Capturing the True Cost of Breast Cancer Treatment: Molecular Subtype and Stage-Specific per-Case Activity-Based Costing.

BACKGROUND: Breast cancer (BC) treatment is rapidly evolving with new and costly therapeutics. Existing costing models have a limited ability to capture current treatment costs. We used an Activity-Based Costing (ABC) method to determine a per-case cost for BC treatment by stage and molecular subtype. METHODS: ABC was used to proportionally integrate multidisciplinary evidence-based patient and provider treatment options for BC, yielding a per-case cost for the total duration of treatment by stage and molecular subtype. Diagnostic imaging, pathology, surgery, radiation therapy, systemic therapy, inpatient, emergency, home care and palliative care costs were included. RESULTS: BC treatment costs were higher than noted in previous studies and varied widely by molecular subtype. Cost increased exponentially with the stage of disease. The per-case cost for treatment (2023C$) for DCIS was C$ 14,505, and the mean costs for all subtypes were C$ 39,263, C$ 76,446, C$ 97,668 and C$ 370,398 for stage I, II, III and IV BC, respectively. Stage IV costs were as high as C$ 516,415 per case. When weighted by the proportion of molecular subtype in the population, case costs were C$ 31,749, C$ 66,758, C$ 111,368 and C$ 289,598 for stage I, II, III and IV BC, respectively. The magnitude of cost differential was up to 10.9 times for stage IV compared to stage I, 4.4 times for stage III compared to stage I and 35.6 times for stage IV compared to DCIS. CONCLUSION: The cost of BC treatment is rapidly escalating with novel therapies and increasing survival, resulting in an exponential increase in treatment costs for later-stage disease. We provide real-time, case-based costing for BC treatment which will allow for the assessment of health system economic impacts and an accurate understanding of the cost-effectiveness of screening.

Multivariate analysis of breast tissue using optical parameters extracted from a combined time-resolved fluorescence and diffuse reflectance system for tumor margin detection.

Significance: Breast conservation therapy is the preferred technique for treating primary breast cancers. However, breast tumor margins are hard to determine as tumor borders are often ill-defined. As such, there exists a need for a clinically compatible tumor margin detection system. Aim: A combined time-resolved fluorescence and diffuse reflectance (TRF-DR) system has been developed to determine the optical properties of breast tissue. This study aims to improve tissue classification to aid in surgical decision making. Approach: Normal and tumor breast tissue were collected from 80 patients with invasive ductal carcinoma and measured in the optical system. Optical parameters were extracted, and the tissue underwent histopathological examination. In total, 761 adipose, 77 fibroglandular, and 347 tumor spectra were analyzed. Principal component analysis and decision tree modeling were performed using only TRF optical parameters, only DR optical parameters, and using the combined datasets. Results: The classification modeling using TRF data alone resulted in a tumor margin detection sensitivity of 72.3% and specificity of 88.3%. Prediction modeling using DR data alone resulted in greater sensitivity and specificity of 80.4% and 94.0%, respectively. Combining both datasets resulted in the improved sensitivity and specificity of 85.6% and 95.3%, respectively. While both sensitivity and specificity improved with the combined modeling, further study of fibroglandular tissue could result in improved classification. Conclusion: The combined TRF-DR system showed greater tissue classification capability than either technique alone. Further work studying more fibroglandular tissue and tissue of mixed composition would develop this system for intraoperative use for tumor margin detection.

Breast tissue analysis using a clinically compatible combined time-resolved fluorescence and diffuse reflectance (TRF-DR) system.

OBJECTIVE: This work aims to develop a clinically compatible system that can perform breast tissue analysis in a more time efficient process than conventional histopathological assessment. The potential for such a system to be used in vivo in the operating room or surgical suite to improve patient outcome is investigated. METHOD: In this work, 80 matched pairs of invasive ductal carcinoma and adjacent normal breast tissue were measured in a combined time-resolved fluorescence and diffuse reflectance (DA) system. Following measurement, the fluorescence intensity of collagen and flavin adenine dinucleotide (FAD); the fluorescence lifetime of collagen, nicotinamide adenine dinucleotide (NADH), and FAD; the DA; absorption coefficient; and reduced scattering coefficient were extracted. Samples then underwent histological processing and H&E staining to classify composition as tumor, fibroglandular, and/or adipose tissue. RESULTS: Statistically significant differences in the collagen and FAD fluorescence intensity, collagen and FAD fluorescence lifetime, DA, and scattering coefficient were found between each tissue group. The NADH fluorescence lifetime and absorption coefficient were statistically different between the tumor and fibroglandular groups, and the tumor and adipose groups. While many breast tissue analysis studies label fibroglandular and adipose together as "normal" breast tissue, this work indicates that some differences between tumor and fibroglandular tissue are not the same as differences between tumor and adipose tissue. Observations of the reduced scatter coefficient may also indicate further classification to include fibro-adipose may be necessary. Future work would benefit from the additional tissue classification. CONCLUSION: With observable differences in optical parameters between the three tissue types, this system shows promise as a breast analysis tool in a clinical setting. With further work involving samples of mixed composition, this combined system could potentially be used intraoperatively for rapid margin assessment.

Bacteria pyruvate metabolism modulates AFB1 toxicity in Caenorhabditis elegans.

Aflatoxin B1 (AFB1), the most potent mycotoxin and Group 1 human carcinogen, continues to pose a significant public health burden, particularly in developing countries. Increasing evidence has shown the gut microbiota as a key mediator of AFB1 toxicity through multiple interactive host-microbiota activities. In our previous study we observed that disturbances in bacterial pyruvate metabolism might have a significant impact on AFB1 in the host. To further investigate the impact of the pyruvate pathway on AFB1 toxicity in C. elegans, we engineered two bacterial strains (triple-overexpressed and triple-knockout strains with aceB, lpd, and pflB). Additionally, we employed two mutant worm strains (pyk-1 and pdha-1 mutants) known to affect pyruvate metabolism. Our results revealed that the co-metabolism of pyruvate by the host and bacterial strains synergistically influences AFB1 toxicity. Remarkable, we found that bacterial pyruvate metabolism, rather than that of the host, plays a pivotal role in modulating AFB1 toxicity in C. elegans. Our study sheds light on the role of gut microbiota involved in pyruvate metabolism in influencing AFB1 toxicity in C. elegans.

Host-microbiota affects the toxicity of Aflatoxin B1 in Caenorhabditis elegans.

Aflatoxins are a group of potent fungal metabolites produced by Aspergillus and commonly contaminate groundnuts and cereal grains. Aflatoxin B1 (AFB1), the most potent mycotoxin, has been classified as Group 1 human carcinogen because it can be metabolically activated by the cytochrome P450 (CYP450) in the liver to form AFB1-DNA adducts and induce gene mutations. Increasing evidence has shown the gut microbiota as a key mediator of AFB1 toxicity through multiple interactive host-microbiota activities. To identify specific bacterial activity that modulates AFB1 toxicity in Caenorhabditis (C.) elegans, we established a 3-way (microbe-worm-chemical) high-throughput screening system using C. elegans fed E. coli Keio collection on an integrated robotic platform, COPAS Biosort. We performed 2-step screenings using 3985 Keio mutants and identified 73 E. coli mutants that modulated C. elegans growth phenotype. Four genes (aceA, aceB, lpd, and pflB) involved in the pyruvate pathway were identified from the screening and confirmed to increase the sensitivity of all animals to AFB1. Taking together, our results indicated that disturbances in bacterial pyruvate metabolism might have a significant impact on AFB1 toxicity in the host.

A physiologic increase in brain glucagon action alters the hepatic gluconeogenic/glycogenolytic ratio but not glucagon's overall effect on glucose production.

It has been proposed that brain glucagon action inhibits glucagon-stimulated hepatic glucose production (HGP), which may explain, at least in part, why glucagon's effect on HGP is transient. However, the pharmacologic off-target effects of glucagon in the brain may have been responsible for previously observed effects. Therefore, the aim of this study was to determine if central glucagon action plays a physiologic role in the regulation of HGP. Insulin was maintained at baseline while glucagon was either infused into the carotid and vertebral arteries or into a peripheral (leg) vein at rates designed to increase glucagon in the head in one group, while keeping glucagon at the liver matched between groups. The extraction rate of glucagon across the head was high (double that of the liver), and hypothalamic cAMP increased twofold, in proportion to the exposure of the brain to increased glucagon, but HGP was not reduced by the increase in brain glucagon signaling, as had been suggested previously (the areas under the curve for HGP were 840 ± 14 vs. 871 ± 36 mg/kg/240 min in head vs. peripheral infusion groups, respectively). Central nervous system glucagon action reduced circulating free fatty acids and glycerol, and this was associated with a modest reduction in net hepatic gluconeogenic flux. However, offsetting autoregulation by the liver (i.e., a reciprocal increase in net hepatic glycogenolysis) prevented a change in HGP. Thus, while physiologic engagement of the brain by glucagon can alter hepatic carbon flux, it does not appear to be responsible for the transient fall in HGP that occurs following the stimulation of HGP during a square wave rise in glucagon.NEW & NOTEWORTHY Glucagon stimulates hepatic glucose production through its direct effects on the liver but may indirectly inhibit this process by acting on the brain. This was tested by delivering glucagon via the cerebral circulatory system. Central nervous system glucagon action reduced liver gluconeogenic flux, but glycogenolysis increased, resulting in no net change in hepatic glucose production. Surprisingly, brain glucagon also appeared to suppress lipolysis (plasma free fatty acid and glycerol levels were reduced).

Physician and Surgeon Communication Assessed via the Pathology Requisition in a Regional Laboratory Over Ten Years.

Background Ineffective communication between healthcare providers is a known risk factor for adverse events. Objective The aim of this study was to retrospectively assess the communication with pathology via an analysis of the information provided on the pathology requisitions over ten years. Methods All in-house surgical specimens and all non-gynecologic cytopathology specimens accessioned from 2011 to 2020 were retrieved at a regional laboratory. Cases with any clinical information were deemed to have a clinical history present (CHP). CHP was tabulated by submitting physicians/surgeons (SPS), hospital site, year, and tissue group. Results The study period contained 554,817 relevant pathology reports, of which 553,966 could be extracted. The overall CHP rate was 74% and varied from 76% to 67% over the study period. SPSes submitting ≥200 cases (n=314) had a mean/median/standard deviation/max/min CHP rate of 81%/92%/23%/100%/5%. The CHP varied between four hospital sites, from 53% to 97%. CHP varied from 61% to 99% by tissue group. Conclusions CHP is associated with several factors and appears to depend on the hospital culture, specialty, and individual physician/surgeon. The pathology requisition is a way to measure and track the communication that is clinically relevant. Improving communication with pathologists/the pathology department will likely require process changes and mandates. Hospital and laboratory accreditation bodies should consider effective communication with pathology a marker of quality and an accreditation issue.

Effect of special operational forces surgical resuscitation teams on combat casualty survival: A narrative review.

IMPORTANCE: The most common cause of preventable death on the conventional battlefield or on special operations force (SOF) missions is hemorrhage. SOF missions may take place in remote and austere locations. Many preventable deaths in combat occur within 30 min of wounding. Therefore, SOF damage control resuscitation (DCR) and damage control surgery (DCS) teams may improve combat casualty survival in the SOF environment. OBJECTIVE: To determine the effect of SOF DCR and DCS teams on combat casualty survival. Also, to describe commonalities in team structure, logistics, and blood product usage. DESIGN: A narrative review of the English literature used a Medline and Embase search strategy. The authors were contacted for more details as required. The risk of bias was assessed using the Cochrane Collaboration's ROBINS-I tool. Pooling of data was not done to the heterogeneity of studies. RESULTS: Weak evidence was identified showing a clinical benefit of SOF DCR and DCS teams. Conflicting evidence from less rigorous studies was also found. The overall risk of bias using ROBINS-I was serious to critical. Several commonalities in team structure, training, and logistics were found. CONCLUSIONS AND RELEVANCE: There is conflicting evidence regarding the effect SOF DCR and DCS teams have on combat casualty survival. There is no strong evidence that SOF DCR and DCS teams cause harm. More robust data collection is recommended to evaluate these teams.

Clinical Utility of Multigene Profiling Assays in Early-Stage Invasive Breast Cancer: An Ontario Health (Cancer Care Ontario) Clinical Practice Guideline.

OBJECTIVE: The purpose of this guideline is to determine the clinical utility of multigene profiling assays in individuals with early-stage invasive breast cancer. METHODS: This guideline was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care (PEBC) through a systematic review of relevant literature, patient- and caregiver-specific consultation and internal and external reviews. Recommendation 1: In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and the Breast Cancer Index) to help guide the use of systemic therapy. Recommendation 2: In patients with early-stage node-negative ER-positive/HER2-negative disease, clinicians may use a low-risk result from Oncotype DX, MammaPrint, Prosigna, EndoPredict/EPclin, or Breast Cancer Index assays to support a decision not to use adjuvant chemotherapy. Recommendation 3: In patients with node-negative ER-positive/HER2-negative disease, clinicians may use a high-risk result from Oncotype DX to support a decision to offer chemotherapy. A high Oncotype DX recurrence score is capable of predicting adjuvant chemotherapy benefit. Recommendation 4: In postmenopausal patients with ER-positive/HER2-negative tumours and one to three nodes involved (N1a disease), clinicians may withhold chemotherapy based on a low-risk Oncotype DX or MammaPrint score if the decision is supported by other clinical, pathological, or patient-related factors. Recommendation 5: The evidence to support the use of molecular profiling to select the duration of endocrine therapy is evolving. In patients with ER-positive disease, clinicians may consider using a Breast Cancer Index (H/I) high assay result to support a decision to extend adjuvant endocrine therapy if the decision is supported by other clinical, pathological, or patient-related factors.

Case report of a breast granular cell tumor in a young transgender man.

INTRODUCTION AND IMPORTANCE: Granular cell tumors (GCTs) can be diagnostically challenging due to their rarity, diverse anatomic locations, and clinical and radiologic similarities to other more common entities. GCTs involving the breast are rare and are most commonly encountered in premenopausal cisgender women. We report an unusual case of a breast GCT in a young transgender man. CASE PRESENTATION: A 20-year-old transgender man who was on testosterone therapy for about 1 year presented with a painless, palpable mass in the right breast which radiologically resembled a lymph node. A fine needle aspiration showed morphology and immunohistochemistry consistent with a GCT. The tumor was excised by a mastectomy for therapeutic and gender-affirming purposes which confirmed the diagnosis of a breast GCT. CLINICAL DISCUSSION: Breast GCTs are most commonly found in cisgender women, however the mechanisms behind this relationship and whether transgender persons have an altered risk profile are not well understood. Breast GCTs are typically benign lesions with a low chance of recurrence following excision. CONCLUSION: GCTs are rare and poorly understood entities which have not been previously documented in transgender patients and can resemble other benign or malignant lesions.

Error reduction in trauma care: Lessons from an anonymized, national, multicenter mortality reporting system.

BACKGROUND: Twenty years ago, the landmark report To Err Is Human illustrated the importance of system-level solutions, in contrast to person-level interventions, to assure patient safety. Nevertheless, rates of preventable deaths, particularly in trauma care, have not materially changed. The American College of Surgeons Trauma Quality Improvement Program developed a voluntary Mortality Reporting System to better understand the underlying causes of preventable trauma deaths and the strategies used by centers to prevent future deaths. The objective of this work is to describe the factors contributing to potentially preventable deaths after injury and to evaluate the effectiveness of strategies identified by trauma centers to mitigate future harm, as reported in the Mortality Reporting System. METHODS: An anonymous structured web-based reporting template based on the Joint Commission on Accreditation of Healthcare Organizations taxonomy was made available to trauma centers participating in the Trauma Quality Improvement Program to allow for reporting of deaths that were potentially preventable. Contributing factors leading to death were evaluated. The effectiveness of mitigating strategies was assessed using a validated framework and mapped to tiers of effectiveness ranging from person-focused to system-oriented interventions. RESULTS: Over a 2-year period, 395 deaths were reviewed. Of the mortalities, 33.7% were unanticipated. Errors pertained to management (50.9%), clinical performance (54.7%), and communication (56.2%). Human failures were cited in 61% of cases. Person-focused strategies like education were common (56.0%), while more effective system-based strategies were seldom used. In 7.3% of cases, centers could not identify a specific strategy to prevent future harm. CONCLUSION: Most strategies to reduce errors in trauma centers focus on changing the performance of providers rather than system-level interventions such as automation, standardization, and fail-safe approaches. Centers require additional support to develop more effective mitigations that will prevent recurrent errors and patient harm. LEVEL OF EVIDENCE: Therapeutic/Care Management, level V.

Insulin Infusion Is Linked to Increased NPPC Expression in Muscle and Plasma C-type Natriuretic Peptide in Male Dogs.

The purpose of this study was to assess insulin-stimulated gene expression in canine skeletal muscle with a particular focus on NPPC, the gene that encodes C-type natriuretic peptide, a key hormonal regulator of cardiometabolic function. Four conscious canines underwent hyperinsulinemic, euglycemic clamp studies. Skeletal muscle biopsy and arterial plasma samples were collected under basal and insulin-stimulated conditions. Bulk RNA sequencing of muscle tissue was performed to identify differentially expressed genes between these 2 steady-state conditions. Our results showed that NPPC was the most highly expressed gene in skeletal muscle in response to insulin infusion, rising 4-fold between basal and insulin-stimulated conditions. In support of our RNA sequencing data, we found that raising the plasma insulin concentration 15-fold above basal elicited a 2-fold (P = 0.0001) increase in arterial plasma concentrations of N-terminal prohormone C-type natriuretic peptide. Our data suggest that insulin may play a role in stimulating secretion of C-type natriuretic peptide by skeletal muscle. In this context, C-type natriuretic peptide may act in a paracrine manner to facilitate muscle-vascular bed crosstalk and potentiate insulin-mediated vasodilation. This could serve to enhance insulin and glucose delivery, particularly in the postprandial absorptive state.

Excess Polymer in Single-Walled Carbon Nanotube Thin-Film Transistors: Its Removal Prior to Fabrication Is Unnecessary.

Ultrapure semiconducting single-walled carbon nanotube (sc-SWNT) dispersions produced through conjugated polymer sorting are ideal candidates for the fabrication of solution-processed organic electronic devices on a commercial scale. Protocols for sorting and dispersing ultrapure sc-SWNTs with conjugated polymers for thin-film transistor (TFT) applications have been well refined. Conventional wisdom dictates that removal of excess unbound polymer through filtration or centrifugation is necessary to produce high-performance TFTs. However, this is time-consuming, wasteful, and resource-intensive. In this report, we challenge this paradigm and demonstrate that excess unbound polymer during semiconductor film fabrication is not necessarily detrimental to device performance. Over 1200 TFT devices were fabricated from 30 unique polymer-sorted SWNT dispersions, prepared using two different alternating copolymers. Detailed Raman spectroscopy, x-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) studies of the random-network semiconductor films demonstrated that a simple solvent rinse during TFT fabrication was sufficient to remove unbound polymer from the sc-SWNT films, thus eliminating laborious polymer removal before TFT fabrication. Furthermore, below a threshold polymer concentration, the presence of excess polymer during fabrication did not significantly impede TFT performance. Preeminent performance was achieved for devices prepared from native polymer-sorted SWNT dispersions containing the "original" amount of excess unbound polymer (immediately following enrichment). Lastly, we developed an open-source Machine Learning algorithm to quantitatively analyze AFM images of SWNT films for surface coverage, number of tubes, and tube alignment.

Postneoadjuvant Pure and Predominantly Pure Intralymphatic Breast Carcinoma: Case Series and Literature Review.

Locally advanced breast cancer is typically treated with neoadjuvant chemotherapy to decrease tumor size and optimize surgical results. Cases of pathologic complete response, are associated with favorable long-term outcomes. The American Joint Committee on Cancer (AJCC) defines pathologic complete response as a lack of residual invasive disease in the breast or lymph nodes or only residual ductal carcinoma in situ. Three studies have examined the unique pattern of postneoadjuvant pure or predominantly pure intralymphatic carcinoma. These studies are small and the prognosis associated with this disease pattern is still unclear. The current study aims to describe clinicopathologic findings associated with pure and predominantly pure intralymphatic carcinoma postneoadjuvant chemotherapy. Electronic medical records were searched to identify patients treated with postneoadjuvant mastectomy between 2010 and 2017. Cases were included if they met the previously defined definitions for pure or predominantly pure intralymphatic carcinoma. Of 479 postneoadjuvant mastectomies, 5 patients had pure intralymphatic carcinoma and 6 patients had predominantly pure. Overall, 50% (3/6) of patients with predominantly pure pattern died of metastatic disease within 14 months of mastectomy, whereas 1 patient with pure intralymphatic carcinoma (ypN0) died of metastatic disease 25 months postmastectomy, revealing a better prognosis associated with pure intralymphatic carcinoma when compared with predominantly pure. The diligent gross examination is required to identify patients with both patterns of residual disease. A standardized approach to incorporating lymphovascular invasion into postneoadjuvant staging may be useful from both a clinical and research perspective. The published case numbers remain small and understanding the true clinical significance still depends on additional studies.

Variation in breast cancer grading in 1,636 resections assessed using control charts and in silico kappa.

OBJECTIVE: Assess interpretative variation in Nottingham grading using control charts (CCs) and in silico kappa (ISK). METHODS: In house invasive breast cancer cases (2011-2019) at two institutions with a synoptic report were extracted. Pathologist interpretative rates (PIRs) were calculated and normed for Nottingham grade (G) and its components (tubular score (TS), nuclear score (NS), mitotic score (MS)) for pathologists interpreting >35 cases. ISKs were calculated using the ordered mutually exclusive category assumption (OMECA) and maximal categorical overlap assumption (MCOA). RESULTS: The study period included 1,994 resections. Ten pathologists each assessed 38-441 cases and together saw 1,636; these were further analyzed. The PIR medians (normed ranges) were: G1:24%(18-27%), G2:53%(43-56%) and G3:26%(19-33%). The MCOA ISK and the number of statistical outliers (p< 0.05/p< 0.001) to the group median interpretive rate (GMIR) for the ten pathologists was G1: 0.82(2/0 of 10), G2: 0.76(1/1), G3: 0.71(3/1), TS1: 0.79(1/0), TS2: 0.63(5/1), TS3: 0.66(5/1), NS1: 0.37(5/4), NS2: 0.60(4/3), NS3: 0.59(4/4), MS1: 0.78(3/1), MS2: 0.78(3/1), MS3: 0.77(2/0). The OMECA ISK was 0.62, 0.49, 0.69 and 0.71 for TS, NS, MS and G. CONCLUSIONS: The nuclear score has the most outliers. NS1 appears to be inconsistently used. ISK mirrors trends in conventional kappa studies. CCs and ISK allow insight into interpretive variation and may be essential for the next generation in quality.

Detoxification mechanisms of nickel sulfate in nematode Caenorhabditis elegans.

Nickel is the most prevailing metal allergen with the highest sensitization rate among the "TOP 25" contact allergens and can affect about 15% of the human population. It is an essential trace metal in plants, animals, and humans. However, the environmental levels of nickel are considerably higher than what is needed for human life. Exposure to high levels of nickel can lead to skin allergies, lung fibrosis, and carcinogenesis. Few existing studies have closely examined the toxicity of nickel, let alone investigated the effective detoxification pathways. Here, we developed a high-throughput screening platform to comprehensively evaluate the nickel toxicity in wild-type C. elegans and explore the underlying detoxification mechanisms in transgenic nematodes. We demonstrated that nickel exerted multiple toxic effects on growth, brood size, feeding, and locomotion in C. elegans. Of which, brood size is the most sensitive endpoint. Nickel was found to first bind to phytochelatin (PC) after entering the worms' body and this PC-Ni complex was further transported by the ABC transporter, CeHMT-1, into the coelomocytes for further detoxification. Our study also demonstrated that the high-throughput screening platform is a promising system for evaluation and investigation of the ecological risks of heavy metals.

The kinetics of glucagon action on the liver during insulin-induced hypoglycemia.

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg-1·min-1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg-1·min-1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg-1·min-1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg-1·min-1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Predictors of Outcome in Mammary Adenoid Cystic Carcinoma: A Multi-Institutional Study.

Mammary adenoid cystic carcinoma (ACC) is a rare subtype of breast cancer with a favorable prognosis. Here we report on predictors of outcome based on a detailed morphologic review and analysis of 108 mammary ACC. Sixty-four tumors (59.2%) were pure conventional ACC, 23 (21.3%) were pure basaloid ACC. Follow-up was available for 87 patients (median: 51 mo). Eighteen patients (20.7%) developed recurrence: 7 (8%) had local recurrence and 14 (16%) had distant metastasis. Two patients died of disease, 1 died of an unrelated cause, 14 were alive with disease (including 8 in palliative care), and 70 (80.5%) were alive with no evidence of disease. Of 90 patients with known lymph node (LN) status 9 (10%) had nodal involvement (all with basaloid ACC). Distant metastases in patients with predominantly basaloid ACC compared with pure conventional ACC were more common (40% vs. 7.7%) and occurred earlier (22 vs. 84 mo). The following factors were found to be predictive of recurrence-free survival: positive margin, Nottingham grade, neovascularization, basaloid component, perineural invasion, lymphovascular invasion, >30% solid growth, necrosis and LN involvement; the first 3 remained statistically significant on multivariate analysis. Factors predictive of distant disease-free survival were neovascularization, Nottingham grade, lymphovascular invasion, solid component >50%, LN involvement, basaloid component >50%, tumor necrosis, perineural invasion, and final margin. Only neovascularization remained statistically significant on multivariate analysis. Basaloid ACC is an aggressive variant of mammary ACC with more frequent nodal involvement and higher incidence of distant spread. LN staging should be performed for all mammary basaloid ACC.

Benign breast papillary lesions diagnosed on core biopsy: upgrade rate and risk factors associated with malignancy on surgical excision.

Evaluation of radiologically detected breast lesions is a common task in surgical pathology. Some benign lesions on biopsy are associated with an upgrade to in situ or invasive carcinoma on excision. The non-atypical breast papilloma has published upgrade rates of 0 to 29%. Traditionally, papillomas have been managed surgically, but the wide range of upgrade rates has raised uncertainty about the need for routine surgical excision. This study aims to identify risk factors associated with upgrade and determine the upgrade rate of non-atypical papillomas at our institution. In a retrospective review of pathology reports, we identified 266 patients with a diagnosis of benign papilloma on breast core biopsy. One hundred eighty-two patients underwent surgical resection. The final surgical pathology reports of all patients were reviewed and divided into one of two groups-benign or malignant. Twenty-one patients had a final diagnosis of in situ or invasive carcinoma, resulting in an upgrade rate of 12%. Radiologically detected lesions with calcifications were at higher risk for upgrade (OR = 4.45, 95% CI 1.08-18.27) than lesions without calcifications. Additionally, advanced patient age (OR = 1.07, 95% CI 1.03-1.13) and lesion size greater than 0.5 cm (OR = 2.59, 95% CI 0.38-17.48) was associated with upgrade to malignancy. Routine surgical excision of all papillomas is not recommended. Younger patients without high-risk features may benefit from clinical and radiologic follow-up alone. Accurate risk stratification will spare low-risk women unnecessary surgery.