Advancing Evidence Generation for Circulating Tumor DNA: Lessons Learned from A Multi-Assay Study of Baseline Circulating Tumor DNA Levels across Cancer Types and Stages.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

The Effect of Transversus Abdominis Plane Block Timing on Milliequivalents of Opioid Use and Immediate Postoperative Pain Scores in Patients Undergoing Minimally Invasive Hysterectomy: A Retrospective Cohort Study.

STUDY OBJECTIVE: To examine the effect of transversus abdominis plane (TAP) block timing (preoperative or postoperative) on postoperative opioid use (quantified via morphine milligram equivalents; MME) and pain scores in patients undergoing minimally invasive hysterectomy for benign indications. DESIGN: Retrospective, single-institution cohort study SETTING: Academic-affiliated community hospital PATIENTS: A total of 2982 patients were included who underwent a minimally invasive total hysterectomy between January 2018 and December 2022, excluding patients with a malignancy diagnosis, concurrent urogynecological procedure, vaginal hysterectomy, supracervical hysterectomy, or those with baseline narcotic use (opioid use within the 3 months before surgery). Patients were separated into 3 groups: no TAP blocks (n = 1966, 65.9%), preoperative TAP blocks (854, 28.6%), and postoperative TAP blocks (162, 5.4%). INTERVENTIONS: Summary statistics and mixed-effects regression methods were used for data analysis. MEASUREMENTS AND MAIN RESULTS: There was a statistically significant lower mean use of opioids (MME 43.2 vs 53.9, p = .002) among patients who received a TAP block (either pre or postoperatively) than those who did not receive a block. However, when comparing preoperative vs postoperative patients with TAP block, there was no statistically significant difference in mean opioid use (MME 43.4 vs 42.1, p = .752). There were no differences in postoperative pain scores between patients with and without a TAP block, however, more opioids were required in patients who did not receive a TAP block to achieve the same pain scores as those who did receive a TAP block. There was a statistically significant shorter time to discharge for TAP versus patients without TAP block(median 5.5 vs 6.3 hours, p ≤ .001) as well as preoperative versus postoperative patients with TAP block (median 5.3 vs 6.2 hours, p = .001). CONCLUSION: While TAP block use at the time of minimally invasive hysterectomy reduced use of postoperative opioids, the timing of TAP block, either preoperatively or postoperatively, did not significantly affect opioid use. Preoperative compared with postoperative TAP block administration significantly shortened the time to discharge.

Cartilage diversification and modularity drove the evolution of the ancestral vertebrate head skeleton.

The vertebrate head skeleton has evolved a myriad of forms since their divergence from invertebrate chordates. The connection between novel gene expression and cell types is therefore of importance in this process. The transformation of the jawed vertebrate (gnathostome) head skeleton from oral cirri to jointed jaw elements required a diversity of cartilages as well as changes in the patterning of these tissues. Although lampreys are a sister clade to gnathostomes, they display skeletal diversity with distinct gene expression and histologies, a useful model for addressing joint evolution. Specifically, the lamprey tissue known as mucocartilage has noted similarities with the jointed elements of the mandibular arch in jawed vertebrates. We thus asked whether the cells in lamprey mucocartilage and gnathostome joint tissue could be considered homologous. To do this, we characterized new genes that are involved in gnathostome joint formation and characterized the histochemical properties of lamprey skeletal types. We find that most of these genes are minimally found in mucocartilage and are likely later innovations, but we do identify new activity for gdf5/6/7b in both hyaline and mucocartilage, supporting its role as a chondrogenic regulator. Contrary to previous works, our histological assays do not find any perichondrial fibroblasts surrounding mucocartilage, suggesting that mucocartilage is non-skeletogenic tissue that is partially chondrified. Interestingly, we also identify new histochemical features of the lamprey otic capsule that diverge from normal hyaline. Paired with our new insights into lamprey mucocartilage, we propose a broader framework for skeletal evolution in which an ancestral soxD/E and gdf5/6/7 network directs mesenchyme along a spectrum of cartilage-like features.

Adnexal torsion: a review of diagnosis and management strategies.

PURPOSE OF REVIEW: Adnexal torsion remains a diagnostic challenge heavily reliant on high clinical suspicion, with patient presentation and imaging used as adjuncts to aid in its diagnosis. This review summarizes diagnostic and management techniques of adnexal torsion to assist providers when encountering this surgical emergency. RECENT FINDINGS: Common findings of adnexal torsion include abdominal pain, nausea, vomiting, and adnexal mass or ovarian enlargement. An elevated neutrophil to lymphocyte ratio may be useful for diagnosis. A 'whirlpool' sign, 'follicular ring' sign, enlarged/edematous ovary, and absent Doppler flow to the ovary are highly suggestive of adnexal torsion. Intraoperative visual diagnosis of ovarian death is highly inaccurate, with only 18-20% of ovaries necrotic on pathological examination. Necrotic appearing ovaries have been shown to have follicular activity on ultrasound one year postoperatively. SUMMARY: Pelvic ultrasound remains the first-line imaging modality. In patients of reproductive age, we recommend performing detorsion with ovarian conservation, even in cases where the tissue appears necrotic, given poor intraoperative diagnostic rates of tissue death. Retention of ovarian function is also reliant on a timely diagnosis and intervention. We emphasize that the risk of ovarian damage/loss outweigh the risk of a diagnostic laparoscopy in patients of reproductive age.

A Comprehensive Analysis of Fibrillar Collagens in Lamprey Suggests a Conserved Role in Vertebrate Musculoskeletal Evolution.

Vertebrates have distinct tissues which are not present in invertebrate chordates nor other metazoans. The rise of these tissues also coincided with at least one round of whole-genome duplication as well as a suite of lineage-specific segmental duplications. Understanding whether novel genes lead to the origin and diversification of novel cell types, therefore, is of great importance in vertebrate evolution. Here we were particularly interested in the evolution of the vertebrate musculoskeletal system, the muscles and connective tissues that support a diversity of body plans. A major component of the musculoskeletal extracellular matrix (ECM) is fibrillar collagens, a gene family which has been greatly expanded upon in vertebrates. We thus asked whether the repertoire of fibrillar collagens in vertebrates reflects differences in the musculoskeletal system. To test this, we explored the diversity of fibrillar collagens in lamprey, a jawless vertebrate which diverged from jawed vertebrates (gnathostomes) more than five hundred million years ago and has undergone its own gene duplications. Some of the principal components of vertebrate hyaline cartilage are the fibrillar collagens type II and XI, but their presence in cartilage development across all vertebrate taxa has been disputed. We particularly emphasized the characterization of genes in the lamprey hyaline cartilage, testing if its collagen repertoire was similar to that in gnathostomes. Overall, we discovered thirteen fibrillar collagens from all known gene subfamilies in lamprey and were able to identify several lineage-specific duplications. We found that, while the collagen loci have undergone rearrangement, the Clade A genes have remained linked with the hox clusters, a phenomenon also seen in gnathostomes. While the lamprey muscular tissue was largely similar to that seen in gnathostomes, we saw considerable differences in the larval lamprey skeletal tissue, with distinct collagen combinations pertaining to different cartilage types. Our gene expression analyses were unable to identify type II collagen in the sea lamprey hyaline cartilage nor any other fibrillar collagen during chondrogenesis at the stages observed, meaning that sea lamprey likely no longer require these genes during early cartilage development. Our findings suggest that fibrillar collagens were multifunctional across the musculoskeletal system in the last common ancestor of vertebrates and have been largely conserved, but these genes alone cannot explain the origin of novel cell types.

Cancer Risk-Reducing Opportunities in Gynecologic Surgery.

This review article discusses cancer risk-reducing opportunities in gynecologic surgery. We cover strategies to reduce ovarian and uterine cancer risk by presenting general practice guidelines and expanding on the literature behind clinical decision points. We address populations of women at increased hereditary risk and those at population risk. We specifically discuss risk-reducing salpingo-oophorectomy, prophylactic salpingectomy with delayed oophorectomy, concomitant hysterectomy, opportunistic salpingectomy, bilateral tubal ligation, and hysterectomy. For clinical scenarios in which data are limited or conflicting, we detail the studies on which clinicians' decisions hinge to allow the reader to weigh the available evidence.

Blinded measure of Trendelenburg angle in pelvic robotic surgery.

STUDY OBJECTIVE: To estimate the Trendelenburg angle needed to perform robotic gynecologic surgical procedures. DESIGN: Cross-sectional study (Canadian Task Force classification III). SETTING: Community hospital. PATIENTS: All women undergoing gynecologic pelvic surgery using the da Vinci surgical robot at a single institution between December 2010 and April 2011. INTERVENTIONS: The primary surgeon determined the Trendelenburg angle needed for adequate visualization to perform surgery defined as small bowel and sigmoid colon displaced out of the surgical field. MEASUREMENTS AND MAIN RESULTS: The primary outcome, measured in blinded fashion, was the degree of Trendelenburg positioning needed to complete the surgical procedure robotically. Secondary data collected included body mass index, type of surgery performed, maximum end-tidal CO(2), and maximum peak inspiratory pressure. Sixteen surgeons performed a total of 104 robotic gynecologic pelvic surgeries during the study. Data were available for 86 cases. The mean Trendelenburg angle used was 28.0 degrees (95% confidence interval, 26.9-29.1). This was significantly less than the 40 degrees (p < .001) commonly recommended. The Trendelenburg angle used did not correlate with body mass index (r = -0.2; p = .13) or type of surgery performed (p = .41). Neither the maximum end-tidal CO(2) or maximum peak inspiratory pressure was influenced by the Trendelenburg angle used when adjusted for age and body mass index. CONCLUSIONS: A mean Trendelenburg angle of 28.0 degrees was adequate to complete most gynecologic robotic surgical procedures when compared with historical control angle of 40 degrees.

Robotic surgical staging for obese patients with endometrial cancer.

OBJECTIVE: To compare surgical outcomes for robotic vs laparotomy staging in obese endometrial cancer patients. STUDY DESIGN: This was a retrospective cohort study of patients with body mass index ≥30 kg/m(2) staged in a community gynecologic oncology practice. Patients undergoing robotic staging were compared with historic laparotomy controls. RESULTS: One hundred twenty-nine patients underwent robotic staging, compared with 110 laparotomy patients. The robotic cohort had fewer abdominal wound complications (13.9% vs 32.7%, P < .001), but more vaginal cuff complications (4.7% vs 0%, P = .032). Blood loss was lower in the robotic group (P < .001), as was length of stay (P < .001). Surgical times were longer in the robotic group (P < .001). There was no difference in terms of percentage of patients undergoing pelvic or paraaortic lymph node dissection. CONCLUSION: Robotic staging for endometrial cancer is feasible in obese women, with fewer abdominal wound complications, but more vaginal cuff complications.

Vaginal fluid human chorionic gonadotropin for detection of rupture of membranes.

OBJECTIVE: To evaluate the accuracy of qualitative and quantitative human chorionic gonadotropin (hCG) assays to detect ruptured amniotic membranes (ROM) in term patients. STUDY DESIGN: We conducted a prospective cohort study enrolling 100 term pregnancies with intact membranes. Samples were collected before and immediately following ROM, and at 2 and 4 hours post-ROM. Quantitative and qualitative hCG assays were performed on all samples. Outcome measures included the detection and measured amount of hCG before and after ROM. Sensitivity, specificity and positive predictive values for the qualitative assays were determined. RESULTS: A total of 98% pre-ROM and 100% post-ROM qualitative assays tested positive with mean quantitative hCG levels of 181.30 mIU/mL and 208.24 mIU/mL, respectively. The qualitative post-ROM sensitivity was 100%; however, the pre-ROM specificity was only 2%. The positive predictive value for detecting ROM was 50%. CONCLUSION: Qualitative and quantitative hCG assays are not useful for determining ROM in term pregnancies.

Primary intussusception in pregnancy: a case report.

BACKGROUND: Intussusception is a rare cause of bowel obstruction in adults, typically associated with malignancy, granuloma formation, a foreign body or an anatomic defect. CASE: A 21-year-old, primiparous woman presented at 33 5/7 weeks' gestation with vague abdominal symptoms consistent with acute viral gastroenteritis. She did not improve with conservative measures. A presumptive diagnosis of severe preeclampsia was made based on elevated blood pressure, abnormal liver function tests and epigastric pain. Labor was induced 34 5/7 weeks' gestation. The patient did not improve after an uncomplicated vaginal delivery. Abdominal radiographs and computed tomography were consistent with intussusception. Surgical findings were consistent with the radiologic findings. The patient underwent a right hemicolectomy with stapled anastomosis. No pathologic or anatomically anomalous lead point was identified intraoperatively or on final pathology. CONCLUSION: Intussusception is a rare finding in the peripartum period, often presenting with vague abdominal symptoms and mistaken for benign obstetric and nonobstetric diseases. This case is only the second one of adult perinatal intussusception without an anatomic or pathologic lead point.