Trends in estimated PARP inhibitor eligibility and benefit among US epithelial ovarian cancer patients.

OBJECTIVE: To estimate the annual percentage of patients with epithelial ovarian cancer (EOC) who could be eligible for and benefit from PARP inhibitor therapy amidst changing US Food and Drug Administration (FDA)-approved indications. METHODS: This is a simulated retrospective observational study using publicly available data on patients with advanced-stage EOC. PARPi eligibility is based on FDA approvals and withdrawals from 2014 through 2023, along with published demographic and genomic data. Clinical trial data is used to estimate treatment benefit. PARPi including olaparib, niraparib, and rucaparib are analyzed in aggregate with sub-analyses by molecular classification and treatment timing. Results are reported as the percentage of EOC patients appropriate for any cancer-directed therapy. RESULTS: PARPi were approved for 9 different indications in EOC between 2014 and 2021; reduced to 6 indications by 2023. Eligibility increased from 2.0% (95% CI,1.3%-1.6%) in 2014 to a maximum of 93.4% (95% CI,90.1%-94.6%) in 2021. The maximum percentage of patients with 2-year PFS benefit was 22.0% (95% CI, 17.2%-26.8%) in 2021, projected to decrease to 13.0% (95% CI, 9.9%-15.9%) in 2024. Most of this decrease was seen in the homologous recombination deficient, BRCA wild-type population (8.4% to 4.0%). CONCLUSIONS: PARPi eligibility increased at a greater rate than benefit resulting in a low population-level benefit-to-eligibility ratio until 2021. Recent FDA withdrawals improved this ratio with an accompanied decrease in the absolute number of patients benefiting. To further optimize population-level benefit-to-eligibility ratio of targeted therapies in ovarian cancer, we need to identify better biomarkers, treatment combinations, and novel therapeutic targets.

Implementation of a standardized voiding management protocol to reduce unnecessary re-catheterization - A quality improvement project.

OBJECTIVE: To design and implement a standardized postoperative voiding management protocol that accurately identifies patients with urinary retention and reduces unnecessary re-catheterization. METHODS: A postoperative voiding management protocol was designed and implemented in patients undergoing major, inpatient, non-radical abdominal surgery with a gynecologic oncologist. No patients had epidural catheters. The implemented quality improvement (QI) protocol included: 1) Foley removal at six hours postoperatively; 2) universal bladder scan after the first void; and 3) limiting re-catheterization to patients with bladder scan volumes >150 ml. A total of 96 patients post-protocol implementation were compared to 52 patients pre-protocol. Along with baseline demographic data and timing of catheter removal, we recorded the presence or absence of urinary retention and/or unnecessary re-catheterization and postoperative urinary tract infection rates. Fisher's exact test and student's t-tests were performed for comparisons. RESULTS: The overall rate of postoperative urinary retention was 21.6% (32/148). The new voiding management protocol reduced the rate of unnecessary re-catheterization by 90% (13.5% vs 2.1%, p = 0.01), without overlooking true urinary retention (23.1% vs 20.8%, p = 0.83). Additionally, there was a significant increase in hospital-defined early discharge prior to 11:00 AM (4.0% vs 22.0%, p = 0.022). There was no difference in the postoperative urinary tract infection rate between the groups (p = 1.00). Risk factors associated with urinary retention included older age (p < 0.01), use of medications with anticholinergic properties (p < 0.01), and preexisting urinary dysfunction (p < 0.01). CONCLUSIONS: Implementation of this new voiding management protocol reduced unnecessary re-catheterization, captured and treated true urinary retention, and facilitated early hospital discharge.

Cost-effectiveness of hyperthermic intraperitoneal chemotherapy at primary cytoreduction of epithelial ovarian cancer based on residual disease status.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin when used at the time of interval cytoreductive surgery (ICS) after neoadjuvant chemotherapy (NACT) has been shown to provide a survival advantage compared to interval cytoreduction alone for patients with advanced epithelial ovarian cancer in a cost-effective manner. A recent large multi-center retrospective cohort study showed a survival advantage with HIPEC given during primary debulking surgery compared to surgery alone. While there is an ongoing randomized controlled trial examining HIPEC at the time of primary cytoreductive surgery (PCS) before chemotherapy (OVHIPEC-2), there is currently no study of this practice in the United States or cost data to inform incorporation of this practice. To help guide the use of HIPEC in the upfront setting until the results of the OVHIPEC-2 are available in 2026, a decision-analytic cost-effectiveness model of the US healthcare sector was developed for patients undergoing PCS with or without HIPEC. Effectiveness inputs were extracted from a Chinese retrospective cohort study of 425 patients who underwent PCS with HIPEC and 159 patients who underwent PCS alone. We found incremental cost effectiveness ratios (ICER) of $9,789 per life year saved (LYS) for optimal PCS, $18,164/LYS for suboptimal PCS, and $7,854/LYS for all patients. Our findings provide preliminary data to support that HIPEC at the time of primary cytoreductive surgery can be considered cost-effective regardless of residual disease status when using a standard willingness to pay threshold.

Recurrent uterine inflammatory myofibroblastic tumor previously managed as leiomyosarcoma has sustained response to alectinib.

Soft tissue sarcomas encompass a wide range of histologic subtypes with varied clinical implications. The incorporation of comprehensive genetic profiling into clinical practice is refining our ability to make these distinctions in diagnosis to better reflect prognosis and clinical behavior of a tumor. In this report, we describe a case of recurrent inflammatory myofibroblastic tumor (IMT) of the uterus, initially diagnosed and managed as leiomyosarcoma. At the time of recurrence, the patient was found to have a TNS1-ALK rearrangement and was treated successfully with alectinib, a second-generation anaplastic lymphoma kinase (ALK)-inhibitor. She had a complete response by imaging six months after initiation of alectinib and remains without evidence of disease at 36 months follow-up. Pathology review in the setting of her known ALK fusion and the 2020 update to the World Health Organization Classification of Female Genital Tumors led to a change in diagnosis from leiomyosarcoma to IMT. Our case highlights the role of molecular testing in the diagnosis and management of uterine mesenchymal tumors and the efficacy of alectinib in this ALK-rearranged recurrent IMT of the uterus. Care must be taken to differentiate between IMT and other uterine mesenchymal tumors as this distinction can impact prognosis and management. Furthermore, this case adds to the growing body of evidence supporting the paradigm shift toward developing molecularly targeted therapies rather than disease site-specific treatments, especially in cases of recurrence as recommended by the National Comprehensive Cancer Network.

Surgical outcomes of adnexal masses classified by IOTA ultrasound simple rules.

IOTA (International Ovarian Tumor Analysis) Simple Rules classifies adnexal masses as benign, malignant, or indeterminate based on sonographic features. We seek to determine if IOTA inappropriately directed women to surgery, or more aggressive surgery, than their final diagnosis warranted. This is a retrospective study of sonographically detected adnexal masses with known clinical outcomes from two institutions (n = 528). Surgically managed patients (n = 172) were categorized based on pathology and compared using Chi-square and t-test for categorical and continuous variables respectively. A logistic regression was used to predict characteristics that predicted surgery or imaging follow up of indeterminate masses. Of the 528 masses imaged, 29% (n = 155) underwent surgery for benign pathology. Only 1.9% (n = 10) underwent surgery after classification as malignant by IOTA for what was ultimately a benign mass. Surgical complications occurred in 10 cases (5.8%), all benign. Fifteen (3.2%) patients went into surgically induced menopause for benign masses, one of which was inaccurately classified by IOTA as malignant. Of the 41 IOTA indeterminate masses, the presence of soft tissue nodules on ultrasound was the only statistically significant predictor of the patient being triaged directly to surgery (OR 1.79, p = 0.04). Our findings support that the IOTA ultrasound classification system can provide clinical guidance without incurring unnecessary surgeries or surgical complications.

Benign ovarian thecoma with markedly elevated serum inhibin B levels mimicking adult granulosa cell tumor.

INTRODUCTION: Elevated serum inhibin B is a classic marker of adult granulosa cell tumors. Here we discuss an extremely rare and informative case of elevated inhibin B associated with an ovarian thecoma. CASE: A 57 year-old postmenopausal female presented with recurrent bleeding and was found to have an adnexal mass with an elevated serum inhibin B level of 1,915 pg/mL (normal range 10-200 pg/mL). With a preoperative diagnosis of adult granulosa cell tumor, she underwent surgical management for what was ultimately a benign ovarian thecoma. The diagnosis of thecoma was confirmed by a pericellular pattern of reticulin staining and the lack of a FOXL2 mutation by molecular testing. CONCLUSION: This case demonstrates that inhibin B lacks specificity as a tumor marker for adult granulosa cell tumor, even at very high levels. Knowledge of benign alternative explanations for this finding can facilitate improved preoperative patient counseling. Pertinent literature is reviewed, with an emphasis on proposed hypotheses for inhibin overproduction.

Challenges training left-handed surgeons.

BACKGROUND: Being left-handed (LH) is considered a disadvantage in surgical training. We sought to understand the perspectives of LH trainees and surgical educators on the challenges and modifications in training LH surgeons. METHODS: A survey was distributed to surgeons, surgical residents, and medical students about challenges teaching and learning surgical technique. RESULTS: 25 LH surgeons, 65 right-handed (RH) surgeons, and 39 LH trainees completed the survey. Compared to LH surgeons, RH surgeons reported more difficulty (46% vs 16%, p = 0.003) and less comfort teaching LH trainees (28% vs 4%, p = 0.002), and 10 (15%) reported that LH trainees have less technical ability. RH surgeons identified challenges translating technique to LH trainees and physical limitations of an environment optimized for right-handed mechanics. CONCLUSIONS: The disadvantage LH surgical trainees face is due to barriers in training rather than inherent lesser ability. Nonetheless, minimal modifications are made to overcome these barriers.

Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism.

Purpose: One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs) which are highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPC). The development and molecular signature of NPC-derived glioblastomas were analyzed and the therapeutic effect of blocking CXCL12 was tested.Experimental Design: Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis, and expression of proteins regulating survival and cell-cycle progression.Results: Tumors induced from NPCs display histologic features of human glioblastoma and express markers of GSLC. In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals. In vitro, CXCR4 blockade induces apoptosis and inhibits cell-cycle progression, downregulates molecules regulating survival and proliferation, and also blocks the hypoxic induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation.Conclusions: This study demonstrates that the CXCL12/CXCR4 axis operates in glioblastoma cells under hypoxic stress via an autocrine-positive feedback mechanism, which promotes survival and cell-cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced glioblastoma progression, prevent resistance to treatment, and recurrence of the disease. Clin Cancer Res; 23(5); 1250-62. ©2016 AACR.

A cationic peptide, TAT-Cd°, inhibits herpes simplex virus type 1 ocular infection in vivo.

PURPOSE: To test the in vivo activity of a peptide derived from the protein transducing domain of the human immunodeficiency virus (HIV) Tat protein, TAT-Cd°, in a murine herpes simplex type 1 (HSV-1) keratitis model. METHODS: the efficacy of TAT-CD° was assessed in a postinfection treatment model with different concentrations (1 mg/mL, 0.1 mg/mL, 0.01 mg/mL) of the peptide in one of four delivery vehicles: artificial tears, PBS, methylcellulose, and aquaphor cream. Treatment began within 4 or 24 hours postinfection. Viral titers in the tear film were determined by plaque assay. RESULTS: TAT-Cd° reduced the severity of keratitis in all of the delivery vehicles tested when treatment started, 4 hours postinfection. Peptide in the tears or PBS delivery vehicle had the most significant reduction in disease severity and delayed the onset of vascularization and stromal keratitis. The percentage of mice presenting with disease was also significantly reduced and viral titers were reduced by 1 log at 24 hours postinfection in mice treated with 1 mg/mL TAT-Cd°, suggesting that inhibiting replication early is sufficient to achieve clinical effects. Lower concentrations were not effective and delaying treatment by 24 hours was also not effective. CONCLUSIONS: This study shows that TAT-Cd° is an effective antiviral against HSV-1 strain KOS when applied shortly postinfection and that aqueous-based formulations are more suitable.