Seven Strategies to Integrate Equity within Translational Research in Neurology.

The rapidly accelerating translation of biomedical advances is leading to revolutionary therapies that are often inaccessible to historically marginalized populations. We identified and synthesized recent guidelines and statements to propose 7 strategies to integrate equity within translational research in neurology: (1) learn history; (2) learn about upstream forces; (3) diversify and liberate; (4) change narratives and adopt best communication practices; (5) study social drivers of health and lived experiences; (6) leverage health technologies; and (7) build, sustain, and lead culturally humble teams. We propose that equity should be a major goal of translational research, equally important as safety and efficacy. ANN NEUROL 2024;95:432-441.

Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

Post-surgical ctDNA-based molecular residual disease detection in patients with stage I uterine malignancies.

INTRODUCTION: Among uterine malignancies, endometrial cancer (EC) is the most common cancer of the female reproductive tract. Traditionally, risk stratification in EC is determined by standard clinicopathological risk factors. Although circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker in various malignancies, its clinical validity in EC remains to be established. METHODS: In this analysis of real-world data, 267 plasma samples from 101 patients with stage I EC were analyzed using a tumor-informed ctDNA assay (Signatera™ bespoke mPCR-NGS). Patients were followed post-surgically and monitored with ctDNA testing for a median of 6.8 months (range: 0.37-19.1). RESULTS: Patients who tested ctDNA-positive at both their first time point and longitudinally experienced inferior recurrence-free survival (RFS) (HR = 6.2; p = 0.0006 and HR = 15.5; p < 0.0001, respectively), and showed a recurrence rate of 58% and 52%, vs. 6% and 0%, respectively for the ctDNA-negative patients. Most ctDNA-positive patients had high-risk histologies or sarcoma, versus low-risk and high-intermediate risk (H-IR) EC. Furthermore, patients with high-risk histologies who were ctDNA-positive showed shorter RFS compared to those who tested negative (HR = 9.5; p = 0.007), and those who tested positive in the low/H-IR cohort (HR = 0.25; p = 0.04). Post-surgically, detectable ctDNA was highly prognostic of clinical outcome and remained the only significant risk factor for recurrence when adjusted for clinicopathological risk factors, such as histologic risk group, mismatch repair (MMR), and p53 status. CONCLUSION: Incorporating ctDNA monitoring along with traditional known risk factors may aid in identifying patients with stage I EC who are at highest risk of recurrence, and possibly aid in treatment stratification.

Navigating Neurologic Illness: Skills in Neuropalliative Care for Persons Hospitalized with Neurologic Disease.

Persons hospitalized for neurologic illness face multidimensional care needs. They can benefit from a palliative care approach that focuses on quality of life for persons with serious illness. We describe neurology provider "skills" to help meet these palliative needs: assessing the patient as a whole; facilitating conversations with patients to connect prognosis to care preferences; navigating neurologic illness to prepare patients and care partners for the future; providing high-quality end-of-life care to promote peace in death; and addressing disparities in care delivery.

Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer.

OBJECTIVES: External beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects. Radical vulvectomy post-radiation for persistent disease is often compromised with poor wound healing. We describe clinical outcomes for patients who received neoadjuvant chemotherapy plus bevacizumab followed by radical vulvectomy for locally advanced vulvar cancer. METHODS: We performed retrospective analyses of all patients at our institution who underwent radical vulvectomy from January 2015 to November 2023. Of 113 patients, 13 patients underwent neoadjuvant chemotherapy. Demographics and clinicopathologic data were extracted, and descriptive statistical analyses were performed. Cases with neoadjuvant chemotherapy plus bevacizumab were further evaluated for response, adverse effects, and survival. RESULTS: Neoadjuvant chemotherapy was administered to 13 patients with stage II-IV disease that involved the urethra, vagina, or anus. Lesion sizes ranged from 4 to 20 cm (median 7 cm). Patients received 2-6 cycles of carboplatin or cisplatin, paclitaxel, and bevacizumab. Nine (69.2%) patients had partial pathologic responses, and four patients had complete responses. All patients had negative surgical margins. Ten (76.9%) patients had radiographic evidence of inguinal lymph node metastasis prior to neoadjuvant chemotherapy, and four had residual nodal disease. Only one patient developed a superficial groin seroma. Three patients developed recurrence, two locally and one distant, and there was one death. The median follow-up was 23 months (range 6-84 months). CONCLUSIONS: Neoadjuvant chemotherapy using combination platinum/paclitaxel/bevacizumab was efficacious for locally advanced vulvar cancer, resulting in complete resections, negative margins, and excellent wound healing. A multi-institutional phase II trial is warranted to validate these findings.

National Cost Estimates of Invasive Mechanical Ventilation and Tracheostomy in Acute Stroke, 2008-2017.

BACKGROUND: Patients with stroke receiving invasive mechanical ventilation (IMV) and tracheostomy incur intense treatment and long hospitalizations. We aimed to evaluate US hospitalization costs for patients with stroke requiring IMV, tracheostomy, or no ventilation. METHODS: We performed a retrospective observational study of US hospitalizations for acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage receiving IMV, tracheostomy, or none using the National Inpatient Sample, 2008 to 2017. We calculated hospitalization costs using cost-to-charge ratios adjusted to 2017 US dollars for inpatients with stroke by ventilation status (no IMV, IMV alone, tracheostomy). RESULTS: Of an estimated 5.2 million (95% CI, 5.1-5.3) acute stroke hospitalizations, 2008 to 2017; 9.4% received IMV alone and 1.4% received tracheostomy. Length of stay for patients without IMV was shorter (median, 4 days; interquartile range [IQR], 2-6) compared with IMV alone (median, 6 days; [IQR, 2-13]), and tracheostomy (median, 25 days; [IQR, 18-36]; P<0.001). Mortality for patients without IMV was 3.2% compared with 51.2% for IMV alone and 9.8% for tracheostomy (P<0.001). Median hospitalization costs for patients without IMV was $9503 (IQR, $6544-$14 963), compared with $23 774 (IQR, $10 900-$47 735) for IMV alone and $95 380 (IQR, $63 921-$144 019) for tracheostomy. Tracheostomy placement in ≤7 days had lower costs compared with placement in >7 days (median, $71 470 [IQR, $47 863-$108 250] versus $102 979 [IQR, $69 563-$152 543]; P<0.001). Each day awaiting tracheostomy was associated with a 2.9% cost increase (95% CI, 2.6%-3.1%). US hospitalization costs for patients with acute stroke were $8.7 billion/y (95% CI, $8.5-$8.9 billion). For IMV alone, costs were $1.8 billion/y (95% CI, $1.7-$1.9 billion) and for tracheostomy $824 million/y (95% CI, $789.7-$858.3 million). CONCLUSIONS: Patients with acute stroke who undergo tracheostomy account for 1.4% of stroke admissions and 9.5% of US stroke hospitalization costs. Future research should focus on the added value to society and patients of IMV and tracheostomy, in particular after 7 days for the latter procedure given the increased costs incurred and poor outcomes in stroke.

Association of Skilled Nursing Facility Participation in Voluntary Bundled Payments With Postacute Care Outcomes for Joint Replacement.

IMPORTANCE: The Medicare Bundled Payments for Care Improvement (BPCI) model 3 of 2013 holds participating skilled nursing facilities (SNFs) responsible for all episode costs. There is limited evidence regarding SNF-specific outcomes associated with BPCI. OBJECTIVE: To examine the association between SNF BPCI participation and patient outcomes and across-facility differences in these outcomes among Medicare beneficiaries undergoing lower extremity joint replacement (LEJR). DESIGN, SETTING, AND PARTICIPANTS: Observational difference-in-differences (DID) study of 2013-2017 for 330 unique persistent-participating SNFs, 146 unique dropout SNFs, and 14,028 unique eligible nonparticipating SNFs. MAIN OUTCOME MEASURES: Rehospitalization within 30 and 90 days after SNF admission, and rate of successful discharge from the SNF to the community. RESULTS: Total 636,355 SNF admissions after LEJR procedures were identified for 582,766 Medicare patients [mean (SD) age, 76.81 (9.26) y; 424,076 (72.77%) women]. The DID analysis showed that for persistent-enrollment SNFs, no BPCI-related changes were found in readmission and successful community discharge rates overall, but were found for their subgroups. Specifically, under BPCI, the 30-day readmission rate decreased by 2.19 percentage-points for White-serving SNFs in the persistent-participating group relative to those in the nonparticipating group, and by 1.75 percentage-points for non-Medicaid-dependent SNFs in the persistent-participating group relative to those in the nonparticipating group; and the rate of successful community discharge increased by 4.44 percentage-points for White-serving SNFs in the persistent-participating group relative to those in the nonparticipating group, whereas such relationship was not detected among non-White-serving SNFs, leading to increased between-facility differences (differential DID=-7.62). BPCI was not associated with readmission or successful community discharge rates for dropout SNFs, overall, or in subgroup analyses. CONCLUSIONS: Among Medicare patients receiving LEJR, BPCI was associated with improved outcomes for White-serving/non-Medicaid-dependent SNFs but not for other SNFs, which did not help reduce or could even worsen the between-facility differences.

Malignant peritoneal cytologic contamination with robotic hysterectomy for endometrial cancer.

BACKGROUND: Malignant peritoneal cytology in endometrial cancer (EC) is not considered an independent adverse prognostic factor for uterine-confined disease and is not a determinant factor in the International Federation of Gynecology and Obstetrics (FIGO) staging system. NCCN Guidelines still recommend obtaining cytologies. The aim of this study was to determine the prevalence of peritoneal cytologic contamination following robotic hysterectomy for EC. METHODS: Peritoneal cytology from the pelvis and diaphragm were obtained at the initiation of surgery, and from the pelvis only at the completion of robotic hysterectomy with sentinel lymph node mapping (SLNM). Cytology specimens were evaluated for the presence of malignant cells. Pre- and post-hysterectomy cytology results were compared, and pelvic contamination was defined as conversion from negative to positive cytology following surgery. RESULTS: 244 patients underwent robotic hysterectomy with SLNM for EC. Pelvic contamination was identified in 32 (13.1%) cases. In multivariate analysis, pelvic contamination was associated with >50% myometrial invasion, tumor size >2 cm, lymphovascular space invasion (LVSI), and lymph node metastasis. There was no association with FIGO stage or histology subtypes. CONCLUSIONS: Malignant peritoneal contamination occurred during robotic surgery for EC. Large lesions (>2 cm), deep invasion (>50%), LVSI, and lymph node metastasis were each independently associated with peritoneal contamination. Whether or not peritoneal contamination increases risk for disease recurrence should be studied in larger series, including an evaluation of patterns of recurrence and the potential impact of adjuvant therapies. Until the clinical impact of peritoneal contamination during hysterectomy for EC is better understood, methods to reduce peritoneal contamination are warranted.

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032).

OBJECTIVE: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. METHODS: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). RESULTS: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. CONCLUSIONS: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Hospital Discharge and Readmissions Before and During the COVID-19 Pandemic for California Acute Stroke Inpatients.

BACKGROUND: Acute stroke therapy and rehabilitation declined during the COVID-19 pandemic. We characterized changes in acute stroke disposition and readmissions during the pandemic. METHODS: We used the California State Inpatient Database in this retrospective observational study of ischemic and hemorrhagic stroke. We compared discharge disposition across a pre-pandemic period (January 2019 to February 2020) to a pandemic period (March to December 2020) using cumulative incidence functions (CIF), and re-admission rates using chi-squared. RESULTS: There were 63,120 and 40,003 stroke hospitalizations in the pre-pandemic and pandemic periods, respectively. Pre-pandemic, the most common disposition was home [46%], followed by skilled nursing facility (SNF) [23%], and acute rehabilitation [13%]. During the pandemic, there were more home discharges [51%, subdistribution hazard ratio 1.17, 95% CI 1.15-1.19], decreased SNF discharges [17%, subdistribution hazard ratio 0.70, 95% CI 0.68-0.72], and acute rehabilitation discharges were unchanged [CIF, p<0.001]. Home discharges increased with increasing age, with an increase of 8.2% for those ≥85 years. SNF discharges decreased in a similar distribution by age. Thirty-day readmission rates were 12.7 per 100 hospitalizations pre-pandemic compared to 11.6 per 100 hospitalizations during the pandemic [p<0.001]. Home discharge readmission rates were unchanged between periods. Readmission rates for discharges to SNF (18.4 vs. 16.7 per 100 hospitalizations, p=0.003) and acute rehabilitation decreased (11.3 vs. 10.1 per 100 hospitalizations, p=0.034). CONCLUSIONS: During the pandemic a greater proportion of patients were discharged home, with no change in readmission rates. Research is needed to evaluate the impact on quality and financing of post-hospital stroke care.

Perioperative Neurological Evaluation and Management to Lower the Risk of Acute Stroke in Patients Undergoing Noncardiac, Nonneurological Surgery: A Scientific Statement From the American Heart Association/American Stroke Association.

Perioperative stroke is a potentially devastating complication in patients undergoing noncardiac, nonneurological surgery. This scientific statement summarizes established risk factors for perioperative stroke, preoperative and intraoperative strategies to mitigate the risk of stroke, suggestions for postoperative assessments, and treatment approaches for minimizing permanent neurological dysfunction in patients who experience a perioperative stroke. The first section focuses on preoperative optimization, including the role of preoperative carotid revascularization in patients with high-grade carotid stenosis and delaying surgery in patients with recent strokes. The second section reviews intraoperative strategies to reduce the risk of stroke, focusing on blood pressure control, perioperative goal-directed therapy, blood transfusion, and anesthetic technique. Finally, this statement presents strategies for the evaluation and treatment of patients with suspected postoperative strokes and, in particular, highlights the value of rapid recognition of strokes and the early use of intravenous thrombolysis and mechanical embolectomy in appropriate patients.

Carcinomatosis in Early-Stage Cervical Cancer Treated with Robotic Radical Hysterectomy: Recurrence Patterns, Risk Factors, and Survival.

PURPOSE: Minimally invasive radical hysterectomy has been associated with increased recurrence of disease and worse survival compared with open radical hysterectomy for early-stage cervical cancer. We evaluated patterns of recurrence and histopathologic risk factors in patients who underwent robotic radical hysterectomy (RRH). METHODS: Patients who underwent RRH (4/2007-12/2018) were evaluated for specific locations of recurrent disease, disease-free survival, overall survival (OS), and histopathologic risk factors for recurrence. Inclusion criteria were follow-up ≥ 1 year, histology with adenocarcinoma, adenosquamous, or squamous carcinoma and clinical stage IA2 to IB ≤ 4-cm tumor size cervical cancers (FIGO-2018). RESULTS: A total of 140 patients underwent RRH and 112 met criteria. Median tumor size was 2.1 cm [interquartile range (IQR): 1.1-3.3]. Median follow-up was 61 months (IQR: 36-102). Fifty (45%) patients underwent adjuvant radiation ± cisplatin with either Sedlis' or Peters' risk factors. There were 11 (9.8%) recurrences with median disease-free survival of 12 (IQR 8.5) months. All patients with recurrence had measured tumor size ≥ 2 cm (median tumor size 3-cm (IQR: 2.6-4.0). Tumor size > 2 cm was associated with Sedlis' intermediate-risk factors (p < 0.05) and Peters' high-risk factors (p < 0.05). Forty patients underwent preoperative conization, and two (5%) with deep positive margins in lesions > 2 cm recurred. Five (4.5%) of patients had carcinomatosis representing 45% of all recurrences. Carcinomatosis was associated with reduced OS compared with other recurrence patterns (22 months vs. 7.8 years, p < 0.05). CONCLUSIONS: Carcinomatosis was observed in early-stage cervical cancers treated with RRH and was associated with reduced OS. All recurrences were associated with lesions ≥ 2 cm, and no recurrences were identified with negative conization margins.

Skilled Nursing Facility Participation in a Voluntary Medicare Bundled Payment Program: Association With Facility Financial Performance.

IMPORTANCE: Model 3 of the Bundled Payments for Care Improvement (BPCI) is an alternative payment model in which an entity takes accountability for the episode costs. It is unclear how BPCI affected the overall skilled nursing facility (SNF) financial performance and the differences between facilities with differing racial/ethnic and socioeconomic status (SES) composition of the residents. OBJECTIVE: The objective of this study was to determine associations between BPCI participation and SNF finances and across-facility differences in SNF financial performance. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study spanning 2010-2017, based on difference-in-differences analyses for 575 persistent-participation SNFs, 496 dropout SNFs, and 13,630 eligible nonparticipating SNFs. MAIN OUTCOME MEASURES: Inflation-adjusted operating expenses, revenues, profit, and profit margin. RESULTS: BPCI was associated with reductions of $0.63 million in operating expenses and $0.57 million in operating revenues for the persistent-participation group but had no impact on the dropout group compared with nonparticipating SNFs. Among persistent-participation SNFs, the BPCI-related declines were $0.74 million in operating expenses and $0.52 million in operating revenues for majority-serving SNFs; and $1.33 and $0.82 million in operating expenses and revenues, respectively, for non-Medicaid-dependent SNFs. The between-facility SES gaps in operating expenses were reduced (differential difference-in-differences estimate=$1.09 million). Among dropout SNFs, BPCI showed mixed effects on across-facility SES and racial/ethnic differences in operating expenses and revenues. The BPCI program showed no effect on operating profit measures. CONCLUSIONS: BPCI led to reduced operating expenses and revenues for SNFs that participated and remained in the program but had no effect on operating profit indicators and mixed effects on SES and racial/ethnic differences across SNFs.

Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian carcinoma.

OBJECTIVE: ARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. METHODS: Patients were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were evaluated for association with exceptional benefit (progression-free survival ≥2 years) versus progression on first scan (short-term subgroup) and other efficacy outcomes. RESULTS: Rucaparib treatment was significantly associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001). Exceptional benefit was more frequent among patients with favorable baseline clinical characteristics and with carcinomas harboring molecular evidence of homologous recombination deficiency (HRD). A comparison between patients who derived exceptional benefit from rucaparib and those in the short-term subgroup revealed both clinical markers (no measurable disease at baseline, complete response to latest platinum, longer penultimate platinum-free interval) and molecular markers (BRCA1, BRCA2, RAD51C, and RAD51D alterations and genome-wide loss of heterozygosity) significantly associated with exceptional benefit. CONCLUSIONS: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics or molecular features associated with HRD. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of patients with recurrent high-grade ovarian carcinoma.

Institutional Postacute Care Use May Help Reduce Readmissions for Ischemic Stroke Patients.

OBJECTIVES: Readmissions for Medicare patients initially admitted for stroke are common and costly. Rehabilitation in an institutional postacute care (PAC) setting is an evidence-based component of recovery for stroke. Under current Medicare payment reforms, care coordination across hospitals and PAC providers is key to improving quality and efficiency of care. We examined the causal impact of institutional PAC use on 30-day readmission rates for Medicare fee-for-service patients initially admitted for ischemic stroke. DATA SOURCES: The 2010-2016 Medicare Provider Analysis and Review files. RESEARCH DESIGN: We used the method of instrumental variable (IV) analysis to control for unobserved differences in the types of patients admitted to each PAC facility. We chose the distance from the patient's residence to the closest institutional PAC provider and the number of PAC providers of each type within a county where the patient resides as IVs. PRINCIPAL FINDINGS: In the naive model, an increase in institutional PAC use was significantly associated with an increase in 30-day readmission by 0.03 percentage points. However, using IV analysis to control for endogeneity bias, an increase in institutional PAC use was associated with a decrease in 30-day readmission rate by 0.19 percentage points. Our findings indicate that reducing institutional PAC use among patients typically requiring rehabilitation in institutional settings for recovery may potentially lead to adverse postdischarge outcomes that require rehospitalization. Thus, payment incentives to reduce institutional PAC use should be balanced with postdischarge outcomes among ischemic stroke patients.

The Effect of Medicare Shared Savings Program on Readmissions and Variations by Race/Ethnicity and Payer Status (December 9, 2020).

OBJECTIVE: Accountable care organizations in the Medicare Shared Savings Program (MSSP) in the United States attempt to reduce cost and improve quality for their patients by improving care coordination across care settings. We examined the impact of hospital participation in the MSSP on 30-day readmissions for several groups of Medicare inpatients, and by race/ethnicity and payer status. MAIN DATA SOURCE: A 2010-2016 Medicare Provider Analysis and Review files. RESEARCH DESIGN: With propensity score matched sample of MSSP and non-MSSP-participating hospitals, patient-level linear probability models with difference-in-differences approach were used to compare the changes in readmission rates for Medicare fee-for-service patients initially admitted for ischemic stroke, hip fracture, or total joint arthroplasty in MSSP-participating hospitals with non-MSSP-participating hospitals as well as to compare the changes in disparities in readmission rates over time. PRINCIPAL FINDINGS: Hospital participation in MSSP was associated with further reduced readmission rate by 1.1 percentage points (95% confidence interval: -0.02 to 0.00, P<0.05) and 1.5 percentage points (95% confidence interval: -0.03 to 0.00, P=0.08) for ischemic stroke and hip fracture cohorts, respectively, compared with non-MSSP-participating hospitals, after the third year of hospital participation in the MSSP. There was no evidence that MSSP had an impact on racial/ethnic disparities, but increased disparity by payer status (dual vs. Medicare-only) was observed. These findings together suggest that MSSP accountable care organizations may take at least 3 years to achieve reduced readmissions and may increase disparities by payer status.

Neoadjuvant chemotherapy followed by fertility sparing surgery in cervical cancers size 2-4 cm; emerging data and future perspectives.

BACKGROUND: Approach to the management of early stage cervical cancers with tumor size >2 cm in women who desire fertility preservation has been fraught with controversy. Fertility sparing surgery for FIGO 2018 stage IB cancers has been validated most for tumors ≤2 cm. In this review, our objective was to evaluate the oncologic and obstetric outcomes for women that underwent neoadjuvant chemotherapy (NACT) before fertility sparing surgery for tumors 2-4 cm. METHODS: We performed a systematic literature review and searched PubMed, Google Scholar, Cochrane Reviews and UpToDate (from January 2000 to February 2021) using the terms: cervical cancer, fertility preservation, trachelectomy, radical trachelectomy, neoadjuvant chemotherapy, cervical cancer treatment, stage IB1 or IB2 cervical cancer, and cervical cancer size 2-4 cm. We included manuscripts with information on patients with tumor sizes 2-4 cm, lymph node status, follow-up, obstetric and oncologic outcome. We excluded review articles or articles without all pertinent patient information. RESULTS: Eighteen articles were identified including 249 patients. For final analysis, 114 met inclusion criteria. All included patients had FIGO 2018 stage IB2 cervical cancer, underwent neoadjuvant chemotherapy and subsequent fertility sparing surgery. Vaginal radical trachelectomy, cold knife conization, abdominal radical trachelectomy, laparoscopic radical trachelectomy, simple vaginal trachelectomy, and cone laser were performed in 46 (40.4%), 26 (22.8%), 14 (12.3%), 13 (11.4%), 8 (7%), and 7 (6.1%) women, respectively. The most common regimen of chemotherapy was platinum-based therapy with cisplatin. The follow-up time reported in all studies ranged from 1 to 225 months. Of 64 attempted pregnancies, there were 49 (76.6%) viable deliveries which included 6 preterm births (9.4%). The recurrence rate was 6.1% and two patients (1.8%) died of disease. CONCLUSION: Fertility sparing surgery following NACT is an option for women with cervical cancers that are 2-4 cm that wish to preserve fertility without sacrificing oncologic or obstetric outcomes. Confirmation of these findings are anticipated from an ongoing international phase II clinical trial [1].

A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Our objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). METHODS: Olvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. RESULTS: Twelve patients (median age: 69 years, range: 45-77) with median 5 prior therapies (range: 2-10) and 2 prior platinum lines (range: 1-5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7-34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. CONCLUSIONS: Oncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.

Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics.

OBJECTIVE: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280). DATA SOURCES: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials. STUDY ELIGIBILITY CRITERIA: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data. METHODS: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m2 (range, 19.4-43.7 kg/m2). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I2=59%) and 64% bilaterally (95% confidence interval, 53%-73%; I2=69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I2=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I2=0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I2=0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I2=0%). CONCLUSION: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.