Citations

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.

Abstract Background: Older adults with acute myeloid leukemia (AML) represent a vulnerable population in whom disease-based and clinical risk factors, patient goals, prognosis, and practitioner- and patient-perceived treatment risks and benefits influence treatment recommendations. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about management of AML in older adults. Methods: ASH formed a multidisciplinary guideline panel that included specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology, as well as patients. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline-development process, including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes according to their importance to patients, as judged by the panel. The panel used the GRADE approach, including GRADE’s Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 6 critical questions in managing older adults with AML, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management, the intensity of therapy, the role and duration of postremission therapy, combination vs monotherapy for induction and beyond, duration of less-intensive therapy, and the role of transfusion support for patients no longer receiving antileukemic therapy. Conclusions: Treatment is recommended over best supportive management. More-intensive therapy is recommended over less-intensive therapy when deemed tolerable. However, these recommendations are guided by the principle that throughout a patient’s disease course, optimal care involves ongoing discussions between clinicians and patients, continuously addressing goals of care and the relative risk-benefit balance of treatment.

Abstract Introduction Calcinosis cutis is a condition characterized by pathologic calcium deposition into superficial dermal skin layers. It is often associated with an autoimmune disease. However, it may also occur after minor localized trauma and infection. Description of Problem We report a case of lumbar epidural placement of labor analgesia in a parturient with severe dystrophic calcinosis cutis without apparent complications. Clinical Solution We recommend fastidious optimization of epidural placement conditions for all patients who may be at high risk for neuraxial anesthesia, including consideration of ultrasound use, use of an experienced anesthesia provider for neuraxial placement, and placement in early labor. Additionally, judicious discussion of risks, benefits, and alternatives when obtaining informed consent is critical, ideally with the patient identified for a comprehensive visit in a preoperative obstetric anesthesia clinic before delivery.

Abstract Background Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. Methods A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Results Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Conclusions Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

OBJECTIVE The goal of this study was to compare different recognized definitions of osteoporosis in patients with degenerative lumbar spine pathology undergoing elective spinal fusion surgery to determine which patient population should be considered for preoperative optimization. METHODS A retrospective review of patients in whom lumbar spine surgery was planned at 2 academic medical centers was performed, and the rate of osteoporosis was compared based on different recognized definitions. Assessments were made based on dual-energy x-ray absorptiometry (DXA), CT Hounsfield units (HU), trabecular bone score (TBS), and fracture risk assessment tool (FRAX). The rate of osteoporosis was compared based on different definitions: 1) the WHO definition (T-score ≤ −2.5) at total hip or spine; 2) CT HU of < 110; 3) National Bone Health Alliance (NBHA) guidelines; and 4) “expanded spine” criteria, which includes patients meeting NBHA criteria and/or HU < 110, and/or “degraded” TBS in the setting of an osteopenic T-score. Inclusion criteria were adult patients with a DXA scan of the total hip and/or spine performed within 1 year and a lumbar spine CT scan within 6 months of the physician visit. RESULTS Two hundred forty-four patients were included. The mean age was 68.3 years, with 70.5% female, 96.7% Caucasian, and the mean BMI was 28.8. Fracture history was reported in 53.8% of patients. The proportion of patients identified with osteoporosis on DXA, HUs, NBHA guidelines, and the authors’ proposed “expanded spine” criteria was 25.4%, 36.5%, 75%, and 81.9%, respectively. Of the patients not identified with osteoporosis on DXA, 31.3% had osteoporosis based on HU, 55.1% had osteoporosis with NBHA, and 70.4% had osteoporosis with expanded spine criteria (p < 0.05), with poor correlations among the different assessment tools. CONCLUSIONS Limitations in the use of DXA T-scores alone to diagnose osteoporosis in patients with lumbar spondylosis has prompted interest in additional methods of evaluating bone health in the spine, such as CT HU, TBS, and FRAX, to inform guidelines that aim to reduce fracture risk. However, no current osteoporosis assessment was developed with a focus on improving outcomes in spinal surgery. Therefore, the authors propose an expanded spine definition for osteoporosis to identify a more comprehensive cohort of patients with potential poor bone health who could be considered for preoperative optimization, although further study is needed to validate these results in terms of clinical outcomes.

Objectives: Anterior cruciate ligament reconstruction (ACLR) remains one of the most readiness-impairing surgical conditions treated in the US Military. Greater time from the index injury to surgical management (ACLR) unnecessarily prolongs the total time of limited duty. Additionally, prolonged wait times from the index injury to ACLR may increase the patient’s likelihood of sustaining concomitant or secondary intraarticular pathologies (e.g., cartilage and meniscus damage). The optimal timing for surgical reconstruction following ACL injury is debated. The purpose of this study was to determine the impact of prolonged time from injury to surgery on medical separation within five years of primary ACLR. We hypothesized that longer durations from injury to primary ACLR would be associated with greater medical separation risk within five years following surgery. Methods: We conducted a retrospective database review using data from the Military Health System Data Repository (MDR) of primary ACLR without and with concomitant procedures (meniscus [M] and/or cartilage [C]) performed within Military Treatment Facilities (MTF) from fiscal year 2009 to and/or cartilage [C]) performed within Military Treatment Facilities (MTF) from fiscal year 2009 to 2011. At the time of the ACLR, ADSMs had to be continuously enrolled for two years prior to the surgery with no history of knee surgeries in direct care (i.e., MTFs) or purchased care to ensure a higher likelihood of the index event being a primary ACLR and not an ACLR revision. A total 2,809 active duty service members were included with primary ACLR. The MDR was queried for baseline demographic, military service, and surgical information at the time of ACLR. Duty status at the time of the ACLR and cause of separation up to five years after primary ACLR were abstracted. The time from the index injury diagnosis to the primary ACLR was calculated and grouped as follows: Acute = 0-42 days, Subacute = 43-91 days, Delayed = 92-179 days, Chronic ≥ 180 days. Kaplan-Meier survivability curves were estimated and evaluated with Log-rank. Cox Proportional Hazard Models calculated Hazard Ratios (HR) with 95% confidence intervals (95% CI) to identify time from injury to surgery, demographic, and military status factors that influenced medical separation risk for patients with primary ACLR (ACLR, ACLR+M, ACLR+C, ACLR+M+C). Results: The index surgical events were categorized by isolated ACLR (48%), ACLR+M (42%), ACLR+C (5%), and ACLR+M+C (4%). Overall, the time from diagnosis to ACLR was approximately equivalent across all time categories: Acute (19%), Subacute (31%), Delayed (23%), and Chronic (25%). The probability of medical separation 5 years following primary ACLR (ACLR, ACLR+M, ACLR+C, ACLR+M+C) was highest for the delayed [92-179 days] group (17%) and lowest for the acute [0-42 days] group (12%). Patients in the delayed group were over 51% more likely to medically separate in the 5 years following the primary ACLR than those who were treated within 42 days from injury (acute group). The difference between the acute group and subacute or chronic was not statistically significant. Those in infantry and combat support related military occupation classifications were 27% more likely to medically separate. Service members in the Army were more than 4.5 times more likely to medically separate compared to those in the Air Force. Smoking and BMI over 29 also increased the risk of medical separation within 5 years by 42% and 91%, respectively. The type of injury at the index event (ACLR, ACLR+M, ACLR+C, ACLR+M+C) did not significantly influence the likelihood of medical separation risk. Conclusion: Delay in treatment from injury to primary ACLR increases the number of limited duty days, effects medical readiness of ADSM, and military retention rates post ACLR. Specifically, when primary ACLR is delayed 3 to 6 months from injury, ADSM have a 51% increased likelihood of military medical separation risk in the 5 years following the ACLR than if they would have been treated within 41 days of injury. Early recognition of ACL tears as well as availability of surgeons and Operative Rooms (ORs) should be evaluated to determine their contribution to the delay in ACLR in the MHS.

Study Design: Retrospective cohort study. Objectives: Studies in the lumbar spine suggest a correlation between sarcopenia and worse patient outcomes. The purpose of this study was to determine whether paraspinal Goutalier grade of fat degeneration is associated with patient-reported outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF). Methods: We performed a retrospective review of a prospective cohort of patients undergoing 1- to 3-level ACDF at a single institution between the years 2011-2014. We utilized preoperative magnetic resonance images to classify patients into Goutalier grades. Patient-reported outcomes, including Neck Disability Index (NDI), RAND score, and EQ-5D score were collected and analyzed according to patients’ Goutalier grade. Results: We identified 69 patients for inclusion. A total of 29 patients were classified as Goutalier 0-1 (group 1), 29 were Goutalier 1.5-2 (group 2), and 11 were Goutalier 2.5-4.0 (group 3). All Goutalier groups experienced significant improvement in all 3 outcome scores. Average postoperative NDI scores were 25.3 in group 1, 13.9 in group 2, and 25.1 in group 3 ( P = .02). The percentage of patients in each group reporting worse disability after surgery was 17.2%, 3.3%, and 9.1%, respectively ( P = .05). No statistically significant difference was seen between groups in postoperative EQ-5D ( P = .07) or RAND scores ( P > .05). Conclusions: The present study is the first to assess the association between cervical paraspinal muscle Goutalier grade and patient-reported outcomes following ACDF. Based on our study, patients with worse cervical paraspinal degeneration may benefit from improved symptom relief in comparison to patients with a lesser degree of degeneration undergoing ACDF.