A spatially resolved single-cell genomic atlas of the adult human breast.

The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue1-3. Although most previous studies have focused on the breast epithelial system4-6, many of the non-epithelial cell types remain understudied. Here we constructed the comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics study profiled 714,331 cells from 126 women, and 117,346 nuclei from 20 women, identifying 12 major cell types and 58 biological cell states. These data reveal abundant perivascular, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Spatial mapping using four different technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide a reference of the adult normal breast tissue for studying mammary biology and diseases such as breast cancer.

A spatially resolved single cell genomic atlas of the adult human breast.

The adult human breast comprises an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue. While previous studies have mainly focused on the breast epithelial system, many of the non-epithelial cell types remain understudied. Here, we constructed a comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics data profiled 535,941 cells from 62 women, and 120,024 nuclei from 20 women, identifying 11 major cell types and 53 cell states. These data revealed abundant pericyte, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Our spatial mapping using three technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells in the ducts and lobules, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide an unprecedented reference of adult normal breast tissue for studying mammary biology and disease states such as breast cancer.

Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis.

Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.

Crater detection from commercial satellite imagery to estimate unexploded ordnance in Cambodian agricultural land.

Unexploded ordnance (UXO) pose a significant threat to post-conflict communities, and current efforts to locate bombs rely on time-intensive and dangerous in-person enumeration. Very high resolution (VHR) sub-meter satellite images may offer a low-cost and high-efficiency approach to automatically detect craters and estimate UXO density. Machine-learning methods from the meteor crater literature are ill-suited to find bomb craters, which are smaller than meteor craters and have high appearance variation, particularly in spectral reflectance and shape, due to the complex terrain environment. A two-stage learning-based framework is created to address these challenges. First, a simple and loose statistical classifier based on histogram of oriented gradient (HOG) and spectral information is used for a first pass of crater recognition. In a second stage, a patch-dependent novel spatial feature is developed through dynamic mean-shift segmentation and SIFT descriptors. We apply the model to a multispectral WorldView-2 image of a Cambodian village, which was heavily bombed during the Vietnam War. The proposed method increased true bomb crater detection by over 160 percent. Comparative analysis demonstrates that our method significantly outperforms typical object-recognition algorithms and can be used for wide-area bomb crater detection. Our model, combined with declassified records and demining reports, suggests that 44 to 50 percent of the bombs in the vicinity of this particular Cambodian village may remain unexploded.

Benign Metastasizing Leiomyoma to the Lung and Spine: A Case Report and Literature Review.

Benign metastasizing leiomyomas (BML) represent a rare phenomenon consisting of the extra-uterine spread of smooth muscle cells with similar histological, immunological, and molecular patterns to those of benign uterine leiomyomas. They are considered benign based off their low mitotic activity, lack of anaplasia or necrosis, and limited vascularization. This condition represents an interesting diagnostic and treatment challenge based on their rarity and indolent nature. Our case represents a unique finding of BML in the thoracic spine in a postmenopausal woman many years after hysterectomy and partial oophorectomy. There are currently no standard guidelines for treatment of BML, given the rare nature of this condition, with most patients treated with a combination of surgical resection and radiotherapy, followed by hormonal treatment and radiological surveillance serving as the primary backbone of current management plans. Given that these patients present a unique clinical challenge in terms of diagnosis and management, it is important to delineate and further examine these rare entities.

Orbital Metastases from Breast Cancer with BRCA2 Mutation: A Case Report and Literature Review.

Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Of these women, 5-10% have an inherited form of breast cancer with a mutation in a major gene, such as the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Triple negative (the most common subtype of BRCA1-associated breast cancers) and Her2-positive breast cancer patients have more frequently been observed to develop central nervous system (CNS) metastases compared to other molecular subtypes of breast cancers. However, it remains an open question if BRCA2-associated breast cancers also have a higher propensity to develop CNS metastases. Here we report a rare case of recurrent BRCA2-associated breast cancer which manifested as orbital metastases. At the time of this publication, this is one of the first cases of BRCA2-associated breast cancer to present with orbital metastases. In this article, we discuss the diagnostic challenges and review the literature regarding this rare presentation.

A Prospective, Single Arm, Multi-site, Clinical Evaluation of a Nonradioactive Surgical Guidance Technology for the Location of Nonpalpable Breast Lesions during Excision.

OBJECTIVES: This study was a multicenter evaluation of the SAVI SCOUT(®) breast localization and surgical guidance system using micro-impulse radar technology for the removal of nonpalpable breast lesions. The study was designed to validate the results of a recent 50-patient pilot study in a larger multi-institution trial. The primary endpoints were the rates of successful reflector placement, localization, and removal. METHODS: This multicenter, prospective trial enrolled patients scheduled to have excisional biopsy or breast-conserving surgery of a nonpalpable breast lesion. From March to November 2015, 154 patients were consented and evaluated by 20 radiologists and 16 surgeons at 11 participating centers. Patients had SCOUT(®) reflectors placed up to 7 days before surgery, and placement was confirmed by mammography or ultrasonography. Implanted reflectors were detected by the SCOUT(®) handpiece and console. Presence of the reflector in the excised surgical specimen was confirmed radiographically, and specimens were sent for routine pathology. RESULTS: SCOUT(®) reflectors were successfully placed in 153 of 154 patients. In one case, the reflector was placed at a distance from the target that required a wire to be placed. All 154 lesions and reflectors were successfully removed during surgery. For 101 patients with a preoperative diagnosis of cancer, 86 (85.1 %) had clear margins, and 17 (16.8 %) patients required margin reexcision. CONCLUSIONS: SCOUT(®) provides a reliable and effective alternative method for the localization and surgical excision of nonpalpable breast lesions using no wires or radioactive materials, with excellent patient, radiologist, and surgeon acceptance.

The impact of use of an intraoperative margin assessment device on re-excision rates.

Historically there has been a high rate of surgical interventions to obtain clear margins for breast cancer patients undergoing breast conserving local therapy. An intraoperative margin assessment tool (MarginProbe) has been approved for use in the US since 2013. This study is the first compilation of data from routine use of the device, to assess the impact of device utilization on re-excision rates. We present a retrospective, observational, review from groups of consecutive patients, before and after the implementation of intraoperative use of the device during lumpectomy procedures. Lesions were localized by standard methods. The intraoperative margin assessment device was used on all circumferential margins of the main specimen, but not on any additional shavings. A positive reading by the device led to an additional shaving of the corresponding cavity location. Specimens were also, when feasible, imaged intra-operatively by X-ray, and additional shavings were taken if needed based on clinical assessment. For each surgeon, historical re-excision rates were established based on a consecutive set of patients from a time period proximal to initiation of use of the device. From March 2013 to April 2014 the device was routinely used by 4 surgeons in 3 centers. In total, 165 cases lumpectomy cases were performed. Positive margins resulted in additional re-excision procedures in 9.7% (16/165) of the cases. The corresponding historical set from 2012 and 2013 consisted of 186 Lumpectomy cases, in which additional re-excision procedures were performed in 25.8% (48/186) of the cases. The reduction in the rate of re-excision procedures was significant 62% (P < 0.0001). Use of an intraoperative margin assessment device contributes to achieving clear margins and reducing re-excision procedures. As in some cases positive margins were found on shavings, future studies of interest may include an analysis of the effect of using the device on the shavings intra-operatively.

Olfactory groove meningioma: discussion of clinical presentation and surgical outcomes following excision via the subcranial approach.

OBJECTIVES/HYPOTHESIS: To describe surgical outcomes and radiographic features of olfactory groove meningiomas treated by excision through the subcranial approach. Special emphasis is placed on paranasal sinus and orbit involvement. STUDY DESIGN: Retrospective review of a series of patients. METHODS: Nineteen patients underwent excision of olfactory groove meningioma (OGM) via the transglabellar/subcranial approach between December 1995 and November 2009. Nine patients had previously undergone prior resection at outside institutions, and four had prior radiotherapy in addition to a prior excision. Transglabellar/subcranial surgical approach to the anterior skull base was performed. RESULTS: Tumor histology included three World Health Organization (WHO) grade III lesions, one WHO grade II lesion, and 15 WHO grade I lesions. Fourteen patients had evidence of extension into the paranasal sinuses, with the ethmoid sinus being most commonly involved. Kaplan-Meier estimates of mean overall and disease-free survival were 121.45 months and 93.03 months, respectively. The mean follow-up interval was 41.0 months, and at the time of data analysis three patients had recurrent tumors. Seven (36.8%) patients experienced a major complication in the perioperative period; there were no perioperative mortalities. Orbit invasion was observed in four patients, with optic nerve impingement in 11 patients. Of these, three patients had long-term diplopia. No patients experienced worsening of preoperative visual acuity. CONCLUSIONS: Olfactory groove meningiomas demonstrate a propensity to spread into the paranasal sinuses, particularly in recurrent cases. Given a tendency for infiltrative recurrence along the skull base, this disease represents an important area of collaboration between neurosurgery and otolaryngology. The subcranial approach offers excellent surgical access for excision, particularly for recurrences that involve the paranasal sinuses and optic apparatus.

Perioperative lumbar drain placement: an independent predictor of tension pneumocephalus and intracranial complications following anterior skull base surgery.

OBJECTIVE: To measure the effect of routine perioperative lumbar drain placement during anterior skull base surgery on the frequency of: 1) tension pneumocephalus and 2) total intracranial complications. DESIGN: Retrospective review of a series of patients (n = 161) who underwent the transglabellar/subcranial approach to lesions of the anterior skull base between December 1995 and November 2009. A retrospective cohort (n = 45) underwent routine lumbar drain placement at the time of skull base surgery. The remainder of the series did not undergo routine perioperative lumbar drain placement. INTERVENTION: Transglabellar/subcranial surgical approach to the anterior skull base, with or without routine perioperative lumbar drain placement. RESULTS: Routine placement of perioperative lumbar drains was an independent predictor of tension pneumocephalus (P =.022, odds ratio = 11.22 [1.218-103.3]). In addition, this practice was also associated with an increased risk of intracranial complications overall (P =.025, odds ratio = 2.623 [1.104-6.233]). CONCLUSION: Routine placement of perioperative lumbar drain may be associated with an increased risk of tension pneumocephalus and intracranial complications during surgery of the anterior cranial base.

Perioperative outcomes in patients undergoing the transglabellar/subcranial approach to the anterior skull base.

We analyzed the effect of predefined patient demographic, disease, and perioperative variables on the rate of complications in the perioperative period following subcranial surgery for anterior skull base lesion. A secondary goal of this study was to provide a benchmark rate of perioperative mortality and morbidity through comprehensive analysis of complications. Retrospective review of a consecutive series of patients (n = 164) who underwent the transglabellar/subcranial approach to lesions of the anterior skull base between December 1995 and November 2009 in a tertiary referral center. Main outcome measures were perioperative morbidity and mortality. No perioperative mortalities were observed over the period of consecutive review. The overall complication rate was 28.7%, with 30 (18%) patients experiencing major complication. Multivariate analysis revealed that the following variables were independent predictors of perioperative complication of any type: positive margins on final pathology, perioperative lumbar drain placement, and dural invasion. The subcranial approach provides excellent access to the anterior skull base with zero mortality and acceptable morbidity in comparison with other contemporary open surgical approaches. It should be considered a procedure with distinct advantages in terms of perioperative morbidity and mortality when selecting a therapeutic approach for patients with anterior skull base lesions.

Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution.

We present our experience with sinonasal undifferentiated carcinoma at the University of Michigan over 13 years and review prior published data. We conducted a retrospective review of 19 patients who presented to a tertiary care academic center multidisciplinary skull base clinic with sinonasal undifferentiated carcinoma between 1995 and 2008. Overall survival was 22% at 5 years, and the estimated 5-year distant metastasis-free survival was 35%. At 2 years, local control was 83%, regional control was 50%, and distant control was 83%. Local control was best in those patients treated nonsurgically, as was median survival, though this was not statistically significant. Nodal disease in the neck, either at presentation or at recurrence, was noted in 26% of patients. Survival for sinonasal undifferentiated carcinoma remains poor. It is possible that up-front radiation or chemoradiation will lead to better local control rates, though surgery remains a mainstay of treatment. In all cases, the cervical nodes should be addressed with primary treatment.

Importance of complete pterygomaxillary separation in the le fort I osteotomy: an anatomic report.

This article reports on the presence of an anatomic feature of the extracranial skull base that may result in internal carotid artery injury if secure and complete pterygomaxillary separation is not achieved before maxillary downfracture in the Le Fort I osteotomy. The extracranial skull base of 129 adult skulls and 10 pediatric skulls was examined in the region near the foramen lacerum. This region was inspected for the presence or absence of a bony protrusion that projected posteriorly from the base of the sphenoid, lying inferior to the foramen lacerum. The bony protrusion was present bilaterally in 71% of the adult skulls and 60% of the pediatric skulls. The protrusion was a bony "spike" that pointed posteriorly and was located inferior to the foramen lacerum on the extracranial skull base. Due to its size, shape, and location, the bony protrusion described in this study poses considerable risk to the internal carotid artery if the protrusion is displaced superiorly through the foramen lacerum. In the Le Fort I osteotomy, secure and complete pterygomaxillary separation is crucial to avoid injury to the internal carotid artery during maxillary downfracture.

Cochlear implantation with ipsilateral petroclival chondrosarcoma.

OBJECTIVE: To highlight a case of cochlear implantation in the setting of ipsilateral petrous apex chondrosarcoma. BACKGROUND: A patient with bilateral progressive hearing loss was incidentally found to have a destructive right petrous apex lesion on computed tomography before cochlear implantation. The patient had no associated symptoms and a magnetic resonance imaging scan was obtained, narrowing the differential diagnosis. A middle cranial fossa approach was performed for synchronous biopsy of the lesion and cochlear implantation. RESULTS: Frozen sections revealed a low-grade chondroid lesion, and a Med-El Combi 40+ cochlear implant with a split electrode array was inserted via the middle fossa. Final pathologic examination revealed a Grade I chondrosarcoma. The patient suffered no complications postoperatively and was followed-up over 5 years with serial computed tomographic scans and clinical examinations. No additional treatment was administered. Eighteen months postoperatively, the patient experienced episodic vertigo. There were no new findings on computed tomography, and the vertigo improved with a low-salt diet. Otherwise, the patient had excellent hearing results, and the lesion has not progressed under observation. CONCLUSION: The implications of observing low-grade chondrosarcomas in well-selected patients and the unique aspect of cochlear implantation on the affected side are discussed.

The effect of phenol on ingrown toenail excision in children.

PURPOSE: Ingrown toenails in children are a common problem with a high recurrence rate. The objective of this retrospective data review was to compare simple excision of the nail matrix with excision plus phenol (EPP) application in the treatment of ingrown toenails. METHODS: The charts of 69 children who underwent surgical treatment of one or more ingrown toenails from 1994 to 2000 were reviewed. The primary procedure was noted (excision alone [EA] vs EPP) and dates of recurrences and reoperations were recorded. Parents were then surveyed by phone regarding complications, cosmetic outcome, and overall satisfaction with the procedure. Five scale categories, ranging from "strongly agree" to "strongly disagree", were used, with responses of "strongly agree" and "agree" considered as a good outcome. Either Student's t test or the chi2 test (P < .05 considered significant) was used for analysis. RESULTS: Thirty-one patients (45%) were in the EPP group whereas the remaining 38 had EA. Mean length of follow-up was 4.3 years for the EA group and 2.1 years for the EPP group. There was no difference in age at operation or length of follow-up between the 2 groups. Boys were predominant in both groups. The survey response rate was 50/69 (73%). The recurrence rate of ingrown toenails in the EA group was 42% vs 4% in the EPP group (P = .003). There were no significant differences in parental response with regard to operative experience (P = .31) and the cosmetic result (P = .13), with most of the respondents (78%) indicating a good outcome for both questions. CONCLUSIONS: The addition of phenol to the surgical excision of ingrown toenail significantly reduced the incidence of recurrence, with similar patient satisfaction and an equivalent cosmetic result.