The impact of external beam radiation therapy on shoulder surgical outcomes: a case series study.

HYPOTHESIS: External beam radiation therapy (XRT) is a commonly used treatment adjunct in patients with breast cancer and is known to cause soft tissue dysfunction. However, data on XRT as a preoperative risk factor for shoulder surgery is limited. The purpose of this study was to assess whether prior history of breast cancer treated with XRT has an impact on surgical complications or outcomes. We hypothesize that patients treated with XRT will have a higher rate of surgical complications and lower outcomes. METHODS: A 20-year retrospective chart review across a large, academic health care system was performed. Inclusion criterion comprised any patient with history of breast cancer of the upper-outer or axillary region treated with XRT. Patients also must have undergone a surgical procedure to the ipsilateral shoulder with at least 1-year postoperative follow-up. Patients were stratified by demographics, hand dominance, and surgery type. Postoperative outcomes including range of motion (ROM) and visual analog scale (VAS) scores for pain were also collected. RESULTS: Eighteen patients were identified (100% female) with an average age of 66.3 years (standard deviation 10.5 years). Ten shoulders underwent rotator cuff repair (RCR), 4 total shoulder arthroplasty (TSA), 3 reverse shoulder arthroplasty (RSA), and 1 arthroscopic superior labrum anterior to posterior (SLAP) repair. Four patients treated with RCR (40%) experienced postoperative complications related to their procedure. These included scapular winging, adhesive capsulitis, stiffness, and one retear. Two patients treated with shoulder arthroplasty (28.6%) experienced postoperative complications that included lymphedema and periprosthetic fracture following a mechanical fall in one RSA patient and periprosthetic infection in a TSA patient. ROM across all groups improved, most significantly in forward flexion and internal rotation among RCR patients (P < .001). Furthermore, a statistically significant improvement in VAS scores was achieved in each group (6.2 ± 2.14 preoperation, 1.06 ± 1.75 postoperation; P < .001). CONCLUSION: When compared to national averages, complication rates in our cohort were higher (40% vs. 10%-17% in RCR patients and 28.6% vs. 4%-14% in arthroplasty patients). On further scrutiny, many of these complications were independent of a history of XRT and many resolved with appropriate therapy. Most importantly, functional outcomes as measured by ROM and pain scores showed appropriate improvement consistent with normal populations without history of XRT. Thus, our results suggest that performing shoulder surgery after ipsilateral XRT for breast cancer is likely safe and may offer improved pain and ROM compared to forgoing surgery without necessarily increasing the risk for postoperative complication.

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation.

Iron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.

MicroRNA-135a regulates NHE9 to inhibit proliferation and migration of glioblastoma cells.

BACKGROUND: Glioblastoma multiformae (GBM) is the most aggressive type of malignant brain tumor with complex molecular profile. Overexpression of Na+/H+ Exchanger isoform 9 (NHE9) promotes tumor progression and correlates positively with insensitivity to radiochemotherapy and poor prognosis. However, molecular mechanisms responsible for increase in NHE9 levels beyond a critical threshold have not been identified. METHODS: Bioinformatics analysis, luciferase reporter assays, real-time PCR and western blotting were conducted to examine the expression profiles and identify microRNAs (miRNA) that target NHE9. Cell proliferation and migration assays were conducted in U87 glioblastoma cells to determine the consequence of miRNA mediated targeting of NHE9. Endosomal pH measurements, immunofluorescence microscopy and surface biotinylation experiments were conducted to characterize the mechanistic basis of regulation. RESULTS: We show that microRNA 135a (miR-135a) targets NHE9 to downregulate its expression in U87 cells. MiR-135a levels are significantly lower in glioblastoma cells compared to normal brain tissue. Downregulation of NHE9 expression by miR-135a affects proliferative and migratory capacity of U87 cells. Selectively increasing NHE9 expression in these cells restored their ability to proliferate and migrate. We demonstrate that miR-135a takes a two-pronged approach affecting epidermal growth factor receptors (EGFRs) to suppress tumor cell growth and migration. EGFR activity is a potent stimulator of oncogenic signaling. While miR-135a targets EGFR transcripts to decrease the total number of receptors made, by targeting NHE9 it routes the few EGFRs made away from the plasma membrane to dampen oncogenic signaling. NHE9 is localized to sorting endosomes in glioblastoma cells where it alkalinizes the endosome lumen by leaking protons. Downregulation of NHE9 expression by miR-135a acidifies sorting endosomes limiting EGFR trafficking to the glioblastoma cell membrane. CONCLUSIONS: We propose downregulation of miR-135a as a potential mechanism underlying the high NHE9 expression observed in subset of glioblastomas. Future studies should explore miR-135a as a potential therapeutic for glioblastomas with NHE9 overexpression.

Anterior Cruciate Ligament Reconstruction Surgery Outcomes: A Comparison Between Patients Who Underwent the Procedure During the COVID-19 Pandemic and a Cohort Treated Prior to the Pandemic.

Background and objective During the coronavirus disease 2019 (COVID-19) pandemic, many elective orthopedic surgeries, including anterior cruciate ligament reconstruction (ACLR), were temporarily postponed. The purpose of this study was to compare the outcomes of ACLR in patients who underwent surgery during the COVID-19 pandemic with those in a cohort treated before the pandemic. Materials and methods This retrospective review compared patients who underwent primary ACLR during two periods: March to June 2020 (the pandemic group) and January to December 2018 (the pre-pandemic group). Matched cohorts (1:1) were created using propensity matching. Time from injury-to-first visit, injury-to-surgery, and first visit-to-surgery were calculated. Subjective and objective outcomes, minimal clinically important difference (MCID) achievement, and complication rates were recorded for up to two years postoperatively. Statistical analysis included 𝛘2 or Fisher's exact tests for categorical data, and t- or Wilcoxon signed-rank tests for continuous data with significance set at P < 0.05. Results The pandemic and pre-pandemic groups consisted of 33 and 217 patients, respectively. Matched cohorts consisted of 33 patients each. The time from injury-to-surgery and the first visit-to-surgery was prolonged in the pandemic group. When unmatched, visual analog scale (VAS) scores at three months postoperatively and Patient-Reported Outcomes Measurement Information System (PROMIS)-pain interference (PI) at six months postoperatively and at the final follow-up were higher in the pandemic group. When matched, PROMIS-PI at six months postoperatively was higher in the pandemic group, and VAS scores at one year postoperatively were higher in the pre-pandemic group. MCID achievement and complication rates did not significantly differ between the groups. Conclusions ACLR procedures were significantly delayed in the early months of the COVID-19 pandemic. While patients treated before and during the pandemic experienced varying pain levels during recovery, their functional outcomes, MCID achievement, and complication rates did not differ significantly.

Time-to-Surgery and Short-Term Outcomes of Trimalleolar Ankle Fracture During the COVID-19 Pandemic.

Introduction During the coronavirus disease 2019 (COVID-19) pandemic, a rapid and significant transformation in patient management occurred across the healthcare system in order to mitigate the spread of the disease and address resource constraints. Numerous surgical cases were either postponed or canceled, permitting only the most critical and emergent cases to proceed. The impact of these modifications on patient outcomes remains uncertain. The purpose of this study was to compare time-to-surgery and outcomes of open reduction and internal fixation for trimalleolar ankle fractures during the pandemic to a pre-pandemic group. We hypothesized that the pandemic group would have a prolonged time-to-surgery and worse outcomes compared to the pre-pandemic cohort. Materials and methods This retrospective cohort study was conducted within a single healthcare system, examining the treatment of trimalleolar ankle fractures during two distinct periods: April to July 2020 (COVID-19 group) and January to December 2018 (2018 group). Cases were identified using Current Procedural Terminology code 27822. Information on demographics, fracture characteristics, and outcomes was obtained through chart review. Outcomes analyzed included time-to-surgery, mean visual analog scale scores, ankle strength and range of motion, and complications. Results COVID-19 and 2018 groups consisted of 32 and 100 patients, respectively. No significant difference was observed in group demographics and comorbidities (p > 0.05). Fracture characteristics were similar between groups apart from tibiofibular syndesmosis injury, 62.5% (20/32) in COVID-19 vs 42.0% (42/100) in 2018 (p = 0.03). Time-to-surgery was not significantly different between the two groups (8.84 ± 6.78 days in COVID-19 vs 8.61 ± 6.02 days in 2018, p = 0.85). Mean visual analog scale scores, ankle strength, and ankle range of motion in plantarflexion were not significantly different between the two groups at three and six months postoperatively (p > 0.05). Dorsiflexion was significantly higher in the COVID-19 group at three months (p = 0.03), but not six months (p = 0.94) postoperatively. No significant difference in postoperative complication was seen between groups, 25.0% (8/32) COVID-19 group compared to 15.0% (15/100) 2018 group (p = 0.11). Conclusions Patients who underwent surgery during the early months of the COVID-19 pandemic did not experience prolonged time-to-surgery and had similar outcomes compared to patients treated prior to the pandemic.