Physiologic Treatment of Severe Hypertension in Pregnancy and Postpartum.

We aimed to evaluate physiologic treatment of severe hypertension. This was a retrospective cohort study of pregnant and postpartum patients with severe hypertension (systolic blood pressure [BP] 160 mm Hg or higher or diastolic BP 110 mm Hg or higher) treated with intravenous labetalol or hydralazine at a single tertiary care center between 2013 and 2018. Patients were classified as having physiologic treatment if they had hyperdynamic physiology (pulse pressure 65 mm Hg or higher) and received labetalol or had vasoconstrictive physiology (diastolic BP 100 mm Hg or higher) and received hydralazine. The primary outcome was number of antihypertensive doses to achieve nonsevere BP. Of 1,120 patients included in the analysis, 653 had physiologic treatment and 467 had nonphysiologic treatment, with 16 (1.4%) excluded for inability to classify physiology. Physiologic treatment was associated with fewer antihypertensive doses (1.4±0.9 doses vs 1.6±1.4 doses; adjusted ß -0.28, 95% CI, -0.42 to -0.14) and lower odds of medication conversion (2.5% vs 4.7%; adjusted odds ratio 0.48, 95% CI, 0.24-0.93) but no difference in time to nonsevere BP (31 minutes [interquartile range 16-66 minutes] vs 34 minutes [interquartile range 15-76 minutes]; adjusted hazard ratio 1.0, 95% CI, 0.9-1.2). Physiologic treatment of severe hypertension warrants further evaluation.

Occipital Nerve Block Compared With Acetaminophen and Caffeine for Headache Treatment in Pregnancy: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of occipital nerve block compared with standard care , defined as acetaminophen with caffeine, for treatment of acute headache in pregnancy. METHODS: We conducted a single-center, unblinded, parallel, randomized controlled trial of pregnant patients with headache and pain score higher than 3 on the visual rating scale. Patients with secondary headache, preeclampsia, or allergy or contraindication to study medications were excluded. Participants were randomized to occipital nerve block or standard care (oral 650 mg acetaminophen and 200 mg caffeine). Crossover treatment was given at 2 hours and second-line treatment at 4 hours to those with worsening visual rating scale score or visual rating scale score higher than 3. The primary outcome was headache improvement to a visual rating scale score of 3 or lower within 2 hours of initial therapy. Secondary outcomes included serial visual rating scale scores, receipt of crossover or second-line therapy, patient satisfaction, and perinatal outcomes. Outcomes were assessed in an intention-to-treat analysis. We estimated that a sample of 62 would provide 80% power to detect a difference from 85% to 50% between groups. RESULTS: From February 2020 to May 2022, 62 participants were randomized to occipital nerve block (n=31) or standard care (n=31). Groups were similar except payer status. The primary outcome, headache improvement to visual rating scale score of 3 or lower, was not significantly different between groups (64.5% vs 51.6%, P =.30). The occipital nerve block group experienced lower median [interquartile range] visual rating scale scores at 1 hour (2 [0-5] vs 6 [2-7], P =.014), and more patients in the occipital nerve block group had visual rating scale scores of 3 or lower at 1 hour. Among patients receiving crossover treatment at 2 hours, the standard care group had a significantly lower visual rating scale score 1 hour after crossover to occipital nerve block than the occipital nerve block group receiving crossover to standard care ( P =.028). There were no significant differences in second-line treatment, refractory headache, satisfaction, or complications. Patients receiving occipital nerve block delivered earlier (36.6 weeks vs 37.8 weeks), but preterm birth did not differ between groups. CONCLUSION: Occipital nerve block is an effective and quick-acting treatment option for acute headache in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03951649.

Metabolic Alterations and WNT Signaling Impact Immune Response in HGSOC.

PURPOSE: Our study used transcriptomic and metabolomic strategies to determine the molecular profiles of HGSOC patient samples derived from primary tumor and ascites cells. These data identified clinically relevant heterogeneity among and within patients and highlighted global and patient-specific cellular responses to neoadjuvant chemotherapy (NACT). EXPERIMENTAL DESIGN: Tissue from 61 treatment-naïve patients with HGSOC were collected. In addition, 11 benign, 32 ascites, and 18 post-NACT samples (matched to the individual patient's pre-NACT sample) were collected. RNA sequencing (RNA-seq) was performed on all samples collected. Two-dimensional spatial proteomic data was collected for two pairs of pre- and post-NACT. Untargeted metabolomics data using GCxGC-MS was generated for 30 treatment-naive tissues. Consensus clustering, analysis of differential expression, pathway enrichment, and survival analyses were performed. RESULTS: Treatment-naïve HGSOC tissues had distinct transcriptomic and metabolomic profiles. The mesenchymal subtype harbored a metabolomic profile distinct from the other subtypes. Compared with primary tumor tissue, ascites showed significant changes in immune response and signaling pathways. NACT caused significant alterations in gene expression and WNT activity, and this corresponded to altered immune response. Overall, WNT signaling levels were inversely correlated with immune cell infiltration in HGSOC tissues and WNT signaling post-NACT was inversely correlated with progression-free survival. CONCLUSIONS: Our study concluded that HGSOC is a heterogenous disease at baseline and growing molecular differences can be observed between primary tumor and ascites cells or within tumors in response to treatment. Our data reveal potential exploratory biomarkers relevant for treatment selection and predicting patient outcomes that warrant further research.

EMR 20006-012: A phase II randomized double-blind placebo controlled trial comparing the combination of pimasertib (MEK inhibitor) with SAR245409 (PI3K inhibitor) to pimasertib alone in patients with previously treated unresectable borderline or low grade ovarian cancer.

OBJECTIVE: To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior. METHODS: Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events. RESULTS: Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation. CONCLUSIONS: Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.

Extending the platinum-free interval: The impact of omitting 2nd line platinum chemotherapy in intermediate platinum-sensitive ovarian cancer.

OBJECTIVES: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12 months after primary platinum chemotherapy have worse prognosis than those recurring in >12 months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12 months after completion of primary platinum-based chemotherapy. METHODS: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12 months following primary chemotherapy was performed comparing platinum versus non-platinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. RESULTS: Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2 months (95% CI 8-9 months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was longer than non-platinum (7.1 vs 3 months, p = 0.0114). Median PFS2 was significantly longer for platinum vs. targeted therapy (7.1 vs. 3 months p = 0.0431). Median OS for platinum in 2nd line vs. no platinum was 43.6 vs. 37.6 months (p = 0.0174). CONCLUSIONS: Use of non-platinum chemotherapy and even targeted therapy to prolong PFI in patients with EOC recurring between 6 and 12 months leads to worse survival.