Unique genomic alterations in the circulating tumor DNA of patients with solid tumors brain metastases.

Background: Although serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in 3 groups: Isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs. Methods: Patients with a Guardant360 ctDNA profile with (n = 253) and without BrMs (n = 449) from the Duke Molecular Registry between January 2014 and December 2020 were identified. Actionable alterations were defined as FDA-recognized or standard-of-care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection. Results: Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC; 12.0%) and non-small cell lung cancer (NSCLC; 76.4%) were the most common tumor types. ESR1 (60% vs 25%, P < .001) and BRCA2 (17% vs 5%, P = .022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, P = .08) and in patients with BrMs (36% vs 17%, P < .001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations. Conclusions: This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.

Use, access, and initial outcomes of off-label ivosidenib in patients with IDH1 mutant glioma.

Background: Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Methods: Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. Results: The cohort age range was 21-74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Conclusions: Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.

Radical hysterectomy case volume and cervical cancer treatment in the era of COVID-19: A multi-site analysis of National Cancer Institute-designated Comprehensive Cancer Centers.

OBJECTIVE: To compare radical hysterectomy case volume, cancer stage, and biopsy-to-treatment time of invasive cervical cancer diagnosed before and after onset of the COVID-19 pandemic. METHODS: In a multi-institution retrospective cohort study conducted at 6 large, geographically diverse National Cancer Institute-designated cancer centers, patients treated for newly diagnosed invasive cervical cancer were classified into 2 temporal cohorts based on date of first gynecologic oncology encounter: (1) Pre-Pandemic: 3/1/2018-2/28/2020; (2) Pandemic & Recovery: 4/1/2020-12/31/2021. The primary outcome was total monthly radical hysterectomy case volume. Secondary outcomes were stage at diagnosis and diagnosis-to-treatment time. Statistical analyses used chi-squared and two sample t-tests. RESULTS: Between 3/1/2018-12/31/2021, 561 patients were diagnosed with cervical cancer. The Pre-Pandemic and Pandemic & Recovery cohorts had similar age, race, ethnicity, smoking status, and Body Mass Index (BMI). During Pandemic & Recovery, the mean monthly radical hysterectomy case volume decreased from 7[SD 2.8] to 5[SD 2.0] (p = 0.001), the proportion of patients diagnosed with Stage I disease dropped from 278/561 (49.5%) to 155/381 (40.7%), and diagnosis of stage II-IV disease increased from 281/561 (50.1%) to 224/381 (58.8%). Primary surgical management was less frequent (38.3% Pandemic & Recovery versus 46.7% Pre-Pandemic, p = 0.013) and fewer surgically-treated patients received surgery within 6 weeks of diagnosis (27.4% versus 38.9%; p = 0.025). CONCLUSIONS: Lower radical hysterectomy case volume, a shift to higher cervical cancer stage, and delay in surgical therapy were observed across the United States following the COVID-19 outbreak. Decreased surgical volume may result from lower detection of early-stage disease or other factors.

Understanding the spectrum of malignant bowel obstructions in gynecologic cancers and the application of the Henry score.

OBJECTIVE: Malignancy-associated bowel obstruction (MBO) is a potential sequela of advanced gynecologic cancers, adversely impacting both quality of life and prognosis. The Henry score (HS) was developed in a gastrointestinal cancer-predominant population to predict 30-day mortality. We aim to characterize MBO in gynecologic cancers and assess the utility of the HS in this population. METHODS: This is a retrospective review of patients with gynecologic cancer and MBO admitted to a single academic institution from 2016 to 2021. The primary outcome is to characterize malignant small and large bowel obstructions in primary and recurrent gynecologic cancer using readmission and mortality rates. Secondary outcomes are to assess the Henry score and inpatient MBO management. RESULTS: 179 patients totaling 269 were admissions identified, most commonly affecting patients with ovarian cancer. The majority (89.4%) were managed non-operatively while 10.6% were managed surgically. No significant differences were observed in survival for medical versus surgical management. Thirty-day mortality increased with increasing HS (0%, 0-1; 14.3%, 2-3; 40.9%, 4-5). Over 1/3 (34.1%) of patients were readmitted for recurrent or persistent MBO. Goals of care conversations were documented for 56.8% of patients with HS 4-5. Mortality rates across the entire cohort were high-20.1% and 60.9% had died by 1 and 6 months, respectively. CONCLUSIONS: Survival rates following an initial MBO admission are poor. The HS has utility in gynecologic cancers for assessing 30-day mortality and may be a useful tool to aid in the management and counseling of patients with gynecologic cancer and MBO.

Erratum to "E.C. Lerner, E.S. Srinivasan, G. Broadwater, et al. Factors Associated With New-Onset Seizures Following Stereotactic Radiosurgery for Newly Diagnosed Brain Metastases. Adv Radiat Oncol. 2022;7:101054."

[This corrects the article DOI: 10.1016/j.adro.2022.101054.].

Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer.

PURPOSE: Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. METHODS: A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). RESULTS: In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4 m) compared to those with progressive or stable/responding ECD (48.8 m and 71.5 m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9 m) versus stable/responding (36.6 m) or isolated intracranial relapse (28.4 m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). CONCLUSION: OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

Factors Associated With New-Onset Seizures Following Stereotactic Radiosurgery for Newly Diagnosed Brain Metastases.

Purpose: Stereotactic radiosurgery (SRS) is a highly effective therapy for newly diagnosed brain metastases. Prophylactic antiepileptic drugs are no longer routinely used in current SRS practice, owing to a perceived low overall frequency of new-onset seizures and potential side effects of medications. It is nonetheless desirable to prevent unwanted side effects following SRS. Risk factors for new-onset seizures after SRS have not been well established. As such, we aimed to characterize variables associated with increased seizure risk. Methods and Materials: Patients treated with SRS for newly diagnosed brain metastases between 2013 and 2016 were retrospectively reviewed at a single institution. Data on baseline demographics, radiation parameters, and clinical courses were collected. Results: The cohort consisted of 305 patients treated with SRS without prior seizure history. Median age and baseline Karnofsky Performance Scale score were 64 years (interquartile range, 55-70) and 80 (interquartile range, 80-90), respectively. Twenty-six (8.5%) patients developed new-onset seizures within 3 months of SRS. There was no association between new-onset seizures and median baseline Karnofsky Performance Scale score, prior resection, or prior whole brain radiation therapy. There were significant differences in the combined total irradiated volume (12.5 vs 3.7 cm3, P < .001), maximum single lesion volume (8.8 vs 2.8 cm3, P = .003), lesion diameter (3.2 vs 2.0 cm, P = .003), and number of lesions treated (3 vs 1, P = .018) between patients with and without new-onset seizures, respectively. On multivariate logistic regression, total irradiated volume (odds ratio, 1.09 for every 1-cm1 increase in total volume; confidence interval, 1.02-1.17; P = .016) and pre-SRS neurologic symptoms (odds ratio, 3.08; 95% confidence interval, 1.19-7.99; P = .020) were both significantly correlated with odds of seizures following SRS. Conclusions: Our data suggest that larger total treatment volume and the presence of focal neurologic deficits at presentation are associated with new-onset seizures within 3 months of SRS. High-risk patients undergoing SRS may benefit from counseling or prophylactic antiseizure therapy.

Which Factors Are Important to Women When Choosing a Breast Reconstruction Surgeon?

BACKGROUND: Women undergoing breast reconstruction often research their health care provider options. The authors studied which factors may influence how a woman selects a plastic surgeon for breast reconstruction surgery. METHODS: An online survey was distributed by means of Amazon Mechanical Turk (MTurk; Amazon Web Services, Inc., Seattle, Wash.) to 1025 adult women. Participants were asked to imagine a scenario in which they had breast cancer, needed to undergo mastectomy, and were choosing a reconstructive surgeon. They were then asked to rank factors influencing this decision on a 1 to 7 Likert scale. Two-sample t tests were used to compare Likert scores between dichotomized categories based on participant characteristics. RESULTS: Women assigned the highest scores [mean (standard deviation)] to online reviews on Vitals or WebMD [6.1 (1.2)], years of experience [5.7 (1.4)], recommendations from another surgeon [5.7 (1.3)] or family/friend [4.9 (1.7)], and attending a top medical school [4.7 (1.7)]. Lowest ranked factors were online advertising and surgeon demographics, including having a sex concordant (female) surgeon. After amalgamation into attribute subsections, mean (standard deviation) rated relative importance of surgeon reputation [0.72 (0.13)] was higher than that of appearance [0.46 (0.19)] and demographics [0.31 (0.13)]. Patient demographics influenced relative importance of certain attributes; older, educated, and higher-income patients placed higher value on surgeon appearance (all p < 0.05). CONCLUSIONS: When selecting a breast reconstruction surgeon, women place the highest value on surgeons' online, educational, and personal reputations. Though most show no strong preferences for surgeon demographics or physical attributes, specific features may be important for some patients. Cognizance of these preferences may enable providers to more effectively understand patient expectations.

A Comparison of Complications in Therapeutic versus Contralateral Prophylactic Mastectomy Reconstruction: A Paired Analysis.

BACKGROUND: Although breast reconstruction after bilateral mastectomies including a contralateral prophylactic mastectomy is known to have a higher overall complication profile, whether reconstructive complication rates differ between the therapeutic mastectomy and contralateral prophylactic mastectomy sides remains unclear. METHODS: Women undergoing bilateral mastectomies with autologous or implant-based breast reconstruction for a unilateral breast cancer at a single institution were identified (2009 to 2019). Postoperative complications were stratified by laterality (therapeutic mastectomy versus contralateral prophylactic mastectomy). Paired data were analyzed to compare the risks of complications between prophylactic and therapeutic reconstruction sides in the same patient. RESULTS: A total of 130 patients (260 reconstructions) underwent bilateral autologous or implant-based reconstruction. Although most women underwent a simple mastectomy, a higher proportion of therapeutic mastectomies were modified radical mastectomies including axillary lymph node dissections compared to contralateral prophylactic mastectomies (15.4 percent versus 0 percent). Forty-four percent of women completed postmastectomy radiation therapy of the therapeutic side before definitive reconstruction. Overall, both therapeutic and prophylactic reconstructions had a similar incidence of reconstructive failure (p = 0.57), return to the operating room (p = 0.44), mastectomy skin flap necrosis (p = 0.32), seroma (p = 0.82), fat necrosis (p = 0.16), wound infection (p = 0.56), and cellulitis (p = 0.56). Nearly one-fifth of patients experienced complications limited to the prophylactic side [contralateral prophylactic mastectomy reconstruction complications, n = 26 (20.0 percent); therapeutic mastectomy reconstruction complications, n = 15 (11.5 percent)]. CONCLUSION: Despite a history of local radiation therapy and more extensive oncologic surgery on the therapeutic side, there are no significant differences in the incidence of postsurgical complications on the therapeutic mastectomy and contralateral prophylactic mastectomy sides after bilateral reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Distress screening in endometrial cancer leads to disparity in referral to support services.

OBJECTIVES: Racial disparities in survival from endometrial cancer (EC) are well known. Cancer distress has also been associated with worse clinical outcomes. We characterized the association between race/ethnicity, patient distress reported on the National Comprehensive Cancer Network Distress Thermometer and Problem List (NCCN DT & PL), referral to support services, time to surgery, and acceptance of adjuvant therapy in patients with EC. METHODS: We included patients presenting at an academic gynecologic oncology practice from 1/2013-6/2020 who had not received prior EC-directed treatment. Demographics, NCCN DT scores, and treatment details were abstracted from the electronic medical record. Difference in initial DT scores by race/ethnicity and treatment type was tested using general linear modeling. The significance of interaction effects was tested using linear mixed models and logistic regression. RESULTS: 393 non-Hispanic White (NHW) and 134 non-Hispanic Black (NHB) patients were included. Median distress scores were higher in NHW patients compared to NHB patients (4 vs. 2, p < 0.001); 51% of NHW patients qualified for referral to support services compared to 40% of NHB patients (p = 0.03). Distress scores were highest at initial appointment and declined over time in NHW patients regardless of treatment, but were initially low and remained low over time in NHB patients. There was no association of initial distress score with time to surgery or acceptance of adjuvant treatment (p-values >0.25). CONCLUSIONS: An observed difference in NCCN DT leads to racial disparities in referral to support services. The NCCN DT may not adequately measure distress in NHB women with EC.

Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia.

BACKGROUND: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). METHODS: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. RESULTS: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. CONCLUSIONS: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.

A Comparison of Surgical Complications in Patients Undergoing Delayed versus Staged Tissue-Expander and Free-Flap Breast Reconstruction.

BACKGROUND: Patients undergoing mastectomy may not be candidates for immediate free-flap breast reconstruction because of medical comorbidities or postmastectomy radiation therapy. In this setting, flap reconstruction may be intentionally delayed or staged with tissue expander placement ("delayed-immediate" reconstruction). The optimal reconstructive choice and incidence of complications for these approaches remain unclear. METHODS: The authors retrospectively identified patients who underwent delayed [n = 140 (72 percent)] or staged [n = 54 (28 percent)] abdominal free-flap breast reconstruction between 2010 and 2018 and compared the incidence of postoperative complications. RESULTS: Patients undergoing staged reconstruction had a higher overall incidence of perioperative complications, including surgical-site infection (40.7 percent versus 6.5 percent; p < 0.001), wound healing complications (29.6 percent versus 12.3 percent; p = 0.004), hematoma (11.1 percent versus 0.7 percent; p < 0.001), and return to the operating room (27.8 percent versus 4.4 percent; p < 0.0001). These complications occurred predominately during the expansion stage, resulting in an 18.5 percent (n = 10) rate of tissue expander failure. Mean time from mastectomy to flap reconstruction was 476.8 days (delayed, 536.4 days; staged, 322.4 days; p < 0.001). At the time of flap reconstruction, there was no significant difference in the incidence of complications between the staged cohort versus the delayed cohort, including microsurgical complications (1.9 percent versus 4.3 percent; p = 0.415), total flap loss (0 percent versus 2.1 percent; p = 0.278), or fat necrosis (5.6 percent versus 5.0 percent; p = 0.875). CONCLUSIONS: The aesthetic and psychosocial benefits of staged free-flap breast reconstruction should be balanced with the increased risk of perioperative complications as compared to a delayed approach. Complications related to definitive flap reconstruction do not appear to be affected by the approach taken at the time of mastectomy. . CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

A Pilot Study of Home-Based Exercise and Personalized Nutrition Counseling Intervention in Endometrial Cancer Survivors.

INTRODUCTION: To assess the feasibility of a home-based aerobic exercise and nutrition counseling intervention and effect on cardiorespiratory fitness, cardiovascular disease risk profile, and immune response in obese endometrial cancer survivors. METHODS: A longitudinal pilot study assessed a 12-week home-based aerobic exercise and nutrition counseling intervention in obese endometrial cancer survivors. The primary outcome was feasibility defined as 80% adherence to weekly walking sessions calculated among individuals that completed the intervention. Secondary outcomes comprised pre- and post-intervention differences in cardiorespiratory fitness, cardiovascular risk factors, and T-cell function. Descriptive statistics summarized data. Wilcoxon sign tests identified differences between and pre and post-intervention variables. RESULTS: Nineteen women with stage 1 endometrial cancer consented; 9 withdrew and one was a screen failure. Median adherence to weekly walking sessions was 83.3%. Body composition was significantly altered with a reduction in median fat mass from 52.5 kg to 46.9 kg (p=0.04), and BMI from 37.5 kg/m2 to 36.2 kg/m2 (p = 0.004). There was no significant difference in cardiorespiratory fitness or cardiovascular parameters. The percentage of CD4+ and CD8+ T-cells producing IFNγ towards MAGE-A4 significantly increased from and 5.9% to 7.2% (p=0.043) and 13.9% to 14.8% (p=0.046), respectively. There were 3 related adverse events: hip pain, back sprain, and abdominal pain. DISCUSSION: Our home-based exercise and nutrition counseling program was feasible based on 80% adherence to walking sessions and favored altered body composition. However, the discontinuation rate was high and further research is needed to overcome barriers to implementation. Improvement in cardiovascular parameters will most likely require longer and more intensive programs.

A quality improvement initiative to reduce venous thromboembolism on a gynecologic oncology service.

OBJECTIVE: To describe and evaluate the effects of implementation of a venous thromboembolism (VTE) prophylaxis quality improvement (QI) initiative on a gynecologic oncology service at a single institution. METHODS: Prior to 2018, no consensus gynecologic oncology VTE prophylaxis protocol existed at the authors' academic institution. Published, evidence-based guidelines were reviewed to create a standardized VTE risk stratification algorithm. Interventions to improve perioperative heparin administration and sequential compression device (SCD) compliance as well as provider/patient education efforts were introduced in January 2018. Initial efforts included nursing and patient SCD education, internal dissemination of VTE prophylaxis guidelines, and creation of a VTE 'dashboard' to track performance. During a second phase, VTE prophylaxis guidelines were reviewed and further refined, non-compliant operative cases reviewed weekly, and guidelines incorporated into the electronic medical record. Performance was measured using Tableau data software (www.tableau.com) and by separately evaluating adherence to the developed guidelines in three retrospective cancer-enriched surgical cohorts (2016-2017, 2018, 2019). RESULTS: Compared to the baseline period, we observed a reduction in VTE rate during the 2018-2019 VTE QI implementation period from 2.1% (19/905) to 1.0% (20/2015, p = 0.02) among gynecologic oncology inpatients. In the retrospective cancer-enriched cohorts, adherence to evidence based guidelines improved: 31.0% in 2016-2017, 69.1% in 2018, and 82.4% in 2019 (p < 0.001). There were no significant differences in rates of peri-operative blood transfusion, surgical site infections, hematomas, or vaginal cuff dehiscences. CONCLUSIONS: Implementation of a robust VTE prophylaxis QI initiative has resulted in improved VTE prophylaxis guideline adherence and higher rates of pre-operative heparin administration.

Endometrial Adenocarcinomas With No Specific Molecular Profile: Morphologic Features and Molecular Alterations of "Copy-number Low" Tumors.

The study evaluated morphologic patterns, mutational profiles, and ß-catenin immunohistochemistry (IHC) in copy-number low (CNL) endometrial adenocarcinomas (EAs). CNL EAs (n=19) with next-generation or whole genome sequencing results and available tissue for IHC were identified from our institutional database. Clinical data and histologic slides were reviewed. IHC for ß-catenin was performed and correlated with mutation status. Images of digital slides of CNL EAs from The Cancer Genome Atlas (TCGA) database (n=90) were blindly reviewed by 4 pathologists, and morphology was correlated with mutation status. Categorical variables were analyzed using the Fisher exact test, and agreement was assessed using Fleiss κ. CTNNB1 mutations were present in 63% (12/19) of CNL EAs. ß-catenin nuclear localization was present in 83% of CTNNB1-mutated tumors (10/12) and in 0% (0/7) of CTNNB1-wildtype tumors (sensitivity 0.83, specificity 1.00). Squamous differentiation (SD) was present in 47% (9/19) and was more often observed in CTNNB1-mutated tumors (P=0.02). Mucinous differentiation (MD) was associated with KRAS mutations (P<0.01). Digital image review of TCGA CNL EAs revealed that pathologist agreement on SD was strong (κ=0.82), whereas agreement on MD was weak (κ=0.48). Pathologists identified SD in 22% (20/90), which was significantly associated with the presence of CTNNB1 mutations (P<0.01). CNL EAs demonstrate several morphologies with divergent molecular profiles. SD was significantly associated with CTNNB1 mutations and nuclear localization of ß-catenin in these tumors. Nuclear expression of ß-catenin is a sensitive and specific IHC marker for CTNNB1 mutations in CNL EAs. CNL EAs with KRAS mutations often displayed MD.

The Effect of Lavender Oil on Perioperative Pain, Anxiety, Depression, and Sleep after Microvascular Breast Reconstruction: A Prospective, Single-Blinded, Randomized, Controlled Trial.

BACKGROUND: Psychosocial distress, depression, or anxiety can occur in up to 50% of women after a breast cancer diagnosis and mastectomy. The purpose of this study was to assess the potential benefit of lavender oil as a perioperative adjunct to improve anxiety, depression, pain, and sleep in women undergoing microvascular breast reconstruction. METHODS: This was a prospective, single-blinded, randomized, controlled trial of 49 patients undergoing microvascular breast reconstruction. Patients were randomized to receive lavender oil or placebo (coconut oil) throughout their hospitalization. The effect of lavender oil on perioperative stress, anxiety, depression, sleep, and pain was measured using the hospital anxiety and depression scale, Richards-Campbell Sleep Questionnaire, and the visual analogue scale. RESULTS: Twenty-seven patients were assigned to the lavender group and 22 patients were assigned to the control group. No significant differences were seen in the perioperative setting between the groups with regard to anxiety (p = 0.82), depression (p = 0.21), sleep (p = 0.86), or pain (p = 0.30) scores. No adverse events (i.e., allergic reaction) were captured, and no significant differences in surgery-related complications were observed. When evaluating the entire cohort, postoperative anxiety scores were significantly lower than preoperative scores (p < 0.001), while depression scores were significantly higher postoperatively as compared with preoperatively (p = 0.005). CONCLUSION: In the setting of microvascular breast reconstruction, lavender oil and aromatherapy had no significant adverse events or complications; however, there were no measurable advantages pertaining to metrics of depression, anxiety, sleep, or pain as compared with the control group.

Results and Clinical Utilization of Foundation Medicine Molecular Tumor Profiling in Uterine and Ovarian Cancers.

BACKGROUND: Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling. OBJECTIVE: We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers. PATIENTS AND METHODS: We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data. RESULTS: Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results. CONCLUSIONS: The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.

Evaluation of pelvic washing specimens in patients with endometrial cancer: Cytomorphological features, diagnostic agreement, and pathologist experience.

BACKGROUND: Pelvic washings for patients with endometrial cancer is recommended but not used for staging. The International System for Reporting Serous Fluid Cytology (TIS) has standardized diagnostic categories, but the criteria remain incomplete. The 3 primary goals of this study were to 1) investigate features that distinguish atypical/indeterminate from malignant specimens, 2) measure the level of agreement between chart and reviewer diagnoses, and 3) determine whether the number of years in practice had an effect on the diagnoses rendered. METHODS: Pelvic washings and surgical pathology specimens for 52 patients with a chart diagnosis of atypical/indeterminate, suspicious, or malignant cytology and 52 age-matched controls with a negative chart diagnosis were included, reviewed blindly by 2 cytopathologists, and assigned a study diagnosis. Morphologic features were assessed. Agreement between original chart diagnoses and reviewer diagnoses were assessed as well as effect of years in practice. RESULTS: The overall cellularity in cell block (CB) slides for the malignant category was significantly increased compared with the atypical/indeterminate category (P < .0001). In addition, the number of atypical groups in ThinPrep for malignant washings was significantly increased compared with the atypical category (P < .001) and the negative and suspicious categories (P < .0001) in the CB. Overall agreement between the original and adjudicated diagnoses was high (γ = 0.983). There was no significant difference between diagnoses rendered and years in practice. CONCLUSION: The overall cellularity and number of atypical cells can be used to distinguish between malignant and atypical pelvic washing specimens. There is high reproducibility in the diagnostic categories and high agreement among pathologists, regardless of practice experience. These findings can help refine the criteria for TIS.

The Influence of Fat Grafting on Breast Imaging after Postmastectomy Reconstruction: A Matched Cohort Analysis.

BACKGROUND: Fat grafting to the reconstructed breast may result in the development of benign lesions on physical examination, prompting further investigation with imaging and biopsy. The aim of this study was to assess the influence of fat grafting on the incidence of imaging and biopsies after postmastectomy reconstruction. METHODS: Patients who underwent autologous or implant-based reconstruction following mastectomy from 2010 to 2018 were identified. Those receiving fat grafting as part of their reconstructive course were propensity matched 1:1 to those that did not with body mass index, reconstruction timing, and reconstruction type as covariates in a multivariable logistic regression model. RESULTS: A total of 186 patients were identified, yielding 93 propensity-matched pairs. Fat-grafted patients had higher incidences of palpable masses (38.0 percent versus 18.3 percent; p = 0.003) and postreconstruction imaging (47.3 percent versus 29.0 percent; p = 0.01), but no significant difference in the number of biopsies performed (11.8 percent versus 7.5 percent; p = 0.32). Imaging was predominately interpreted as normal (Breast Imaging-Reporting and Data System 1, 27.9 percent) or benign (Breast Imaging-Reporting and Data System 2, 48.8 percent), with fat necrosis being the most common finding [n = 20 (45.5 percent)]. No demographic, oncologic, reconstructive, or fat grafting-specific variables were predictive of receiving postreconstruction imaging on multivariate analysis. Fat grafting was not associated with decreased 5-year overall survival or locoregional recurrence-free survival. CONCLUSIONS: Fat grafting to the reconstructed breast is associated with increased incidences of palpable masses and subsequent postreconstruction imaging with benign radiographic findings. Although the procedure is oncologically safe, both patients and providers should be aware that concerning physical examination findings can be benign sequelae of fat grafting and may lead to increased imaging after breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.

PURPOSE: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. EXPERIMENTAL DESIGN: Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination. RESULTS: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. CONCLUSIONS: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).