VA MidSouth Healthcare Network

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.

Myeloid-derived suppressor cells (MDSCs), identified as Gr1(+)CD11b(+) cells in mice, expand during cancer and promote tumor growth, recurrence and burden. However, little is known about their role in bone metastases. We hypothesized that MDSCs may contribute to tumor-induced bone disease, and inoculated breast cancer cells into the left cardiac ventricle of nude mice. Disease progression was monitored weekly by X-ray and fluorescence imaging and MDSCs expansion by fluorescence-activated cell sorting. To explore the contribution of MDSCs to bone metastasis, we co-injected mice with tumor cells or PBS into the left cardiac ventricle and Gr1(+)CD11b(+) cells isolated from healthy or tumor-bearing mice into the left tibia. MDSCs didn't induce bone resorption in normal mice, but increased resorption and tumor burden significantly in tumor-bearing mice. In vitro experiments showed that Gr1(+)CD11b(+) cells isolated from normal and tumor-bearing mice differentiate into osteoclasts when cultured with RANK ligand and macrophage colony-stimulating factor, and that MDSCs from tumor-bearing mice upregulate parathyroid hormone-related protein (PTHrP) mRNA levels in cancer cells. PTHrP upregulation is likely due to the 2-fold increase in transforming growth factor β expression that we observed in MDSCs isolated from tumor-bearing mice. Importantly, using MDSCs isolated from GFP-expressing animals, we found that MDSCs differentiate into osteoclast-like cells in tumor-bearing mice as evidenced by the presence of GFP(+)TRAP(+) cells. These results demonstrate that MDSCs expand in breast cancer bone metastases and induce bone destruction. Furthermore, our data strongly suggest that MDSCs are able to differentiate into osteoclasts in vivo and that this is stimulated in the presence of tumors.

BACKGROUND: Interleukin-12 (IL-12) and interleukin-23 (IL-23) are inflammatory cytokines linked to the Th-1 and Th-17 phenotypes associated with Crohn's disease (CD). We investigated the activity and safety of apilimod mesylate (formerly STA-5326), an oral IL-12 and IL-23 inhibitor, in patients with active CD. METHODS: We performed a multicenter, Phase 2, randomized, double-blinded, placebo-controlled study to evaluate the efficacy of apilimod mesylate in treating 220 adult patients with moderate-to-severe CD (Crohn's Disease Activity Index [CDAI] score 220-450). Patients were stratified according to C-reactive protein (CRP) levels and corticosteroid use and were randomly assigned to receive placebo or apilimod mesylate 50 mg daily or 100 mg daily. The study was divided into an induction phase (43 days) and a maintenance phase (125 days). The primary analysis involved a comparison of the proportion of patients experiencing clinical response, defined as at least a 100-point decrease in CDAI score from baseline at day 29. Data on adverse events were also collected. RESULTS: In all, 220 of the planned 282 patients were enrolled when the Data Monitoring Committee determined that the drug was not efficacious as a treatment and closed enrollment. A clinical response was experienced by 18 patients (24.7%) in the 50-mg daily (QD) group (n = 73) and 19 patients (25.7%) in the 100 mg QD group (n = 74), as compared with 21 patients (28.8%) in the placebo group (n = 73) on day 29 (P = 0.71 for each comparison). No significant adverse safety signal was observed. CONCLUSIONS: Apilimod was well-tolerated but did not demonstrate efficacy over placebo in patients with active CD.

UNLABELLED: WIN-R (Weight-based dosing of pegINterferon alfa-2b and Ribavirin) was a multicenter, randomized, open-label, investigator-initiated trial involving 236 community and academic sites in the United States, comparing response to pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in treatment-naive patients with chronic hepatitis C and compensated liver disease. Patients were randomized to receive PEG-IFN alfa-2b at 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based-dose RBV (800 mg/day for weight <65 kg, 1000 mg/day for 65-85 kg, 1200 mg/day for >85-105 kg, or 1400 mg/day for >105-<125 kg). Sustained virologic response (SVR; undetectable [<125 IU/mL] hepatitis C virus [HCV] RNA at end of follow-up) in patients > or =65 kg was the primary end point. Low SVR rates have been reported among African American individuals, in whom there is a preponderance of HCV genotype 1. This subanalysis of WIN-R was conducted to evaluate the efficacy of weight-based dosing among African American individuals with genotype 1 infection enrolled in the trial. Of 362 African American patients in the primary efficacy analysis, 188 received RBV flat dosing and 174 received weight-based dosing. SVR rates were higher (21% versus 10%; P = 0.0006) and relapse rates were lower (22% versus 30%) in the weight-based-dose group than in the flat-dose group. Safety and rates of drug discontinuation were similar between the 2 groups. CONCLUSION: Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1. Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups.

Loss of TGF-β type II receptor (TβRII, encoded by Tgfbr2) expression in the prostate stroma contributes to prostate cancer initiation, progression, and invasion. We evaluated whether TβRII loss also affected prostate cancer bone metastatic growth. Immunohistologic analysis revealed that TβRII expression was lost in cancer-associated fibroblasts in human prostate cancer bone metastatic tissues. We recapitulated the human situation with a conditional stromal Tgfbr2 knockout (Tgfbr2-KO) mouse model. Conditioned media from primary cultured Tgfbr2-KO or control Tgfbr2-flox prostatic fibroblasts (koPFCM or wtPFCM, respectively) were applied to C4-2B prostate cancer cells before grafting the cells tibially. We found that koPFCM promoted prostate cancer cell growth in the bone and development of early mixed osteoblastic/osteolytic bone lesions. Furthermore, the koPFCM promoted greater C4-2B adhesion to type-I collagen, the major component of bone matrix, compared to wtPFCM-treated C4-2B. Cytokine antibody array analysis revealed that koPFCM had more than two-fold elevation in granulocyte colony-stimulating factor and CXCL1, CXCL16, and CXCL5 expression relative to wtPFCM. Interestingly, neutralizing antibodies of CXCL16 or CXCL1 were able to reduce koPFCM-associated C4-2B type-I collagen adhesion to that comparable with wtPFCM-mediated adhesion. Collectively, our data indicate that loss of TGF-β responsiveness in prostatic fibroblasts results in upregulation of CXCL16 and CXCL1 and that these paracrine signals increase prostate cancer cell adhesion in the bone matrix. These microenvironment changes at the primary tumor site can mediate early establishment of prostate cancer cells in the bone and support subsequent tumor development at the metastatic site.

// Debolina Ganguly 1 , Meiyun Fan 1 , Chuan He Yang 1 , Blazej Zbytek 2 , David Finkelstein 3 , Martine F. Roussel 4 and Lawrence M. Pfeffer 1 1 Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA 2 Pathology Group of the Midsouth, Germantown, TN, USA 3 Department of Computational Biology, St. Jude Children&rsquo;s Research Hospital, Memphis, TN, USA 4 Department of Tumor Cell Biology, St. Jude Children&rsquo;s Research Hospital, Memphis, TN, USA Correspondence to: Lawrence M. Pfeffer, email: lpfeffer@uthsc.edu Keywords: STAT3; glioblastoma; phosphorylation; gene expression; tumorigenesis Received: March 19, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: April 02, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: April 24, 2018 ABSTRACT Glioma-Initiating Cells (GICs) are thought to be responsible for tumor initiation, progression and recurrence in glioblastoma (GBM). In previous studies, we reported the constitutive phosphorylation of the STAT3 transcription factor in GICs derived from GBM patient-derived xenografts, and that STAT3 played a critical role in GBM tumorigenesis. In this study, we show that CRISPR/Cas9-mediated deletion of STAT3 in an established GBM cell line markedly inhibited tumorigenesis by intracranial injection but had little effect on cell proliferation in vitro . Tumorigenesis was rescued by the enforced expression of wild-type STAT3 in cells lacking STAT3. In contrast, GICs were highly addicted to STAT3 and upon STAT3 deletion GICs were non-viable. Moreover, we found that STAT3 was constitutively activated in GICs by phosphorylation on both tyrosine (Y705) and serine (S727) residues. Therefore, to study STAT3 function in GICs we established an inducible system to knockdown STAT3 expression (iSTAT3-KD). Using this approach, we demonstrated that Y705-STAT3 phosphorylation was critical and indispensable for GIC-induced tumor formation. Both phosphorylation sites in STAT3 promoted GIC proliferation in vitro . We further showed that S727-STAT3 phosphorylation was Y705-dependent. Targeted microarray and RNA sequencing revealed that STAT3 activated cell-cycle regulator genes, and downregulated genes involved in the interferon response, the hypoxia response, the TGF&beta; pathway, and remodeling of the extracellular matrix. Since STAT3 is an important oncogenic driver of GBM, the identification of these STAT3 regulated pathways in GICs will inform the development of better targeted therapies against STAT3 in GBM and other cancers.

The investigators report the clinical and pathologic features of 19 cases of intraepithelial neoplasia occurring in the anal canal mucosa of routinely excised hemorrhoidal tissue, a condition that has been infrequently described. The patients were 12 women and seven men having an age range of 21 to 74 years (mean, 48 years). Two patients had coexistent anogenital condylomata acuminata. Leukoplakia of the hemorrhoidal surface was noted in two patients. Intraepithelial neoplasia arose in the transition zone of the anal canal of 11 cases, in the squamous zone of three cases, and in both sites of five cases. All were high-grade intraepithelial neoplasms; one was classified moderate to severe dysplasia, 17 exhibited severe dysplasia/carcinoma in situ, and one contained microinvasive carcinoma. Both keratinizing and cloacogenic type neoplasms were observed. Associated koilocytotic atypia was identified in 16 cases (84%). In situ hybridization for human papillomavirus (HPV) messenger RNA demonstrated HPV RNA sequences in seven of nine neoplasms (78%) studied by that technique (five HPV type 16, one HPV type 18, and one coinfection with HPV types 6 and 18). Eighteen patients had no clinically evident recurrent or progressive disease at mean follow-up of 6.6 years. Residual/recurrent intraepithelial neoplasia was noted in one patient at 1, 2, 5, and 49 months posthemorrhoidectomy. Our data indicate that incidentally discovered high-grade intraepithelial neoplasia present in hemorroidal tissue is a clinically nonaggressive lesion frequently associated with HPV infection. Hemorrhoidectomy alone is curative in most cases.

BACKGROUND: Subcutaneous fat necrosis associated with pancreatic disease is a rare event. The clinical cutaneous findings are non-specific erythematous nodules with central softening located predominantly on the lower extremities. The histopathologic features of these lesions are very characteristic and diagnostic. METHODS: We present an unusual case of pancreatic panniculitis associated with lupus pancreatitis in a 21-year-old African American female. The patient presented with lower extremity skin nodules, arthralgia, and serositis prior to the diagnosis of systemic lupus and pancreatitis. The skin lesions progressed despite normalization of serum pancreatic enzymes. Following femoral vein catheterization for renal dialysis, she developed a large indurated area over the left lower quadrant, flank, groin, and upper thigh measuring 25 cm. She was treated with repeated debridement, tissue grafts, and hyperbaric oxygen because of a clinical suspicion of necrotizing fasciitis. RESULTS: Examination of skin biopsies and debrided tissue revealed the pathognomonic features of pancreatic panniculitis without any evidence of necrotizing fasciitis. Organisms were not detected by tissue examination or microbiologic cultures. CONCLUSIONS: This case illustrates the potential role of vascular trauma in the pathogenesis of pancreatic panniculitis.

BACKGROUND: Restrictive dermopathy is a rare autosomal recessive skin disorder that is fatal in the neonatal period. Clinical and pathologic findings are distinctive and allow for a specific diagnosis in most cases. METHODS: We present a case of an affected infant and a review of the previously reported cases in the literature. RESULTS: The infant had thick shiny skin with reduced compliance and multiple spontaneous linear splits. Additional findings included an abnormal facies with a distinctive small, round and open mouth, low set ears, small nose, widely spaced sutures, flexion contractures of the extremities, and poorly expanded lungs. The infant expired 65 h after birth. Histologic findings of the skin at autopsy included a relatively unremarkable epidermis, a flat dermal-epidermal junction (absent rete ridges), an overall thinned dermis with hypoplastic appendage structures, a dense fibrotic reticular dermis with collagen parallel to the epidermis, a sharp subcutaneous margin, and an abnormally thick layer of subcutaneous adipose tissue. Electron microscopic findings included dense dermal patches of collagen and fibroblasts with abundant endoplasmic reticulum and unusually small tonofilaments. Review of previously reported cases reveals strikingly consistent findings. CONCLUSIONS: This rare condition illustrates that abnormal cutaneous development may produce fetal hypokinesia, leading to profound effects on intrauterine growth and development. The autosomal recessive pattern of inheritance and morphologic changes of the skin and skeletal system in this disorder suggest that a structural protein or enzyme defect, perhaps of collagen metabolism, may underlie the pathogenesis.

Current methods for detecting disseminated tumor cells in the skeleton are limited by expense and technical complexity. We describe a simple and inexpensive method to quantify, with single cell sensitivity, human metastatic cancer in the mouse skeleton, concurrently with host gene expression, using TRIzol-based DNA/RNA extraction and Alu sequence qPCR amplification. This approach enables precise quantification of tumor cells and corresponding host gene expression during metastatic colonization in xenograft models.

OBJECTIVES: Aims were (1) to determine the proportion of patients with lumbar impairments who could be classified at intake by McKenzie syndromes (McK) and pain pattern classification (PPCs) using Mechanical Diagnosis and Therapy (MDT) assessment methods, manipulation, and stabilization clinical prediction rules (CPRs) and (2) for each Man CPR or Stab CPR category, determine classification prevalence rates using McK and PPC. METHODS: Eight physical therapists practicing in eight diverse clinical settings classified patients typically referred to rehabilitation by McKenzie syndromes (i.e. derangement, dysfunction, posture, or other), pain pattern classification [i.e. centralization (CEN), not centralization (Non CEN), and not classified (NC)], Manipulation CPR (positive, negative), and stabilization CPR (positive, negative). Prevalence rates with 95% confidence intervals (CI) were calculated for each classification category by McK, PPC, and manipulation and stabilization CPRs. Prevalence rates (95% CIs) for McK and PPC were calculated for each CPR category separately. RESULTS: Data from 628 adults [mean age: 52±17 years, 56% female] were analyzed. Prevalence rates were: McK - derangement 67%, dysfunction 5%, posture 0%, other 28%; PPC - CEN 43%, Non CEN 39%, NC 18%; manipulation CPR - positive 13%; Stab CPR - positive 7%. For patients positive for manipulation CPR (n = 79), prevalence rates for derangement were 89% and CEN 68%. For patients positive for stabilization CPR (n = 41), prevalence rates for derangement were 83% and CEN 80%. DISCUSSION: The majority of patients classified based on initial clinical presentation by manipulation and stabilization CPRs were also classified as derangements whose symptoms centralized. Manipulation and stabilization CPRs may not represent a mutually exclusive treatment subgroup but may include patients who can be initially treated using a different classification method.

3D printing enables the creation of scaffolds with precisely controlled morphometric properties for multiple tissue types, including musculoskeletal tissues such as cartilage and bone. Computed tomography (CT) imaging has been combined with 3D printing to fabricate anatomically scaled patient-specific scaffolds for bone regeneration. However, anatomically scaled scaffolds typically lack sufficient resolution to recapitulate the <100 micrometer-scale trabecular architecture essential for investigating the cellular response to the morphometric properties of bone. In this study, it is hypothesized that the architecture of trabecular bone regulates osteoblast differentiation and mineralization. To test this hypothesis, human bone-templated 3D constructs are fabricated via a new micro-CT/3D inkjet printing process. It is shown that this process reproducibly fabricates bone-templated constructs that recapitulate the anatomic site-specific morphometric properties of trabecular bone. A significant correlation is observed between the structure model index (a morphometric parameter related to surface curvature) and the degree of mineralization of human mesenchymal stem cells, with more concave surfaces promoting more extensive osteoblast differentiation and mineralization compared to predominately convex surfaces. These findings highlight the significant effects of trabecular architecture on osteoblast function.

Synovial cysts of the thoracic spine are quite rare. Bilateral presentation is even less frequent, and to the authors' knowledge multilevel occurrence and consistent calcification have not been reported so far. The pathogenesis of these cysts is unknown and their histological features have not been studied. They may be overlooked as the cause of myelopathy. The authors report a series of 4 cases of bilateral, multilevel, consistently calcified thoracic synovial cysts. The details of clinical, radiological, and histological findings are presented, along with a review of the literature, and a hypothesis on the pathogenesis of these lesions is formulated based on results of the clinical and pathological studies performed in these patients.

Study Design Retrospective cohort. Background Patient-classification subgroupings may be important prognostic factors explaining outcomes. Objectives To determine effects of adding classification variables (McKenzie syndrome and pain patterns, including centralization and directional preference; Symptom Checklist Back Pain Prediction Model [SCL BPPM]; and the Fear-Avoidance Beliefs Questionnaire subscales of work and physical activity) to a baseline risk-adjusted model predicting functional status (FS) outcomes. Methods Consecutive patients completed a battery of questionnaires that gathered information on 11 risk-adjustment variables. Physical therapists trained in Mechanical Diagnosis and Therapy methods classified each patient by McKenzie syndromes and pain pattern. Functional status was assessed at discharge by patient-reported outcomes. Only patients with complete data were included. Risk of selection bias was assessed. Prediction of discharge FS was assessed using linear stepwise regression models, allowing 13 variables to enter the model. Significant variables were retained in subsequent models. Model power (R(2)) and beta coefficients for model variables were estimated. Results Two thousand sixty-six patients with lumbar impairments were evaluated. Of those, 994 (48%), 10 (<1%), and 601 (29%) were excluded due to incomplete psychosocial data, McKenzie classification data, and missing FS at discharge, respectively. The final sample for analyses was 723 (35%). Overall R(2) for the baseline prediction FS model was 0.40. Adding classification variables to the baseline model did not result in significant increases in R(2). McKenzie syndrome or pain pattern explained 2.8% and 3.0% of the variance, respectively. When pain pattern and SCL BPPM were added simultaneously, overall model R(2) increased to 0.44. Although none of these increases in R(2) were significant, some classification variables were stronger predictors compared with some other variables included in the baseline model. Conclusion The small added prognostic capabilities identified when combining McKenzie or pain-pattern classifications with the SCL BPPM classification did not significantly improve prediction of FS outcomes in this study. Additional research is warranted to investigate the importance of classification variables compared with those used in the baseline model to maximize predictive power. Level of Evidence Prognosis, level 4. J Orthop Sports Phys Ther 2016;46(9):726-741. Epub 31 Jul 2016. doi:10.2519/jospt.2016.6266.

BACKGROUND: Deltoid muscle function is paramount to the success of reverse total shoulder arthroplasty. The purpose of this study was to investigate the role of deltoid volume on shoulder range of motion and patient-reported outcomes following reverse total shoulder arthroplasty in rotator cuff-intact and rotator cuff-deficient conditions. METHODS: Retrospective review of records identified 107 patients who met inclusion criteria. The rotator cuff integrity was evaluated by two musculoskeletal-trained radiologists. Volumetric deltoid measurements were calculated from preoperative computed tomography or magnetic resonance imaging scans. Satisfactory outcomes were defined as forward elevation of at least 135°, external rotation of at least 35°, and American Shoulder and Elbow Surgeons and Single Assessment Numerical Evaluation scores of at least 70. RESULTS: Mean total deltoid muscle volume was significantly higher in patients with satisfactory forward elevation (57.8 ± 18.1 cm³) versus unsatisfactory forward elevation (48.6 ± 19.5 cm³) (p = 0.013). When separated by rotator cuff integrity, total deltoid volume was significantly higher (p = 0.030) in patients who achieved satisfactory forward elevation in the rotator cuff-deficient group but not the rotator cuff-intact group (p = 0.533). DISCUSSION: Preoperative deltoid volume directly correlated with achieving satisfactory forward elevation after reverse total shoulder arthroplasty in rotator cuff-deficient conditions and may be one factor in determining the ability to achieve satisfactory outcomes in the rotator cuff-deficient patient.

Background Cerebellar glioblastoma multiforme (GBM) is rare and presents with increased intracranial pressure and cerebellar signs. The recommended treatment is radical resection, if possible, with radiation and chemotherapy. Clinical Presentation A 53-year-old man presented with hypertensive cerebellar bleeding and a 2-day history of severe headaches, nausea, vomiting, gait instability, and elevated blood pressure. Computed tomography (CT) showed a left cerebellar hematoma with no obstruction of cerebrospinal fluid and no hydrocephalus. CT angiography showed no signs of pathologic blood vessels in the posterior cranial fossa. The patient was observed in the hospital and discharged. Subsequent CT showed complete hematoma resorption. Two weeks later, he developed headaches, nausea, and worsening cerebellar symptoms. Magnetic resonance imaging (MRI) showed a 4-cm diameter tumor in the left cerebellar hemisphere where the hemorrhage was located. The tumor was radically resected and diagnosed as GBM. The patient underwent radiation and chemotherapy. At a follow-up of 1.5 years, MRIs showed no tumor recurrence. Conclusion Hypertensive cerebellar hemorrhage may be the first presentation of underlying tumor, specifically GBM. Patients undergoing surgery for cerebellar hemorrhage should have clot specimens sent for histologic examination and have pre- and postcontrast MRIs. Patients not undergoing surgery should have MRIs done after hematoma resolution to rule out underlying tumor.

The COVID-19 pandemic led to rapid expansion of telemedicine services. We surveyed parent/guardians from March 10 to June 29, 2020, in an academic and community pediatric practice, and community pediatric providers from June 5 to July 13, 2020, to better understand their perceptions of telemedicine and compare parent/guardian satisfaction between in-person and telemedicine encounters. Overall patient satisfaction scores were high in both settings and did not differ between in-person and telemedicine visits (community setting: 93.36 ± 12.87 in-person vs. 88.04 ± 22.04 telemedicine; academic setting: 92.25 ± 11.2 vs. 95.37 ± 8.21). Most providers (82.5%) would be willing to use telemedicine in a nonpandemic situation. Telemedicine should remain available for primary care pediatrics during and after resolution of the pandemic.

TPS604 Background: The increased use of neoadjuvant chemotherapy (NCT) has enabled higher rates of breast-conserving surgery (BCS) as well as provided prognostic information for women with breast cancer. High pathological complete response (pCR) rates question the requirement for surgery, with its attendant morbidity. In order to avoid surgery, the ability to predict pCR prior to it must be very high. Trimodality imaging alone is inadequate to predict pCR prior to surgery. We hypothesize that performing core needle biopsy (bx) of the tumor bed in addition to trimodality imaging in pts having had a clinical complete response (cCR) will increase the ability to predict pCR. Utilizing predetermined imaging response criteria of complete or near-complete response coupled with a stereotactic core needle bx of the tumor bed, BR-005 aims to determine the predictive value of imaging followed by tumor bed bx for pCR and demonstrate its reproducibility across a multi-institutional setting. Methods: 175 pts with operable focal or multifocal (T1-T3), stage II/IIIA invasive ductal carcinoma [all receptor subtypes]) will be entered. Pts must have completed a minimum of 8 wks of standard neoadjuvant chemotherapy and achieved a complete or near-complete radiologic tumor response on breast imaging with mammogram, ultrasound, and MRI, and undergo BCS. Following cCR and prior to surgery, pts will undergo a stereotactic-vacuum-assisted breast bx with clip placement. The primary endpoint is the proportion of pts with post-NCT neg image-directed bx who have a pCR. Residual cancer burden (RCB) scores and core bx pathology will be collected along with trimodality imaging data. Evaluation after 135 pts will allow for the possibility of early termination of the study. Results will provide the first step towards a paradigm change in the treatment of breast cancer, enabling a study to assess the criteria for successful avoidance of surgery in pts with high response rates to NCT. Accrual as of 1/19/2018: 13. Support U10CA180868, -180822, UG1CA189867 Clinical trial information: NCT03188393.

OBJECTIVE A fibrous structure located dorsal to the dura at the posterior craniocervical junction stretches horizontally between the bilateral occipital condyles and the upper borders of the C-1 laminae. Partially covered by the occipital bone, this structure is always encountered when the bone is removed from the foramen magnum rim during approaches to the posterior cranial fossa. Although known to surgeons, this structure has not been defined, studied, or named. The most appropriate name for this structure is "the suboccipital ligament," and a detailed rationale for this name is provided. METHODS This 3-year-long study included 10 cadaveric specimens and 39 clinical patients: 31 consecutive surgically treated patients with Chiari Type I malformations (CM-I subgroup) and 8 other patients with posterior fossa pathologies (non-CM-I subgroup). The dimensions were defined, the function of this ligament was hypothesized, size and histological composition were compared between patient subgroups, and its origin and relationship to the surrounding structures were analyzed. Possible statistical differences in the parameters between the 2 groups were also evaluated. RESULTS The suboccipital ligament consists of horizontally oriented hyaline fibers and has a median length of 35 mm, height of 10 mm, and thickness of 0.5 mm. These dimensions are not significantly different between the CM-I and non-CM-I patients. The median age of the patients was 43 years, with CM-I patients being significantly younger (median 35 years) than non-CM-I patients (median 57 years). There was no statistically significant difference in weight, height, and body mass index between patient subgroups. There was no significant correlation between the body mass index or height of the patients and the dimensions of the ligament. No statistically significant differences existed between the subgroups in terms of smoking history, alcohol consumption, and the presence of diabetes mellitus, hypertension, hydrocephalus, or headaches. The ligament tissue in the CM-I patients was disorganized with poorly arranged collagen bands and interspersed adipose tissue. These patients also had more hyalinized fibrosis and showed changes in the direction of fibers, with hyaline nodules ranging from 0 to 2+. The result of the histological evaluation of the suboccipital ligament for hyaline nodules, calcification, and ossification was graded as 2+ if present in 3 or more medium-power magnification fields (MPFs); 1+ if present in 1-2 MPFs; and 0, if present in less than 1 MPF. Histological examination of the ligaments showed structural differences between CM-I and non-CM-I patients, most notably the presence of hyaline nodules and an altered fiber orientation in CM-I patients. CONCLUSIONS The suboccipital ligament extends between the occipital condyle and the superior edge of the C-1 lamina, connecting the contralateral sides, and appears to function as a real ligament. It is ventral to the occipital bone, which covers approximately two-thirds of the height of the ligament and is loosely attached to the dura medially and more firmly laterally. Because of its distinctive anatomy, characteristics, and function, the suboccipital ligament deserves its own uniform designation and name.

Abstract Introduction Lesbian, gay, bisexual, and questioning (LGBQ) adolescents are particularly at risk for suicidal ideation; however, little clinical research is focused on treating this population. Attachment‐based family therapy (ABFT) is among the few empirically supported youth suicide treatments adapted for LGBQ adolescents. The purpose of this exploratory study is to determine the differential treatment effects and rates of change for LGBQ and heterosexual adolescents with depression and suicidal ideation receiving either ABFT or family enhanced nondirective supportive therapy (FE‐NST). Method The sample included 129 adolescents (31% LGBQ), ages 12–18 randomized to the two treatment groups. Multilevel modeling was used to examine individual changes in depression and suicidal ideation over the 16‐week treatment. Results Results revealed that LGBQ adolescents in the ABFT condition showed a greater rate of reduction in depressive symptoms over treatment, slope = −0.94, p &lt; 0.001, than did LGBQ adolescents in the NST condition, slope = −0.41, p = 0.12. Heterosexual adolescents showed symptom reduction in both treatment conditions (ABFT slope = −0.47, p &lt; 0.001; NST slope = −0.79, t (113) = −7.48, p &lt; 0.001). Changes in suicidal ideation were found across time, but not across conditions. Conclusion LGBQ adolescents in the ABFT condition had a sharper decrease in depressive symptoms and better outcomes at week 16.