterobacteriaceae RA in IBS-D. Finally, microbial metabolic pathway analysis revealed enrichment of Kyoto Encyclopedia of Genes and Genomes modules associated with methanogenesis and biosynthesis of methanogenesis cofactor F420 in IBS-C/CH 4 + subjects, whereas modules associated with H 2 S production, including sulfate reduction pathways, were enriched in IBS-D.Our findings identify distinct gut microtypes linked to breath gas patterns in IBS-C and IBS-D subjects, driven by methanogens such as M. smithii and H 2 S producers such as Fusobacterium and Desulfovibrio spp, respectively.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the U.S. NCI's Surveillance Epidemiology and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. A total of 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. A total of 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. Twenty-two (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2-negative and borderline patients, and 3.9% for HER2-positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR, 0.05; P = 0.00006) and HER2 overexpression (increased likelihood; HR, 2.72; P = 0.044). Patients with HER2-positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

Background: Ductal carcinoma in situ (DCIS) now represents nearly a quarter of newly diagnosed breast cancers in the United States. Standard-of-care treatment for DCIS is aggressive local therapy consisting of either mastectomy or breast conserving surgery with radiation. However, DCIS mortality is low regardless of initial treatment, suggesting opportunities to explore a spectrum of treatment options. With these treatment options, there is the potential to create risk-adapted treatment plans, but the question of how to assess risk remains. Molecular tests can help to personalize treatment by stratifying disease sub-types and providing prognosis. One such tool is the Oncotype DX® Breast DCIS Score, a risk measure which was validated in a meta-analysis of 773 patients from the E5194 and Ontario DCIS Cohort studies. Along with calculating a Breast DCIS Score™ from the expression levels of 12 genes, the test provides a predicted 10-year risk of local recurrence from the score result, age, and tumor size for patients who receive breast conserving surgery alone. Understanding how such a tool might impact decision-making will inform its implementation. Eligibility & trial design: The ATHENA Breast Health Network is a consortium of the five University of California Medical centers. Through ATHENA, patients with histologically confirmed DCIS and no concurrent invasive cancer are approached to participate in the Athena DCIS Registry. Patients in the registry facing an active management decision are eligible to participate in the Oncotype DX® DCIS prospective study. Specific aims: The primary aim of the study is to determine whether the additional diagnostic information (i.e. the DCIS Score™) impacts patient treatment decisions and physician recommendation. Additional goals are to correlate the DCIS Score™ with mammographic findings, pathological variables, and treatment recommendations, and to estimate risk within each DCIS Score™ group. Participants and their physicians answer survey questions both before and after receiving the score to evaluate the impact of the DCIS Score™ on treatment recommendations and decisions. Statistical methods: The study will assess the percentage of patients who thought the DCIS risk score influenced their treatment decision. The study will also assess whether a significant proportion of physicians changed their recommendations after considering the DCIS Score™ using the chi-square test. Similarly, the patients’ preferred treatment option pre- and post- test surveys will be evaluated. In addition, the concordance between physicians’ and patients’ choices will be assessed by the Kappa statistic before and after the score. The patients’ and physicians’ confidence levels in their treatment recommendation and decision pre- and post- test will be compared using a Wilcoxon signed-rank test, as well as the percentage of patients and physicians who are glad they used the test. In addition, the study will assess whether the DCIS test influences a patient’s perception of their recurrence risk by comparing the self-reported 10-year breast cancer recurrence risk in their pre- and post- test questionnaires using a Wilcoxon signed-rank test. Current and target accrual: The current accrual across all sites in the Oncotype study is 94 patients. The target accrual for the initial pilot phase data is defined as the first 100 patients accrued. If interested in learning more about the study, please contact Rita Mukhtar, MD (Rita.Mukhtar@ucsf.edu). Citation Format: Jane M Wei, Paul Kim, Cheryl Ewing, Jasmine Wong, Laura J Esserman, Michael D Alvarado, Abimbola O Olusanya, Skye Stewart, Ashley Tydon, Parima Daroui, Jeffrey V Kuo, Hannah L Park, Karen T Lane, Eliza Jeong, Kelsey Brown, Ava Hosseini, Barbara A Parker, Sarah L Blair, Athena Breast Health Network Investigators, Frederick Baehner, Olivier Harismendy, Antonia Petruse, Carlie K Thompson, Helena R Chang, Alexander D Borowsky, Christina Yau, Gillian L Hirst, Richard J Bold, Rita A Mukhtar. Use of Oncotype DX DCIS for disease management in a prospective DCIS registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-01.

BackgroundParavertebral nerve blocks (PVBs) are frequently used to treat pain during and following breast surgery, but have various undesirable risks such as pneumothorax. The erector spinae plane block (ESPB) also provides perioperative breast analgesia, but is purported to be easier to administer with a favorable safety profile. However, it remains unknown if the new ESPB provides comparable analgesia as the decades-old PVB technique.MethodsSubjects undergoing unilateral or bilateral non-mastectomy breast surgery were randomized to a single-injection ESPB or PVB in a subject-blinded fashion (ropivacaine 0.5% with epinephrine; 20 mL unilateral or 16 mL/side for bilateral). We hypothesized that (1) analgesia would be non-inferior in the recovery room as measured on a Numeric Rating Scale (NRS) with ESPB, and (2) opioid consumption would be non-inferior in the operating and recovery rooms with ESPB.ResultsBoth pain scores and opioid consumption were higher in subjects with ESPBs (n=50) than PVBs (n=50; median NRS 3.0 vs 0; 95% CI −3.0 to 0; p=0.0011; and median morphine equivalents 2.0 vs 1.5 mg; 95% CI −1.2 to −0.1; p=0.0043). No block-related adverse events occurred in either group.ConclusionsPVBs provided superior analgesia and reduced opioid requirements following non-mastectomy breast surgery. To compare the relatively rare complications between the techniques will require a sample size 1–2 orders of magnitude greater than the current investigation; however, without a dramatic improvement in safety profile for ESPBs, it appears that PVBs are superior to ESPBs for postoperative analgesia after non-mastectomy breast surgery.Trial registration numberNCT03549234.

Hormone therapy (HT) is used to treat menopause-related conditions and symptoms. The small intestine plays key roles in metabolic and endocrine function, but the effects of HT on the small intestinal microbiome are unknown. Here, we characterize duodenal microbiome differences, and the effects of HT, in postmenopausal women.Female participants undergoing esophagogastroduodenoscopy who were postmenopausal and taking HT (HT+), postmenopausal but not taking HT (HT-), or of reproductive age and not taking exogenous hormones (RA), were identified and matched for body mass index (±3 kg/m2). DNAs were isolated from duodenal aspirates obtained during upper endoscopy. V3 and V4 libraries were used for 16S rRNA sequencing. Serum hormone levels were analyzed by Luminex FlexMap.The core duodenal microbiome was different in HT- participants (n = 12) when compared with RA participants (n = 10), but more similar in HT+ (n = 13) and RA participants. HT- participants had increased Proteobacteria taxa, leading to greater microbial dysbiosis compared with HT+ participants, and had decreased prevalence of Bacteroidetes, which was associated with higher fasting glucose levels, lower duodenal microbial diversity, and lower testosterone levels. HT+ participants had significantly higher estradiol (P = 0.04) and progesterone (P = 0.04), and lower fasting glucose (P = 0.03), than HT- participants, and had increased relative abundance of Prevotella (P = 0.01), and decreased Escherichia (P = 1.12E-7), Klebsiella (P = 5.93E-7), and Lactobacillus (P = 0.02), all associated with lower cardiovascular disease risks.These findings support previous studies suggesting that HT may have beneficial effects following menopause, and although preliminary, may also support a beneficial effect of HT on the duodenal microbiome.

Stool form assessment relies on subjective patient reports using the Bristol Stool Scale (BSS). In a novel smartphone application (app), trained artificial intelligence (AI) characterizes digital images of users' stool. In this study, we evaluate this AI for accuracy in assessing stool characteristics.Subjects with diarrhea-predominant irritable bowel syndrome image-captured every stool for 2 weeks using the app, which assessed images for 5 visual characteristics (BSS, consistency, fragmentation, edge fuzziness, and volume). In the validation phase, using 2 expert gastroenterologists as a gold standard, sensitivity, specificity, accuracy, and diagnostic odds ratios of subject-reported vs AI-graded BSS scores were compared. In the implementation phase, agreements between AI-graded and subject-reported daily average BSS scores were determined, and subject BSS and AI stool characteristics scores were correlated with diarrhea-predominant irritable bowel syndrome symptom severity scores.In the validation phase (n = 14), there was good agreement between the 2 experts and AI characterizations for BSS (intraclass correlation coefficients [ICC] = 0.782-0.852), stool consistency (ICC = 0.873-0.890), edge fuzziness (ICC = 0.836-0.839), fragmentation (ICC = 0.837-0.863), and volume (ICC = 0.725-0.851). AI outperformed subjects' self-reports in categorizing daily average BSS scores as constipation, normal, or diarrhea. In the implementation phase (n = 25), the agreement between AI and self-reported BSS scores was moderate (ICC = 0.61). AI stool characterization also correlated better than subject reports with diarrhea severity scores.A novel smartphone application can determine BSS and other visual stool characteristics with high accuracy compared with the 2 expert gastroenterologists. Moreover, trained AI was superior to subject self-reporting of BSS. AI assessments could provide more objective outcome measures for stool characterization in gastroenterology.

Gut microbiome changes have been associated with human ageing and implicated in age-related diseases including Alzheimer’s disease and Parkinson’s disease. However, studies to date have used stool samples, which do not represent the entire gut. Although more challenging to access, the small intestine plays critical roles in host metabolism and immune function. In this paper (Leite et al. (2021), Cell Reports, doi: 10.1016/j.celrep.2021.109765), we demonstrate significant differences in the small intestinal microbiome in older subjects, using duodenal aspirates from 251 subjects aged 18-80 years. Differences included significantly decreased microbial diversity in older subjects, driven by increased relative abundance of phylum Proteobacteria, particularly family Enterobacteriaceae and coliform genera Escherichia and Klebsiella. Moreover, while this decreased diversity was associated with the ‘ageing process’ (comprising chronologic age, number of medications, and number of concomitant diseases), changes in certain taxa were found to be associated with number of medications alone (Klebsiella), number of diseases alone (Clostridium, Bilophila), or chronologic age alone (Escherichia, Lactobacillus, Enterococcus). Lastly, many taxa associated with increasing chronologic age were anaerobes. These changes may contribute to changes in human health that occur during the ageing process.

Tobacco use is the leading preventable cause of cancer, and affects the respiratory, oral, fecal, and duodenal mucosa-associated microbiota. However, the effects of smoking on the duodenal luminal microbiome have not been studied directly. We aimed to compare the duodenal luminal microbiome in never-smokers, current smokers, and ex-smokers who quit ≥ 10 years ago. In a cross-sectional study, current smokers (CS, n = 24) were identified and matched to never-smokers (NS, n = 27) and ex-smokers (XS, n = 27) by age (± 5 years), body mass index (BMI, ± 3 kg/m2), and sex. Current antibiotic users were excluded. The duodenal luminal microbiome was analysed in 1 aspirate sample per subject by 16S rRNA gene sequencing. Relative abundances (RA) of families associated with increased duodenal microbial diversity, Prevotellaceae, Neisseriaceae, and Porphyromonadaceae, were significantly lower in CS vs. NS. This was driven by lower RA of unknown Prevotella and Porphyromonas species, and Neisseria subflava and N. cinerea, in CS. In contrast, RA of Enterobacteriaceae and Lactobacillaceae (associated with decreased diversity), were significantly higher in CS, due to higher RA of Escherichia-Shigella, Klebsiella and Lactobacillus species. Many of these changes were absent or less pronounced in XS, who exhibited a duodenal luminal microbiome more similar to NS. RA of taxa previously found to be increased in the oral and respiratory microbiota of smokers were also higher in the duodenal luminal microbiome, including Bulledia extructa and an unknown Filifactor species. In conclusion, smoking is associated with an altered duodenal luminal microbiome. However, ex-smokers have a duodenal luminal microbiome that is similar to never-smokers.

Background Obesity and high breast density both increase breast cancer risk but paradoxically are inversely related. Bariatric surgery decreases breast cancer risk, but its impact on mammographic breast density is not well understood. Objectives We investigated how mammographic density changes after bariatric surgery and whether this change is related to weight loss. Setting University of California, San Francisco Medical Center. Methods We reviewed records from 349 prospectively collected patients who underwent bariatric surgery between 2013 and 2015 and identified 42 women with pre- and postoperative screening mammograms within 1.5 years of surgery. We recorded body mass index (BMI), height and Breast Imaging Reporting and Data System density and calculated BMI loss and total weight loss. Data were analyzed in Stata 14.2. Results Average age was 54.2 years, mean preoperative BMI was 43.8 kg/m2, mean BMI lost was 30.9%, and total weight loss was 31.1% at 1.3 years. Over one-third had a change in mammographic breast density, which increased 93.3% of the time (P Conclusions Most women with a mammographic change had an increase in breast density, despite bariatric surgery being associated with reduced breast cancer risk. Baseline breast density was associated with a density change, but amount of weight loss was not. These findings suggest the metabolic effects of bariatric surgery have an effect on breast parenchyma independent of absolute BMI reduction or weight loss.

Background: Post-mastectomy pain syndrome (PMPS) is a common and often debilitating condition. One common cause likely results from injury to the T4 and T5 sensory nerves during breast surgery, with resulting neuroma formation. It manifests as a pain syndrome diagnosed by “trigger points” that reproduce exquisite pain upon palpation. Pain specialists have found a combination of corticosteroids and local anaesthetic given through perineural infiltration, at other sites, effective in alleviating these neuromas or trigger points. Utilizing this principle, we initiated a quality improvement project to treat PMPS. This perineural injection led to remarkable, long-lasting relief of the first few patients, we therefore continued treating patients with clinical symptoms suggestive of a neuroma. We report on long-term pain relief after trigger point injections (TPI) for women with PMPS. Methods: An observational cohort study of women with PMPS and clinical evidence of neuroma was undertaken. Patients were examined by breast surgeons at a single institution. We injected a 2mL mixture of equal parts 0.5% bupivacaine and 4 mg/mL dexamethasone into each trigger point. Demographics, type of breast and axillary surgery, duration of pain, history of surgical complications, adjuvant radiotherapy, number of injections required, location of trigger points and dates of injection were obtained from the electronic medical record. Patients were surveyed via telephone interview for long-term resolution of pain. Descriptive statistics are reported, univariate and bivariate analyses were conducted using Stata 12 (College Station, TX). Results: We identified 89 trigger points on 61 breasts in 53 patients with PMPS. Patient age ranged from 30-92 years. Mean number of surgeries prior to injection was 2.2 (range 1-8). In this cohort, we found mastectomy was the most frequent surgical procedure preceding the development of a neuroma (41 breasts), followed by reduction mammoplasty with or without concurrent partial mastectomy (16 breasts), and least frequently lumpectomy alone (4 breasts). The time from the onset of neuropathic pain to the first trigger point injection varied from as early as 1 week post-operatively to 132 months (mean 22.2 months). Effectiveness of the TPI was assessed by physical examination immediately (1-3 minutes) after the injection, then with telephone interview (at >/=3 months post TPI). All 53 patients had long-term follow-up data (≥3 months). Long-term relief was achieved in 84 of 89 trigger points (94.4%) or 54 of 61 breasts (88.5%). Trigger point injections were well tolerated by all patients and no complications were reported. Discussion: Perineural infiltration with bupivacaine and dexamethasone is a safe, simple, and effective treatment option for PMPS with an associated trigger point. Our data suggest this significant problem can easily be resolved in an outpatient setting. All breast specialists should inquire about the presence of symptoms consistent with PMPS and understand the value of intervention to eliminate neuropathic pain. This technique should be added to the armamentarium of all surgeons who perform breast surgery. Citation Format: Keane HJ, Khoury AL, Hosseini A, Varghese FP, Mukhtar R, Eder SE, Wong J, Esserman LJ. A simple intervention for long-term relief of chronic post mastectomy pain [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-11-01.

With the emergence of the Novel Coronavirus (2019-nCoV), researchers worldwide have started detecting the probable pathogenesis of the disease. The renin-angiotensin system (RAS) and angiotensin-converting enzymes have received a good deal of attention as possible pathways involved in 2019-nCoV pathogenesis. As the experiments seeking to find potential medications acting on these pathways are being conducted in the early phases, having an ecological worldview on the relationship between the prevalence of COVID-19 disease and the genetic differences in the genes involved in the RAS system could be valuable for the field. In this regard, we conducted a meta-analysis study of the prevalence of ACE (I/D) genotype in countries most affected by the COVID-19. In the meta-analysis, 48,758 healthy subjects from 30 different countries were evaluated in 116 studies, using the Comprehensive Meta-analysis software. The I/D allele frequency ratio was pooled by a random-effect model. The COVID-19 prevalence data of death and recovery rates were evaluated as the latitudes for the meta-regression analysis. Our results demonstrated that with the increase of the I/D allele frequency ratio, the recovery rate significantly increased (point estimate: 0.48, CI 95%: 0.05-0.91, p = 0.027). However, there was no significant difference in the case of death rate (point estimate: 1.74, CI 95%: 4.5-1.04, p = 0.22). This ecological perspective coupled with many limitations does not provide a direct clinical relevance between the COVID-19 and RAS system, but it shows potential pathophysiological associations. Our results raise concerns about ethnic and genetic differences that could affect the effectiveness of the currently investigated RAS-associated medications in different regions.

Author(s): Gabriel, Rodney A; Finneran, John J; Swisher, Matthew W; Said, Engy T; Sztain, Jacklynn F; Khatibi, Bahareh; Wallace, Anne M; Hosseini, Ava; Trescot, Andrea M; Ilfeld, Brian M | Abstract: BackgroundAcute post-mastectomy pain is frequently challenging to adequately treat with local anesthetic-based regional anesthesia techniques due to its relatively long duration measured in multiple weeks.CaseWe report three cases in which preoperative ultrasound-guided percutaneous intercostal nerve cryoneurolysis was performed to treat pain following mastectomy. Across all postoperative days and all three patients, the mean pain score on the numeric rating scale was 0 for each day. Similarly, no patient required any supplemental opioid analgesics during the entire postoperative period; and, no patient reported insomnia or awakenings due to pain at any time point. This was a significant improvement over historic cohorts.ConclusionsUltrasound-guided percutaneous cryoanalgesia is a potential novel analgesic modality for acute pain management which has a duration that better-matches mastectomy than other currently-described techniques. Appropriately powered randomized, controlled clinical trials are required to demonstrate and quantify both potential benefits and risks.

The impact of HER2 status in ductal carcinoma in situ (DCIS) on the risk of progression to invasive ductal carcinoma (IDC) has been debated. We aim to use a national database to identify patients with known HER2 status to elucidate the effect of HER2 overexpression on ipsilateral IDC (iIDC) development. We performed survival analysis on patient-level data using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results program. We identified patients diagnosed with DCIS who underwent lumpectomy and had known HER2 status. Competing risks analysis was performed. 1,540 patients had known HER2 status and met inclusion criteria. Median age at diagnosis was 60, median follow-up time was 44.5 months. 417 (27.1%) patients were HER2 positive and 1,035 (67.2%) were HER2 negative. 22 (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% for HER2 negative and borderline patients, and 3.9% for HER2 positive patients. On multivariate competing risks regression, two factors were significant for iIDC: radiation (protective) therapy within 24 months (HR=0.05, p=0.00006) and HER2 overexpression (increased likelihood) (HR=2.72, p=0.044). Patients with HER2 positive DCIS were more likely to have recurrences with receptor discordance. HER2 may serve as a prognostic factor for invasive recurrence and was the only lesion-related factor to significantly relate to iIDC development. It may also be associated with receptor discordance of recurrences. Further large studies will be needed to confirm these results.

Introduction: Close to 65% of BRCA mutation carriers do not choose prophylactic mastectomy, despite their high breast cancer risk. Breast reduction mammoplasty is a surgical technique shown to reduce breast cancer risk and can be modified to target specific areas of the breast. We wondered if a majority of tumors in BRCA mutation carriers would be confined to one quadrant, allowing for the use of targeted cosmetic mammoplasty as a novel method of risk reduction. Methods: We reviewed imaging reports on 103 consecutive patients with BRCA mutations and invasive breast cancer, and categorized tumor location by quadrant. Tumors spanning >1 quadrant were classified as being in both. Bilateral cancers were counted separately. Categorical variables were compared with the chi-squaredtest. Results: Mean age at breast cancer diagnosis was 44 years with mean tumor size of 2.2 cm (0.1-7cm). 92% of tumors were invasive ductal carcinoma, 46% were hormone receptor positive, 10% Her2 positive, and 44% triple negative. 70% of the tumors were unicentric. Tumors were significantly more likely to be in the upper outer quadrant whether or not multicentric tumors were included in the analysis (p Conclusions: More than half of breast cancers in BRCA mutation carriers form in the upper outer quadrant, suggesting that removing this quadrant through breast reduction mammoplasty could significantly reduce breast cancer risk. For women who are not ready for prophylactic mastectomy, this data supports an intermediate risk reduction step instead of only offering surveillance. Citation Format: Hosseini A, Esserman LJ, Wallace AM, Au A, Mukhtar RA. Breast tumor location in BRCA mutation carriers and implications for prevention [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-22.

Background: Bariatric surgery decreases breast cancer risk, but its impact on mammographic findings is not well understood. Obesity and breast density both increase breast cancer risk, but paradoxically are inversely related. We investigated how mammographic density changes after bariatric surgery, and whether or not that change is related to amount of weight loss. Methods: We reviewed records for 349 prospectively collected patients who underwent bariatric surgery between 2013-2015, and identified 45 women with pre- and post-operative screening mammograms within 1.5 years of surgery. We recorded body mass index (BMI), Breast Imaging-Reporting and Data System density, and calculated excess BMI loss. Data were analyzed in Stata 14.2. Results: Average age was 54 years, mean pre-operative BMI was 44 (range 36-72), and mean percentage excess BMI lost was 73% at 1.3 years. One third had a change in mammographic breast density, which increased 93% of the time (p Conclusions: The majority of women with a mammographic change had an increase in breast density, despite bariatric surgery being associated with reduced breast cancer risk. Interestingly, the amount of weight loss was not associated with change in breast density. These findings suggest the metabolic effects of bariatric surgery have an effect on breast cancer risk independent of BMI reduction. Future work will include studying mammographic changes associated with non-surgical weight loss. Citation Format: Hosseini A, Khoury AL, Carter J, Wong JM, Alvarado MD, Ewing C, Esserman LJ, Mukhtar RA. The impact of bariatric surgery on mammographic breast density [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-12-04.

Purpose: The impact of HER2 status in ductal carcinoma in situ (DCIS) lesions on the risk of progression to invasive ductal carcinoma (IDC) has been debated with reports of both increased and decreased risk of development of invasive breast cancer in HER2 positive patients. We aim to use a large national database to elucidate the effect of HER2 positivity on ipsilateral IDC (iIDC) development. Methods: We performed survival analyses on patient-level data using the US National Cancer Institute's Surveillance, Epidemiology, and End Results program to identify patients diagnosed with DCIS who underwent lumpectomy and had known HER2, estrogen and progesterone receptor statuses, grade, comedonecrosis, age, tumor size, and radiation therapy (RT). Competing risks analysis was performed. Results: 1,540 patients meeting inclusion criteria were identified. Median age at diagnosis was 60 with median follow-up time of 44.5 months. 22 (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. 1,035 (67.2%) patients were HER2 negative and 417 (27.1%) were HER2 positive. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% (95% CI 0.6-2.1%) for HER2 negative patients, and 4.0% (95% CI 2.9-5.4%) for HER2 positive patients. On competing risks regression, two factors were significant for iIDC: RT within 20 months (HR=0.02, p=0.0002) and HER2 positivity (HR=2.81, p=0.046). Conclusions: HER2 may serve as a prognostic factor for consideration in decision making in patients for whom it is available, and in our analysis was the only lesion-related factor to significantly relate to iIDC development. Citation Format: Thomas O'Keefe, Sarah Blair, Ava Hosseini, Olivier Harismendy, Anne Wallace. HER2 positive DCIS increases short term risk of ipsilateral invasive ductal carcinoma in breast conserving surgery patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6461.

Objective Laparoscopic adrenalectomy has become the standard of care for many adrenal tumors. However, the success of the operation hinges on identifying the adrenal vein and complete tumor resection. We demonstrate the use of a commercially available near infrared fluorescent imaging system to clearly delineate the vascular anatomy of adrenal neoplasms and enhance the border between tumor and normal tissue. We hypothesize that this will increase the safety of laparoscopic adrenalectomy. Materials and Methods We performed laparoscopic adrenalectomy utilizing indocyanine green (ICG) and a specialized laparoscopic fluorescence imaging system on four consecutive patients undergoing laparoscopic adrenalectomy over a 4-month period. Results The adrenal arteries and vein were vividly enhanced with ICG fluorescence guidance, and the border between tumor and adjacent tissue was clearly demarcated. The operations were performed safely with minimal blood loss and short operative times. There were no complications. Conclusions Adrenal neoplasms can be resected laparoscopically under ICG fluorescence guidance and can be used to clearly identify vascular structures and enhance the borders of the tumor. This technique allows for clear identification of the adrenal vein and has the potential to improve the safety of laparoscopic adrenalectomy. J. Surg. Oncol. 2015;112:650–653. © 2015 Wiley Periodicals, Inc.

BackgroundNo prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM).MethodsThis was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0-100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period.ResultsFifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively.ConclusionsInjection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer.

Randomized trials have clearly established breast conservation therapy (BCT) as appropriate treatment for early-stage invasive breast cancer. Current evidence shows that positive margins confer a greater than twofold risk of ipsilateral breast tumor recurrence. Thus, patients who have positive margins after BCT warrant re-excision. With regard to negative margins, however, the optimal negative margin width remains unclear. This article reviews the recent guidelines set forth by the Society of Surgical Oncology and the American Society of Radiation Oncology regarding the margin width in stage I and II invasive breast cancer. We also discuss the controversies related to implementation of these guidelines.

Introduction No prior trials have compared sentinel lymph node (SLN) identification outcomes between Tc-99m tilmanocept (TcTM) and Tc-99m sulfur colloid (TcSC) in breast cancer (BC). Methods We report on the secondary outcomes from a randomized, double-blinded, single surgeon clinical trial comparing post-injection site pain between TcTM and TcSC. Patients were randomized to receive a preoperative single, peritumoral intradermal injection of TcTM or TcSC. The number of total, “hot”, and blue nodes detected and removed were compared between groups. Results Fifty-two (27-TcSC and 25-TcTM) patients were enrolled and underwent definitive surgical treatment. At least one “hot” SLN was detected in all patients. Three (5.8%) patients had a disease positive-SLN. The total number of SLNs removed was 61 (mean 2.26 (standard deviation (SD) 0.90)) in the TcSC group and 54 (mean 2.16 (SD 0.90)) in the TcTM group, P = 0.69. The total number of “hot” nodes in the TcSC group was 1.96 (SD 0.76) compared to 2.04 (SD 0.73) in the TcTM group, P = 0.71. Conclusions The number of identified SLNs did not differ significantly between TcTM and TcSC. Given that no significant technical advantages exist between the two agents, surgeons should choose a radiopharmaceutical based on cost and side effect profile.

Over-diagnosis and over-treatment are consequences of greater awareness about breast cancer, more intensive screening, and the resultant identification of more cases of breast cancer that are low or ultralow risk. This area represents an important opportunity to optimize the delivery of appropriate targeted therapy for breast cancer patients. Despite the evolution of breast cancer care over the last few decades and our ability to tailor treatment to biology, a one-size fits all approach is still prevalent in the local and regional management of and screening for breast cancer, failing to reflect the unique biology and tumor characteristics of each patient. In this review, we explore how we can use new tools to better define tumor biology and also how we can change current clinical practices based on already available data. Every surgeon should be knowledgeable about how to craft personalized breast cancer care in the areas of systemic therapy, adjuvant radiation therapy, management of ductal carcinoma in situ (DCIS), precision surgery, and breast cancer screening.

Background Dendritic cells (DC) are localized in close proximity to cancer cells in many well-known tumors, and thus maybe a useful target for tumor margin assessment. Materials and methods [ 99m Tc]- cyanine 7 (Cy7)-tilmanocept was synthesized and in vitro binding assays to bone marrow-derived DC were performed. Fifteen mice, implanted with either 4T1 mouse mammary or K1735 mouse melanoma tumors, were administered 1.0 nmol of [ 99m Tc]-Cy7-tilmanocept via tail vein injection. After fluorescence imaging 1 or 2 h after injection, the tumor, muscle, and blood were assayed for radioactivity to calculate percent-injected dose. Digital images of the tumors after immunohistochemical staining for DC were analyzed to determine DC density. Results In vitro binding demonstrated subnanomolar affinity of [ 99m Tc]-Cy7-tilmanocept to DC (K A = 0.31 ± 0.11 nM). After administration of [ 99m Tc]-Cy7-tilmanocept, fluorescence imaging showed a 5.5-fold increase in tumor signal as compared with preinjection images and a 3.3-fold difference in fluorescence activity when comparing the tumor with the surgical bed after tumor excision. Immunohistochemical staining analysis demonstrated that DC density positively correlated with tumor percent of injected dose per gram ( r = 0.672, P = 0.03), and higher DC density was observed at the periphery versus center of the tumor (186 ± 54 K versus 64 ± 16 K arbitrary units, P = 0.001). Conclusions [ 99m Tc]-Cy7-tilmanocept exhibits in vitro and in vivo tumor-specific binding to DC and maybe useful as a tumor margin targeting agent.

Background Surgical rejuvenation alters facial volume distribution to achieve more youthful aesthetic contours. These changes are routinely compared subjectively. The introduction of 3-dimensional (3D) stereophotogrammetry provides a novel method for measuring and comparing surgical results. Objectives We sought to quantify how specific facial areas are changed after rejuvenation surgery using the 3D camera. Methods Patients undergoing facial rejuvenation were imaged preoperatively and postoperatively with 3D stereophotogrammetry. Images were registered using facial surface landmarks unaltered by surgery. Colorimetric 3D analysis depicting postoperative volume changes was performed utilizing the 3D imaging software and quantitative volume measurements were constructed. Results Nine patients who underwent combined facelift procedures and fat grafting were evaluated. Median time for postoperative imaging was 4.8 months. Positive changes in facial volume occurred in the forehead, temples, and cheeks (median changes, 0.9 mL ± 4.3 SD; 0.8 mL ± 0.47 SD; and 1.4 mL ± 1.6 SD, respectively). Negative changes in volume occurred in the nasolabial folds, marionette basins, and neck/submental regions (median changes, −1.0 mL ± 0.37 SD; −0.4 mL ± 0.9 SD; and −2.0 mL ± 4.3 SD, respectively). Conclusions The technique of 3D stereophotogrammetry provides a tool for quantifying facial volume distribution after rejuvenation procedures. Areas of consistent volume increase include the forehead, temples, and cheeks; areas of negative volume change occur in the nasolabial folds, marionette basins, and submental/chin regions. This technology may be utilized to better understand the dynamic changes that occur with facial rejuvenation and quantify longevity of various rejuvenation techniques. Level of Evidence 4![Graphic][1] Diagnostic [1]: /embed/inline-graphic-1.gif

Laparoscopic adrenalectomy has become the standard of care for many adrenal tumors. However, the success of the operation hinges on identifying the adrenal vein and complete tumor resection. We demonstrate the use of a commercially available near infrared fluorescent imaging system to clearly delineate the vascular anatomy of adrenal neoplasms and enhance the border between tumor and normal tissue. We hypothesize that this will increase the safety of laparoscopic adrenalectomy.We performed laparoscopic adrenalectomy utilizing indocyanine green (ICG) and a specialized laparoscopic fluorescence imaging system on four consecutive patients undergoing laparoscopic adrenalectomy over a 4-month period.The adrenal arteries and vein were vividly enhanced with ICG fluorescence guidance, and the border between tumor and adjacent tissue was clearly demarcated. The operations were performed safely with minimal blood loss and short operative times. There were no complications.Adrenal neoplasms can be resected laparoscopically under ICG fluorescence guidance and can be used to clearly identify vascular structures and enhance the borders of the tumor. This technique allows for clear identification of the adrenal vein and has the potential to improve the safety of laparoscopic adrenalectomy.

e13048 Background: Although pathogenic mutations in the BRCA gene are known to confer a high risk of breast cancer, close to 65% of mutation carriers do not opt for prophylactic mastectomy. These women are managed with intense screening, which does not aid in prevention. Breast reduction mammoplasty is a surgical technique shown to reduce breast cancer risk (0.39-0.61 relative risk reduction), and can be modified to target specific areas of the breast. Given that most sporadic breast cancers involve the upper outer quadrant, we wondered if a majority of tumors in BRCA mutation carriers would also be confined to one quadrant, or if they would be equally distributed throughout the breast given the high baseline risk present. Identifying a particularly high risk area of the breast could potentially allow for the use of targeted cosmetic mammoplasty as a novel method of risk reduction. Methods: We reviewed imaging reports on 103 consecutive patients with BRCA mutations and invasive breast cancer, and categorized tumor location by quadrant. Tumors spanning > 1 quadrant were classified as being in both. Bilateral cancers were counted separately. Categorical variables were compared with the chi-squared test. Results: Mean age at breast cancer diagnosis was 44 years. Mean tumor size was 2.2 cm (0.1-7cm) with mean distance from the nipple of 4.8 cm (1-12 cm). 92% of tumors were invasive ductal carcinoma, 46% were hormone receptor positive, 10% Her2 positive, and 44% triple negative. 70% of the tumors were unicentric. Tumors were significantly more likely to be in the upper outer quadrant (54%, with the other quadrants having 11-17% of tumors respectively) whether or not multicentric tumors were included in the analysis (p < 0.00001). Her2 positive tumors were more likely to be multicentric than other subtypes (p = 0.021). Conclusions: More than half of breast cancers in BRCA mutation carriers form in the upper outer quadrant, suggesting that breast reduction mammoplasty targeting removal of the upper outer quadrant could significantly reduce breast cancer risk. For those women who choose not to have prophylactic mastectomies or are not yet ready, these data support an intermediate step to help decrease breast cancer risk, which warrants further study.

Adipose tissue sciences have rapidly expanded since the identification of regenerative cells contained within the stromal vascular fraction (SVF) of fat. Isolation of the SVF, containing adipose-derived stem cells (ADSC), can be accomplished efficiently in the operating room or in the laboratory through enzymatic digestion of the adipose tissue and concentration of SVF. Cells can be directly re-injected as a mesotherapeutic agent, recombined with a tissue scaffold (e.g., cell-enriched fat grafts) or expanded in culture for tissue-engineered cell therapeutics. The potential for cell therapy is under current investigation by researchers around the world. This chapter reviews laboratory methods for isolating ADSCs and the ongoing clinical trials evaluating cell therapeutic efficacy across many specialties, including cardiology, neurology, immunology, tissue engineering, sports medicine, and plastic and reconstructive surgery.

Adipose tissue sciences have rapidly expanded since the identification of regenerative cells contained within the stromal vascular fraction (SVF) of fat. Isolation of the SVF, containing adipose-derived stem cells (ADSC), can be accomplished efficiently in the operating room or in the laboratory through enzymatic digestion of the adipose tissue and concentration of SVF. Cells can be directly re-injected as a mesotherapeutic agent, recombined with a tissue scaffold (e.g., cell-enriched fat grafts) or expanded in culture for tissue-engineered cell therapeutics. The potential for cell therapy is under current investigation by researchers around the world. This chapter reviews laboratory methods for isolating ADSCs and the ongoing clinical trials evaluating cell therapeutic efficacy across many specialties, including cardiology, neurology, immunology, tissue engineering, sports medicine, and plastic and reconstructive surgery.

Merkel cell carcinoma (MCC) is an uncommon cutaneous malignant tumor that presents as a rapidly growing skin nodule on sun-exposed areas of the body. MCC is aggressive with regional nodal and distant metastases to the skin, lung, and bones. There have been no reports of metastatic MCC to the mesentery and 6 reports describing metastasis to the small intestine. We present a case of metastatic MCC to the mesentery with infiltration to the small bowel, 8 years after original tumor resection. This is the 5th metastasis and it encased the small bowel resulting in a hair-pin loop contributing to the unusual clinical presentation. Although MCC metastatic to the bowel is uncommon, it is not rare. It is important to recognize the unusual manifestations of this disease as they are becoming more common in the future. Routine radiologic surveillance and thorough review of systems are important to patient follow-up.

Arf GTPases control vesicle formation from different intracellular membranes and are regulated by Arf guanine nucleotide exchange factors (GEFs). Outside of their conserved catalytic domains, known as Sec7 domains, little is known about Arf GEFs. Rsp5 is a yeast ubiquitin ligase that regulates numerous membrane trafficking events and carries a C2 domain that is specifically required for trans-Golgi network to vacuole transport. In a screen for proteins that interact with the Rsp5 C2 domain we identified Sec7, the GEF that acts on Golgi-associated Arfs. The Rsp5-Sec7 interaction is direct, occurs in vivo, and is conserved among mammalian Rsp5 and Sec7 homologues. A 50-amino acid region near the Sec7 C terminus is required for Rsp5 binding and for normal Sec7 localization. Binding of Sec7 to Rsp5 is dependent on the presence of the phosphoinositide 3-kinase Vps34, suggesting that phosphatidylinositol 3-phosphate (PI(3)P) plays a role in regulating this interaction. Overexpression of Sec7 significantly suppresses the growth and sorting defects of an rsp5 C2 domain point mutant. These observations identify a new functional region within the Sec7/BIG family of Arf GEFs that is required for trans-Golgi network localization.