Citations

Abstract Antibiotic-associated diarrhea (AAD) is a common side effect of antibiotics. We examined the gastrointestinal microbiota in children treated with β-lactams for community-acquired pneumonia. Data were from 66 children (n = 198 samples), aged 6–71 months, enrolled in the SCOUT-CAP trial (NCT02891915). AAD was defined as ≥1 day of diarrhea. Stool samples were collected on study days 1, 6–10, and 19–25. Samples were analyzed using 16S ribosomal RNA gene sequencing to identify associations between patient characteristics, microbiota characteristics, and AAD (yes/no). Nineteen (29%) children developed AAD. Microbiota compositional profiles differed between AAD groups (permutational multivariate analysis of variance, P < .03) and across visits (P < .001). Children with higher baseline relative abundances of 2 Bacteroides species were less likely to experience AAD. Higher baseline abundance of Lachnospiraceae and amino acid biosynthesis pathways were associated with AAD. Children in the AAD group experienced prolonged dysbiosis (P < .05). Specific gastrointestinal microbiota profiles are associated with AAD in children.

OBJECTIVE Suprasellar meningioma resection via either the transcranial approach (TCA) or the endoscopic endonasal approach (EEA) is an area of controversy and active evaluation. Skull base surgeons increasingly consider patient-reported outcomes (PROs) when choosing an approach. No PRO measure currently exists to assess quality of life for suprasellar meningiomas. METHODS Adult patients undergoing suprasellar meningioma resection between 2013 and 2019 via EEA (n = 14) or TCA (n = 14) underwent semistructured interviews. Transcripts were coded using a grounded theory approach to identify themes as the basis for a PRO measure that includes all uniquely reported symptoms. To assess content validity, 32 patients and 15 surgeons used a Likert scale to rate the relevance of items on the resulting questionnaire and the general Patient-Reported Outcomes Measurement Information System–29 (PROMIS29). The mean scores were calculated for all items and compared for TCA versus EEA patient cohorts by using unpaired t-tests. Items on either questionnaire with mean scores ≥ 2.0 from patients were considered meaningful and were aggregated to form the novel Suprasellar Meningioma Patient-Reported Outcome Survey (SMPRO) instrument. RESULTS Qualitative analyses resulted in 55 candidate items. Relative to patients who underwent the EEA, those who underwent the TCA reported significantly worse future outlook before surgery (p = 0.01), tiredness from medications 2 weeks after surgery (p = 0.001), and word-finding and memory difficulties 3 months after surgery (p = 0.05 and < 0.001, respectively). The items that patients who received a TCA were most concerned about included medication-induced lethargy after surgery (2.9 ± 1.3), blurry vision before surgery (2.7 ± 1.5), and difficulty reading due to blurry vision before surgery (2.7 ± 2.7). Items that patients who received an EEA were most concerned about included blurry vision before surgery (3.5 ± 1.3), difficulty reading due to blurry vision before surgery (2.4 ± 1.3), and problems with smell postsurgery (2.9 ± 1.3). Although surgeons overall overestimated how concerned patients were about questionnaire items (p < 0.0005), the greatest discrepancies between patient and surgeon relevance scores were for blurry vision pre- and postoperatively (p < 0.001 and < 0.001, respectively) and problems with taste postoperatively (p < 0.001). Seventeen meningioma-specific items were considered meaningful, supplementing 8 significant PROMIS29 items to create the novel 25-item SMPRO. CONCLUSIONS The authors developed a disease- and approach-specific measure for suprasellar meningiomas to compare quality of life by operative approach. If demonstrated to be reliable and valid in future studies, this instrument may assist patients and providers in choosing a personalized surgical approach.

Background: Since its first description in 2012, the Goldilocks procedure has become an option for immediate breast reconstruction, particularly for obese patients who are poor candidates for traditional implant or autologous reconstruction. In this work, the authors performed a longitudinal study of patients who underwent mastectomy with Goldilocks reconstruction to assess the incidence of additional surgical procedures, and to assess surgical outcomes and patient satisfaction. Methods: A retrospective review of patients who underwent mastectomy with the Goldilocks procedure only at Mayo Clinic Rochester between January of 2012 and September of 2019 was performed. Demographics, complications, additional breast procedures performed to attain the final results, and patient-reported outcomes using the BREAST-Q were recorded. Univariate and multivariable analyses were performed to identify statistical associations and risk factors. Results: Sixty-three patients (108 breasts) were included. Mean age was 57.8 years. Mean body mass index was 37.6 kg/m2. Median follow-up time after the mastectomy with the Goldilocks procedure was 15 months. The major complication rate within the first 30 days was 9.3 percent. Forty-four breasts (40.7 percent) underwent additional surgery. Dyslipidemia was significantly associated with an increased risk of additional surgery (adjusted hazard ratio, 2.00; p = 0.045). Scores in the four BREAST-Q domains were not statistically different between patients who had additional procedures and those who did not. Conclusions: Based on the results, the authors recommend a thorough preoperative discussion with patients who are candidates for the Goldilocks procedure to explore all options for reconstruction and their expectations, because it is crucial to reduce the necessity for additional operations in this high-risk population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

190 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal (GE) cancers are the leading causes of GI cancer–related mortality (5-yr survival rate, 14%, 3% and ̃5-6%, respectively). T-cell immunotherapy targeting GI-associated tumor antigens has been attempted, but efficacy has been constrained by on-target off-tumor toxicity, limiting the therapeutic window. The Tmod (TM) platform is an AND-NOT logic-gated CAR T modular system, versions of which have a CEA- or MSLN-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor to protect normal cells. Tmod CAR T exploits HLA LOH, common in GI malignancies (10-33% in primary solid tumors [TCGA]) and can kill tumor cells without harming healthy cells in vitro and in vivo. However, the prevalence of HLA LOH across GI tumors is unknown in the real-world setting. We utilized the Tempus xT oncology NGS database of patients with multiple GI tumors. From a standard-of-care NGS assay, GI cancer patients can be readily identified for HLA LOH and future treatment with Tmod CAR T therapy. Methods: The occurrence of HLA LOH in GI tumors of 1439 patients was assessed using paired germline and somatic DNA sequencing using a research assay [6]. CRC, PANC and GE patients with ≥ stage 3 were then extracted, and rates of HLA LOH were identified (ie, whether loss occurred across high-frequency HLA-A alleles). In addition, mutations in KRAS and BRAF, as well as MSI status were stratified to determine any association with HLA-A LOH. Results: HLA-A LOH was detected in 830 (17.3%) of all solid tumor records, and a similar proportion when all GI cancer records were analyzed (17.0%). For GI subtypes, these values ranged from 13.5% to 23.1% (Table). No high-frequency HLA-A allele (A*01, A*02, A*03, A*11) was more likely to be lost. Clinical biomarkers ( KRAS, BRAF and MSI status) were not associated with HLA-LOH. Conclusions: The frequency of HLA LOH among advanced solid tumor cancers in this dataset is 17.3%, with a range of 13.5-23% between CRC, PANC and GE. The HLA LOH frequency observed in these GI tumors is consistent with that in primary tumors from TCGA, which also used germline-matched and tumor samples. Clinical biomarkers were not associated with HLA LOH. Tempus NGS was able to identify HLA LOH, which can be used for Tmod CAR T therapy to an enhanced therapeutic window. Identification of these patients in BASECAMP-1 (NCT04981119) will enable novel Tmod CAR T therapy. [Table: see text]

OBJECTIVE Spine robots have seen increased utilization over the past half decade with the introduction of multiple new systems. Market research expects this expansion to continue over the next half decade at an annual rate of 20%. However, because of the novelty of these devices, there is limited literature on their learning curves and how they should be integrated into residency curricula. With the present review, the authors aimed to address these two points. METHODS A systematic review of the published English-language literature on PubMed, Ovid, Scopus, and Web of Science was conducted to identify studies describing the learning curve in spine robotics. Included articles described clinical results in patients using one of the following endpoints: operative time, screw placement time, fluoroscopy usage, and instrumentation accuracy. Systems examined included the Mazor series, the ExcelsiusGPS, and the TiRobot. Learning curves were reported in a qualitative synthesis, given as the mean improvement in the endpoint per case performed or screw placed where possible. All studies were level IV case series with a high risk of reporting bias. RESULTS Of 1579 unique articles, 97 underwent full-text review and 21 met the inclusion and exclusion criteria; 62 articles were excluded for not presenting primary data for one of the above-described endpoints. Of the 21 articles, 18 noted the presence of a learning curve in spine robots, which ranged from 3 to 30 cases or 15 to 62 screws. Only 12 articles performed regressions of one of the endpoints (most commonly operative time) as a function of screws placed or cases performed. Among these, increasing experience was associated with a 0.24- to 4.6-minute decrease in operative time per case performed. All but one series described the experience of attending surgeons, not residents. CONCLUSIONS Most studies of learning curves with spine robots have found them to be present, with the most common threshold being 20 to 30 cases performed. Unfortunately, all available evidence is level IV data, limited to case series. Given the ability of residency to allow trainees to safely perform these cases under the supervision of experienced senior surgeons, it is argued that a curriculum should be developed for senior-level residents specializing in spine comprising a minimum of 30 performed cases.

AbstractSurgical trials in breast cancer have catalyzed contemporary trial design for solid organ cancers and are a prime example of surgeons taking the lead in clinical trial design. Surgeons have lead trials that have improved patient outcomes and quality of life without sacrificing oncologic safety. We have evolved from radical mastectomy to breast conservation and sentinel node biopsy. Contemporary trial design in breast cancer now focus on personalizing care based on tumor genomics

Abstract Low-grade glioma (LGG) are generally slowly growing brain cancers, that frequently undergo malignant progression to aggressive, secondary glioblastoma with a dismal prognosis. By combining genetically engineered Idh1-mutant mice with in vivo CRISPR gene editing we generated a mouse model faithfully recapitulating the founder mutations of LGG. Clonal activation of the neomorphic Idh1 R132H mutation cooperates with Trp53 and Atrx mutations to trigger development of brain tumors but only with ~30% penetrance and very long latency. To elucidate the molecular mechanisms underlying the malignant progression of IDH1-mutant LGG, we devised and deployed a direct in vivo CRISPR screen targeting genes commonly mutated in human IDH-mutant secondary glioblastoma. Stereotaxic delivery of a lentiviral sgRNA library targeting the mouse orthologs of these genes into the brain of Idh1 R132H ;Trp53;Atrx;Cas9 and control Idh1 wt ;Trp53;Atrx;Cas9 compound mutant mice resulted in rapid formation of tumors that recapitulate human Idh1-mutant glioblastoma. Deconvoluting the screen showed that PI3K pathway members Pten and Pik3ca as well as Notch1, Smarca4 and Fat1 are preferentially enriched in Idh1 R132H-tumors, while Rb1 and NF2 were enriched in Idh1 wt tumors. Co-mutation analysis further identified additional co-occurring driver combinations such as Bcor-Met, Olig2-Met, Olig2-Med12 or Bcor-Olig2. We validated the tumor suppressive function of Notch1 and Pten using conventional floxed knock-out alleles and found that Notch1 functions in a haploinsufficient manner. Interestingly, Idh1 R132H did not alter tumor latency or pathology in a high grade p53;Pten;Rb1 mutant background, indicating that the neomorphic IDH-mutations can drive low but not high grade glioma development. Our study provides a functional landscape of gliomagenesis suppressors in vivo.