Procedural interventions for oligoprogression during treatment with immune checkpoint blockade in gynecologic malignancies: a case series.

OBJECTIVE: To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade. METHODS: Patients with gynecologic cancers treated with immune checkpoint blockade between January 2013 and October 2021 who underwent procedural interventions including surgical resection, interventional radiology ablation, or radiation therapy for oligoprogressive disease were identified. Procedures performed before immune checkpoint therapy initiation or ≥6 months after therapy completion were excluded. Long immunotherapy duration prior to intervention was defined as ≥6 months. Progression-free survival and overall survival were calculated from procedure date until disease progression or death, respectively. RESULTS: During the study period, 886 patients met inclusion criteria and received immune checkpoint blockade therapy. Of these, 34 patients underwent procedural interventions for oligoprogressive disease; 7 underwent surgical resection, 3 underwent interventional radiology ablation, and 24 underwent radiation therapy interventions. Primary disease sites included uterus (71%), ovary (24%), and cervix (6%). Sites of oligoprogression included abdomen/pelvis (26%), bone (21%), lung (18%), distant lymph node (18%), brain (9%), liver (6%), and vagina (3%). Most tumors (76%) did not exhibit microsatellite instability or mismatch repair deficiency. Approximately half (53%) of the patients had long immune checkpoint therapy duration prior to intervention. Median progression-free survival following the procedure was 5.3 months (95% CI, 3.1-9.9), and median overall survival was 21.7 months (95% CI, 14.9-not estimable). Long versus short immune checkpoint therapy duration prior to procedure and length of immune checkpoint therapy had no effect on progression-free or overall survival. CONCLUSIONS: Procedural interventions for patients with oligoprogression on immune checkpoint blockade therapy are feasible and demonstrate favorable outcomes. With expanding use of immune checkpoint therapy, it is important to investigate combined modalities to maximize therapeutic benefit for patients with gynecologic cancers.

How does Injury Severity Score derived from International Classification of Diseases Programs for Injury Categorization using International Classification of Diseases, Tenth Revision, Clinical Modification codes perform compared with Injury Severity Score derived from Trauma Quality Improvement Program?

BACKGROUND: Injury Severity Score (ISS) is a measurement of injury severity based on the Abbreviated Injury Scale. Because of the difficulty and expense of Abbreviated Injury Scale coding, there have been recent efforts in mapping ISS from administrative International Classification of Diseases ( ICD ) codes instead. Specifically, the open source and freely available International Classification of Diseases Programs for Injury Categorization (ICDPIC) in R (Foundation for Statistical Computing, Vienna, Austria) converts International Classification of Diseases, Ninth Revision, codes to ISS. This study aims to compare ICDPIC calculations versus manually derived Trauma Quality Improvement Program (TQIP) calculations for International Classification of Diseases, Tenth Revision ( ICD-10 ), codes. Moderate concordance was chosen as the hypothetical relationship because of previous work by both Fleischman et al. ( J Trauma Nurs. 2017;24(1):4-14) who found moderate to substantial concordance between ICDPIC and ISS and Di Bartolomeo et al. ( Scand J Trauma Resusc Emerg Med. 2010;18(1):17) who found none to slight concordance. Given these very different findings, we thought it reasonable to predict moderate concordance with the use of more detailed ICD-10 codes. METHODS: This was an observational cohort study of 1,040,728 encounters in the TQIP registry for the year 2018. International Classification of Diseases Programs for Injury Categorization in R was used to derive ISS from the ICD-10 codes in the registry. The resulting scores were compared with the manually derived ISS in TQIP. RESULTS: The median difference between ISS calculated by ICDPIC-2021 using ICD-10, Clinical Modification (ISS-ICDPIC), and manually derived ISS was -3 (95% confidence interval, -5 to 0), while the mean difference was -2.09 (95% confidence interval, -2.10 to -2.07). There was substantial concordance between ISS-ICDPIC and manually derived ISS ( κ = 0.66). The ISS-ICDPIC was a better predictor of mortality (area under the curve, 0.853 vs. 0.836) but a worse predictor of intensive care unit admission (area under the curve, 0.741 vs. 0.757) and hospital stay ≥10 days (AUC, 0.701 vs. 0.743). The ICDPIC has substantial concordance with TQIP for the firearm ( κ = 0.69), motor vehicle trauma ( κ = 0.71), and pedestrian ( κ = 0.73) injury mechanisms. CONCLUSION: When TQIP data are unavailable, ICDPIC remains a valid way to calculate ISS after transition to ICD-10 codes. The ISS-ICDPIC performs well in predicting a number of outcomes of interest but is best served as a predictor of mortality. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Management of Pelvic Organ Prolapse in the Adult Congenital Genitourinary Patient.

OBJECTIVES: To assess and present our experience with the management and outcomes of female pelvic organ prolapse in the adult congenital genitourinary patient population. METHODS: Retrospective review of our adult congenital GU patients with spina bifida with a documented Pelvic Organ Prolapse Quantification exam (POP-Q) from 2006 - 2021 was undertaken. Spina bifida lesion level, bladder management method, prolapse stage and component, and obstetric history were reviewed. Outcomes of treated patients are from most recent follow up. RESULTS: 37 congenital GU patients were identified. 26 (70%) were nulliparous with many showing advanced prolapse, defined as stage 2 or greater. By POP-Q, only 22% were stage 0, indicating no prolapse. 68% had advanced prolapse, with one case of complete procidentia despite no pregnancy history. The dominant prolapse compartment in advanced prolapse patients regardless of parity was apical, or cervical (47%). 16 had symptomatic prolapse, most with vaginal bulge or noticing bulge with catheterization. 6 patients underwent surgery with 2 vaginal hysterectomy and uterosacral suspensions and 1 sacrocolpopexy with mesh. Due to elongated cervix with protrusion, 3 patients underwent cervical shortening as their primary prolapse intervention. 4 of the patients saw a decrease in POP-Q score post-operatively with 2 patients still pending follow-up. CONCLUSIONS: Congenital GU patients may have more advanced prolapse at younger ages and nulliparity and are frequently apical dominant. A variety of surgical options can provide meaningful improvement in the symptomatic patient.

Design of a Quantitative LC-MS Method for Residual Toxins Adenylate Cyclase Toxin (ACT), Dermonecrotic Toxin (DNT) and Tracheal Cytotoxin (TCT) in Bordetella pertussis Vaccines.

The antigens for acellular pertussis vaccines are made up of protein components that are purified directly from Bordetella pertussis (B. pertussis) bacterial fermentation. As such, there are additional B. pertussis toxins that must be monitored as residuals during process optimization. This paper describes a liquid chromatography mass spectrometry (LC-MS) method for simultaneous analysis of residual protein toxins adenylate cyclase toxin (ACT) and dermonecrotic toxin (DNT), as well as a small molecule glycopeptide, tracheal cytotoxin (TCT) in a Pertussis toxin vaccine antigen. A targeted LC-MS technique called multiple reaction monitoring (MRM) is used for quantitation of ACT and TCT, which have established limits in drug product formulations. However, DNT is currently monitored in an animal test, which does not have an established quantitative threshold. New approaches for DNT testing are discussed, including a novel standard based on concatenated quantitation sequences for ACT and DNT. Collectively, the method represents a "3-in-1" analytical simplification for monitoring process-related residuals during development of B. pertussis vaccines.

Unmet financial burden of infertility care and the impact of state insurance mandates in the United States: analysis from a popular crowdfunding platform.

OBJECTIVE: To examine infertility-related fund-raising campaigns on a popular crowdfunding website and to compare campaign characteristics across states with and without legislative mandates for insurance coverage for infertility-related care. DESIGN: Retrospective cohort study. SETTING: Online crowdfunding platform (GoFundMe) between 2010 and 2020. PATIENT(S): GoFundMe campaigns in the United States containing the keywords "fertility" and "infertility." INTERVENTION(S): State insurance mandates for infertility treatment coverage. MAIN OUTCOME MEASURE(S): Primary outcomes included fund-raising goals, funds raised, campaign location, and campaigns per capita. RESULT(S): Of the 3,332 infertility-related campaigns analyzed, a total goal of $52.6 million was requested, with $22.5 million (42.8%) successfully raised. The average goal was $18,639 (standard deviation [SD] $32,904), and the average amount raised was $6,759 (SD $14,270). States with insurance mandates for infertility coverage had fewer crowdfunding campaigns per capita (0.75 vs. 1.15 campaigns per 100,000 population than states without insurance mandates. CONCLUSION(S): We found a large number of campaigns requesting financial assistance for costs associated with infertility care, indicating a substantial unmet financial burden. States with insurance mandates had fewer campaigns per capita, suggesting that mandates are effective in mitigating this financial burden. These data can inform future health policy legislation on the state and federal levels to assist with the financial burden of infertility.

Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells.

The plasticity of intrinsic excitability has been described in several types of neurons, but the significance of non-synaptic mechanisms in brain plasticity and learning remains elusive. Cerebellar Purkinje cells are inhibitory neurons that spontaneously fire action potentials at high frequencies and regulate activity in their target cells in the cerebellar nuclei by generating a characteristic spike burst-pause sequence upon synaptic activation. Using patch-clamp recordings from mouse Purkinje cells, we find that depolarization-triggered intrinsic plasticity enhances spike firing and shortens the duration of spike pauses. Pause plasticity is absent from mice lacking SK2-type potassium channels (SK2(-/-) mice) and in occlusion experiments using the SK channel blocker apamin, while apamin wash-in mimics pause reduction. Our findings demonstrate that spike pauses can be regulated through an activity-dependent, exclusively non-synaptic, SK2 channel-dependent mechanism and suggest that pause plasticity-by altering the Purkinje cell output-may be crucial to cerebellar information storage and learning.

Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism.

A common feature of autism spectrum disorder (ASD) is the impairment of motor control and learning, occurring in a majority of children with autism, consistent with perturbation in cerebellar function. Here we report alterations in motor behaviour and cerebellar synaptic plasticity in a mouse model (patDp/+) for the human 15q11-13 duplication, one of the most frequently observed genetic aberrations in autism. These mice show ASD-resembling social behaviour deficits. We find that in patDp/+ mice delay eyeblink conditioning--a form of cerebellum-dependent motor learning--is impaired, and observe deregulation of a putative cellular mechanism for motor learning, long-term depression (LTD) at parallel fibre-Purkinje cell synapses. Moreover, developmental elimination of surplus climbing fibres--a model for activity-dependent synaptic pruning--is impaired. These findings point to deficits in synaptic plasticity and pruning as potential causes for motor problems and abnormal circuit development in autism.