Efficacy of spironolactone in treating hidradenitis suppurativa in women of childbearing age: a single-center retrospective analysis.

Background: Hidradenitis suppurativa (HS) is a chronic skin disease characterized by recurrent nodules that affect areas with a high density of apocrine sweat glands, such as the axillae and groin. Androgens are implicated in the pathophysiology of HS. Therefore, spironolactone, an antiandrogen therapy, is recommended. However, data on its use in women of childbearing age are limited, especially since its antiandrogenic effects may affect menstruation, fertility, and pubertal development. Objective: To evaluate the efficacy and safety of spironolactone in the treatment of hidradenitis suppurativa in women of childbearing age and to identify factors associated with treatment response. Methods: A retrospective analysis was conducted on female patients aged 12 to 50 with HS treated with spironolactone at Michigan Medicine dermatology clinics from 2000 to 2021. The patients' demographic data, HS characteristics, and spironolactone responses were examined. Statistical assessments were performed to determine the efficacy indicators. Results: Of the 157 patients reviewed, 31 showed an improvement in treatment. Variables such as axillary involvement, previous treatment failures, and use of intralesional steroids were linked to a lack of improvement in spironolactone. Through adjusted multiple logistic regression analysis, a significant association was observed between improvement status and Hurley stage 3 (odds ratio = 0.15 [95% CI: 0.02-0.79], P = .036), suggesting that patients with Hurley stage 3 were 85% less likely to exhibit improvement in spironolactone therapy. Limitations: The study's retrospective nature and reliance on single-center data can limit generalizability. The sample size is limited and therefore affects the study's statistical power. Conclusion: Thus, spironolactone may offer therapeutic benefits for HS in women of childbearing age. However, patients with severe disease (Hurley stage 3) had reduced response rates. Further prospective studies are recommended to validate these findings and determine the most suitable patient profile for spironolactone therapy for HS.

A Post-COVID Population-Based Analysis of Mohs Micrographic Surgeon Distribution in the United States.

BACKGROUND: Policy changes to Mohs micrographic surgery board certification eligibility and population shifts in the wake of the COVID-19 pandemic have significant implications for the accessibility of Mohs micrographic surgeons across the United States. OBJECTIVE: To examine the geographic distribution of micrographic surgery providers considering recent population trends and assess the impact of certification eligibility changes and population shifts on accessibility. METHODS AND MATERIALS: Medicare claims data were utilized to identify micrographic surgery providers. Surgeon densities were calculated per 100,000 people by county and state. Population changes were analyzed using US census data. RESULTS: Practicing micrographic surgeons were concentrated in metropolitan and nonmetropolitan areas. Overall, 80.4% of counties lacked micrographic surgery providers, with rural areas being the most underserved. Population changes varied among states. CONCLUSION: Shifts in micrographic surgery certification requirements, US population distribution, and micrographic surgeon location emphasize challenges in accessibility, especially in rural areas across the United States.

Patient perspectives on topical minoxidil for hair loss: a survey-based study from the University of Michigan Alopecia Clinic.

Topical minoxidil is a widely used therapy for alopecia. Its availability over the counter in the United States makes it easily accessible. Various factors impact whether an individual decides to pursue treatment and/or continue long-term use. Our study aimed to investigate patient awareness, opinions, and hesitations regarding topical minoxidil use for hair loss treatment. The study also aimed to identify information sources influencing these viewpoints. A survey was administered to new patients seeking evaluation for alopecia aged 18 and above at the University of Michigan Alopecia Clinic. Data collection occurred between August 2022 and August 2023. Demographics, patient-reported hair loss diagnosis, history of minoxidil use, opinions on minoxidil, influential information sources, and concerns about minoxidil were collected. A total of 47 surveys were completed, primarily by females (78.7%) ages 18-40 years (44.7%). Respondents were aware of minoxidil (97.9%), with 63.8% reporting they had heard of minoxidil, but had not used it. Medical professionals were the most influential information source (34%), followed by close contacts (17%), internet searches (10.6%), and television (10.6%). Overall, positive opinions on minoxidil were expressed by 51.1%, negative opinions by 31.9%, and neutral opinions by 17%. Most common concerns included the need for continuous use (46.8%), required regular application (31.9%), skepticism about hair regrowth (29.8%), and expense (25.5%). Addressing personalized concerns and tailoring communication based on hair loss type and information sources may lead to more informed decisions and improved adherence. Gauging the opinions of this population provides valuable insights, aiding dermatologists in patient education and counseling strategies.

Ketorolac and bone healing: a review of the basic science and clinical literature.

Although the efficacy of ketorolac in pain management and the short duration of use align well with current clinical practice guidelines, few studies have specifically evaluated the impact of ketorolac on bony union after fracture or surgery. The purpose of this study was to review the current basic science and clinical literature on the use of ketorolac for pain management after fracture and surgery and the subsequent risk of delayed union or nonunion. Animal studies demonstrate a dose-dependent risk of delayed union in rodents treated with high doses of ketorolac for 4 weeks or greater; however, with treatment for 7 days or low doses, there is no evidence of risk of delayed union or nonunion. Current clinical evidence has also shown a dose-dependent increased risk of pseudoarthrosis and nonunion after post-operative ketorolac administration in orthopedic spine surgery. However, other orthopedic subspecialities have not demonstrated increased risk of delayed union or nonunion with the use of peri-operative ketorolac administration. While evidence exists that long-term ketorolac use may represent risks with regard to fracture healing, insufficient evidence currently exists to recommend against short-term ketorolac use that is limited to the peri-operative period. LEVEL OF EVIDENCE V: Narrative Review.

Multiple Eruptive Keratoacanthomas Secondary to Nivolumab Immunotherapy.

Immune checkpoint inhibitors are increasingly being utilized for the treatment of advanced neoplastic disease and have been associated with wide-ranging cutaneous adverse effects. Though exceedingly rare, eruptive keratoacanthomas have been associated with the use of immune checkpoint inhibitors such as pembrolizumab and nivolumab, whose molecular target is the programmed cell death protein 1. Herein, we detail a case of numerous eruptive keratoacanthomas arising in a patient one month after initiation of nivolumab for recurrent metastatic oropharyngeal squamous cell carcinoma. Treatment with multiple rounds of intralesional corticosteroids and a several-month course of oral acitretin resulted in partial improvement. Subsequent treatment with intralesional 5-fluorouracil demonstrated near-complete resolution of the keratoacanthomas without discontinuation of nivolumab. Although eruptive keratoacanthomas secondary to immune checkpoint inhibitors are exceptionally rare, physicians should be aware of this cutaneous adverse effect as their use becomes more widespread.

Management of hepatic caval stenosis and obstruction with modified Gianturco Z-stents.

Hepatic caval stenosis is managed with stenting; however, stent placement can be complicated by migration, which can be life-threatening. The risk of migration can be mitigated by increasing the length of the stent, which increases contact with the vessel wall. We describe the cases of three patients with hepatic caval stenosis treated with two Z-stents sutured together. Each had an uncomplicated postoperative course and demonstrated clinical improvement. The use of sutured Z-stents can increase the stability of the stent and, therefore, decrease the morbidity associated with stent placement for hepatic caval stenosis.

Delayed Onset of Bullous Pemphigoid Secondary to Nivolumab.

The increasing use of immune checkpoint inhibitors, such as nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced neoplastic disease has revealed significant cutaneous immune-related adverse effects. Herein, we report a case of bullous pemphigoid (BP) secondary to nivolumab therapy for recurrent metastatic oropharyngeal squamous cell carcinoma. In this patient, the time to development of BP was three years, which represents the most delayed onset of BP secondary to a PD-1 inhibitor that has been reported in the literature. Symptoms were initially controlled on low-dose oral prednisone but recurred after two years. The patient was subsequently treated with a several-month taper of high-dose oral prednisone, during which he was able to resume nivolumab without recurrence of skin lesions. Although immune checkpoint inhibitor-induced BP remains rare, physicians should be aware of this serious cutaneous immune-related adverse event as the use of this drug class continues to expand.

Patient satisfaction with follow-up after spinal fusion.

Background: Postoperative follow-up visits (PFUs) allow providers to track patient recovery but can be costly to patients. With the advent of the novel coronavirus pandemic, virtual/phone visits have been utilized as an alternative to in-person PFUs. Patients were surveyed to elucidate patient satisfaction with postoperative care in the setting of increased virtual follow-up visits. A prospective survey with retrospective cohort analysis of chart data was conducted to better understand the factors influencing patient satisfaction related to their PFUs after spine fusion with the goal of improving the value of postoperative care. Methods: Adult patients at least 1 year postoperative from cervical or lumbar fusion surgery completed a telephone survey related to their postoperative clinic experience. Medical record data including complications, number of visits and length of follow-up, and presence of phone/virtual visits were abstracted and analyzed. Results: Fifty patients (54% female) were included. Univariate analysis demonstrated no association between satisfaction and patient demographics, rates of complication, mean length or number of PFUs, or incidence of phone/virtual visits. Patients "very satisfied" with their clinic experience were more likely to be "very satisfied" with their outcome (P<0.01), and to feel their concerns were "very well addressed" (P<0.01). Multivariate analysis additionally demonstrated that satisfaction was positively associated with how well patient concerns were addressed (P<0.01) and the incidence of virtual/phone visits (P=0.01), and negatively associated with age (P=0.01) and level of education (P=0.01). Conclusions: After spinal fusion, patient satisfaction is positively related to virtual/phone visits and to how well their concerns are addressed. As long as patient concerns remain adequately addressed, surgeons can eliminate excess PFUs which are not clinically beneficial without adversely impacting patients' postoperative experience.

Preoperative Comorbidities Associated With Early Mortality in Hip Fracture Patients: A Multicenter Study.

OBJECTIVE: Multiple comorbidities in hip fracture patients are associated with increased mortality and complications. The goal of this study was to characterize the relationship between specific patient factors including comorbidities and outcomes in geriatric hip fractures, including length of stay, unplanned ICU admission, discharge disposition, complications, and mortality. METHODS: This is a retrospective review of a trauma database from five Level 1 and Level 2 trauma centers of patients with hip fractures of the femoral neck and intertrochanteric region who underwent treatment using hip pinning, hemiarthroplasty, total hip arthroplasty, cephalomedullary nailing, or dynamic hip screw fixation. Mortality was the primary outcome variable (including in-hospital mortality, 30-day mortality, 60-day mortality, and 90-day mortality). Secondary outcome variables included in-hospital adverse events, unplanned transfer to the ICU, postoperative length of stay, and discharge disposition. Regression analyses were used for evaluation of relationships between comorbidities as independent variables and primary and secondary outcomes as dependent variables. RESULTS: Two thousand three hundred patients were included. The mortality was 1.8%, 7.0%, 10.9%, and 14.1% for in-hospital, 30-day, 60-day, and 90-day mortality, respectively. Diabetes and cognitive impairment present on admission were associated with mortality at all-time intervals. COPD was the only comorbidity that signaled in-hospital adverse event with an odds ratio of 1.67 (P = 0.012). No patient factors, time to surgery, or comorbidities signaled unplanned ICU transfer. Patients with renal failure and COPD had longer hospital stays after surgery. CONCLUSION: Geriatric hip fractures continue to have high short-term morbidity and mortality. Identifying patients with increased odds of early mortality and adverse events can help teams optimize care and outcomes. Patients with diabetes, cognitive impairment, renal failure, and COPD may benefit from continued and improved medical optimization during the perioperative period as well as being more closely managed by a medicine team without delaying time to the operating room.

Impact of Remote Cardiac Monitoring on Greenhouse Gas Emissions: Global Cardiovascular Carbon Footprint Project.

Background: Remote monitoring (RM) of patients with cardiac implantable electronic devices (CIEDs) is efficient and requires fewer resources than conventional monitoring. However, the impact of RM on the carbon footprint (CF) is not known. Objectives: The authors sought to evaluate the reduction in cost and greenhouse gas (GHG) emissions with RM as compared to conventional monitoring of CIEDs and its relevance to CF. Methods: Data were obtained from a third-party RM provider on 32,811 patients from 67 device clinics across the United States. Distance from home address to the device clinic for patients on RM was calculated. Savings in total distance traveled over 2 years was calculated using frequency of follow-up required for the device type. National fuel efficiency data and carbon emission data were obtained from the Bureau of Transportation Statistics and U.S. Environmental Protective Agency, respectively. The average gas price during the study period was obtained from U.S. Energy Information Administration. Results: In the study population, RM resulted in a total saving of 31.7 million travel miles at $3.45 million and reduction of 12,518 metric ton of GHG from gasoline. There was a reduction of 14.2-million-page printouts, $3 million in cost, and 78 tons of GHG. Improvement in workforce efficiency with RM resulted in savings of $3.7 million. There was a net saving of $10.15 million and 12,596 tons of GHG emissions. Conclusions: RM of patients with a CIED resulted in significant reductions in GHG emissions. Efforts to actively promoting RM can result in significant reduction in CF.

Hammer Toe Correction with Proximal Interphalangeal Joint Arthrodesis.

Background: First described by Soule in 1910, arthrodesis of the proximal interphalangeal joint is a common operative method of treatment of hammer toe, or fixed-flexion deformity of the proximal interphalangeal joint of the lesser toes1. The deformity is often caused by imbalance in intrinsic and extrinsic muscle function across the interphalangeal joint and metatarsophalangeal joint2,3, which can be effectively addressed through proximal interphalangeal joint straightening and arthrodesis in conjunction with soft-tissue balancing of the metatarsophalangeal joint. Description: Following longitudinal skin incision over the joint, a transverse extensor tenotomy and capsulotomy reveal the proximal interphalangeal joint and provide appropriate exposure of the head of the proximal phalanx. With the soft tissues protected, the proximal and middle phalanges undergo resection of the articular surfaces to allow osseous apposition. This step can be performed with a rongeur sagittal saw or with osteotomes4,5. The head of the proximal phalanx is resected proximal to the head-neck junction, and the proximal portion of the middle phalanx is removed to expose the subchondral bone. Often, there is a dorsal contracture of the metatarsophalangeal joint that is elevating the toe, which is addressed with use of a longitudinal incision over the metatarsophalangeal joint, a Z-lengthening of the long extensor tendon to the toe, and a subsequent capsulectomy. If there is an angular component to the deformity, the collateral ligaments are released from the metatarsal neck, and the toe can be balanced. If there is residual subluxation of the joint that is incompletely corrected by soft-tissue procedures, a metatarsal osteotomy should be considered. Fixation is then performed with use of a smooth Kirschner wire. The wire is inserted from the middle phalanx out the tip of the toe and subsequently inserted retrograde across the proximal interphalangeal joint, often into the metatarsal head and neck, holding the metatarsophalangeal joint in appropriate position. This step can also be completed with use of novel methods including screws, bioabsorbable pins, or intramedullary implants6-8. Alternatives: Nonoperative treatments for hammer toe deformity are generally pursued prior to surgery and include shoe modifications such as a wide toe-box, soft uppers, and padding of osseous prominences3,9,10. Alternative surgical treatments include proximal interphalangeal arthroplasty, soft-tissue capsulotomy, extensor tendon lengthening, and amputation11. Rationale: Although nonoperative treatment can alleviate symptoms temporarily, surgical treatment is often necessary for definitive treatment of hammer toe. Soft-tissue procedures such as tendon lengthening can provide a stabilizing benefit, but the degenerative bone changes associated with hammer toe are better addressed with use of resection of the proximal interphalangeal joint3. Arthroplasty allows for some retained motion; however, this motion may lead to deformity and pain over time2. Arthrodesis provides less painful and more reliable fixation as well as equal outcomes compared with other operative techniques. Patient satisfaction rates after this procedure are high, with pain relief in up to 92% of patients and rare complications7-12. Expected Outcomes: Outcomes of this procedure are favorable, with rates of osseous fusion ranging from 83% to 98%2,4,11,13. Patient satisfaction rates range from 83% to 100%4,11. Historically, patients have expressed dissatisfaction with pain and the appearance of exposed hardware, but novel internal fixative devices provide a more natural appearance to the toe without the need for secondary surgical procedures for pin removal8,14. Patients are often able to return to regular activity at 6 weeks postoperatively; however, there may be persistent pain or swelling in the toe. Wide shoes and activity modifications are frequently continued for several more weeks postoperatively, and some patients may benefit from formal physical therapy and at-home rehabilitation. Important Tips: Avoid vascular compromise by ensuring adequate resection of bone at the proximal interphalangeal joint.A longitudinal incision across the joint provides greater exposure but can lead to scar contracture that elevates the toe. One alternative is the use of an elliptically shaped incision over the proximal interphalangeal joint, which can improve cosmesis but does restrict exposure.Excessive osseous resection can lead to a cosmetically undesirable short toe.If using an implant for the arthrodesis, ensure the implant is not too big for the toe. Most implants are too big for fifth-toe arthrodesis.In toes with severe deformity, fixation with a Kirschner wire is often preferred because excessive stretching of the neurovascular bundle can lead to toe compromise and if Kirschner wire is used the pin can easily be removed at bedside.For flexible deformities, a nonoperative approach is recommended, such as stretching exercises, shoe-wear modifications, and metatarsal pads. A tenotomy of the flexor digitorum brevis is a soft-tissue procedure that can be considered if nonoperative treatment is insufficient to correct the deformity. If flexor digitorum brevis tenotomy does not adequately treat proximal interphalangeal joint deformity, a proximal interphalangeal joint arthrodesis should be the next step. Acronyms and Abbreviations: MTP = metatarsophalangealPIP = proximal interphalangeal.

Nutritionist Referral Modestly Improves Weight Loss and Increases Surgery Rate in Obese Patients Seeking Total Joint Arthroplasty.

Background: Obesity is associated with increased complications after total joint arthroplasty (TJA), leading some surgeons to recommend nutrition counseling and weight loss. We aim to evaluate the effect of preoperative nutritionist referral on weight loss and likelihood of surgery in obese patients seeking primary TJA. Methods: A retrospective cohort of patients seeking primary TJA who were referred to a licensed nutritionist for weight loss was matched by age, sex, and body mass index (BMI) to an unreferred control group. BMI change was compared between groups up to 1 year of follow-up. Differences were determined using 2-tailed t-tests and chi-squared tests with a significance cutoff of P < .05. Results: A total of 274 referred patients and 174 controls were included in our analysis. Patients who were referred to a nutritionist achieved significantly greater average BMI change (-1.5 kg/m2) than controls (-0.8 kg/m2) by 6 months after first contact (P = .01) although significance was lost at 1 year after first contact (P = .21). Thirty-eight percent of referred patients went on to TJA compared with 28% of controls (P < .01). Conclusions: Referral to a licensed nutritionist modestly improves early weight loss and is associated with a higher rate of surgery in obese patients seeking primary TJA.

Optimal timing of referral for nerve transfer surgery for postoperative C5 palsy.

OBJECTIVE: Cervical nerve 5 palsy can occur following surgery for cervical spine pathology. The prognosis of C5 palsy is generally favorable, and most patients recover useful function. However, some patients do not recover useful strength. Nerve transfers are a potential effective treatment of postoperative severe C5 palsy. This study aimed to further delineate the natural history of recovery from postoperative C5 palsy, determine whether lack of recovery at specific time points predicts poor recovery prognosis, and thereby determine a reasonable time point for referral to a complex peripheral nerve specialist. METHODS: The authors conducted a retrospective review of 72 patients who underwent surgery for cervical spondylosis and stenosis complicated by C5 palsy. Medical Research Council (MRC) motor strength grades were recorded preoperatively; immediately postoperatively; at discharge; and at 2 weeks, 3 months, 6 months, and 12 months postoperatively. Univariate and multivariate logistic regression models were used to identify demographic and clinical risk factors associated with recovery of useful strength after severe C5 palsy. RESULTS: The mean patient age was 62.5 years, and 36.1% of patients were female. Thirty patients (41.7%) experienced severe C5 palsy with less than antigravity strength (MRC grade 2 or less) at discharge. Twenty-one (70%) of these patients recovered useful strength (MRC grade 3 or greater) at 12 months postoperatively, and 9 patients (30%) did not recover useful strength at 12 months. Of those patients with persistent severe C5 palsy at 3 months postoperatively, 50% recovered useful strength at 12 months. Of those patients with persistent severe C5 palsy at 6 months postoperatively, 25% recovered useful strength at 12 months. No patient with MRC grade 0 or 1 strength at 6 months postoperatively recovered useful strength. A history of diabetes was associated with the occurrence of severe C5 palsy. On multivariate analysis, female sex was associated with recovery of useful strength. CONCLUSIONS: Most patients with severe C5 palsy recover useful strength in their C5 myotome within 12 months of onset. However, at 3 months postoperatively, patients with persistent severe C5 palsy had only a 50% chance of recovering useful strength by 12 months. Lack of recovery of useful strength at 3 months postoperatively is a reasonable time point for referral to a complex peripheral nerve center to establish care and to determine candidacy for nerve transfer surgery if severe C5 palsy persists.

A Signature That May Be Predictive of Early Versus Late Recurrence After Radiation Treatment for Breast Cancer That May Inform the Biology of Early, Aggressive Recurrences.

PURPOSE: Unmet clinical needs in breast cancer (BC) management include the identification of patients at high risk of local failure despite adjuvant radiation and an understanding of the biology of these recurrences. We previously reported a radiation response signature and here extend those studies to identify a signature predictive of recurrence timing (before or after 3 years). METHODS AND MATERIALS: Two independent patient cohorts were used. The training cohort included 119 patients with in-breast tumor recurrence (343 total), and the validation testing cohort had 16 patients with recurrences (112 total). All patients received radiation treatment after breast-conserving surgery. Initial feature selection used Spearman rank correlation, and a linear model was trained and locked before testing and validation. Cox regression was used for univariate and multivariable analyses (UVA and MVA, respectively). Biologically related concepts were identified using gene set enrichment analysis. RESULTS: Spearman correlation identified 485 genes whose expression was significantly associated with recurrence time (early vs late). Feature reduction further refined the list to 41 genes retained within the signature. In training, the correlation of score to recurrence time was 0.85 (P value < 1.3 × 10-31) with an area under the curve (AUC) of 0.91. Application of this early versus late signature to an independent BC testing and validation set accurately identified patients with early versus late recurrences (Spearman correlation = 0.75, P value = .001, AUC = 0.92, sensitivity = 0.75, specificity = 1.0, positive predictive value = 1.0, and negative predictive value = 0.8). Unique associations of breast cancer intrinsic subtype to timing of local recurrence were identified. In UVA and MVA the early versus late recurrence signature remained the most significant factor associated with recurrence. Gene set enrichment analysis identified proliferation and epidermal growth factor receptor concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences demonstrated novel effects on proliferation and clonogenic survival, respectively. CONCLUSIONS: We report a breast cancer gene signature that may identify patients unlikely to respond to adjuvant radiation and may be used to predict timing of recurrences with implications for potential treatment intensification and duration of follow-up for women with breast cancer treated with radiation.

Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells.

Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15-35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 µM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20-1.89 in models of TNBC with high AR expression. AR-negative (AR-) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 µM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an in vivo AR+ TNBC xenograft model where there was a significant reduction in tumor volume and a delay to tumor doubling and tripling times in mice treated with seviteronel and radiation. Following combination treatment with seviteronel and radiation, increased binding of AR occurred at DNA damage response genes, including genes involved both in homologous recombination and non-homologous end joining. This trend was not observed with combination treatment of enzalutamide and RT, suggesting that seviteronel may have a different mechanism of radiosensitization compared to other AR inhibitors. Enzalutamide and seviteronel treatment also had different effects on AR and AR target genes as measured by immunoblot and qPCR. These results implicate AR as a mediator of radioresistance in AR+ TNBC models and support the use of seviteronel as a radiosensitizing agent in AR+ TNBC.

TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination.

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.

PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation.

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC50 > 10 µmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on BRCA1 mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model in vivo, the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT ± PARPi in women with IBC (SWOG 1706, NCT03598257).