Cervical spinal cord dimensions and clinical outcomes in adults with Klippel-Feil syndrome: A comparison with matched controls.

Study Design Retrospective case–control study. Objectives To confirm the fact that spinal cord dimensions are smaller in adults with Klippel-Feil syndrome (KFS) than in pediatric patients with KFS and to compare the clinical characteristics and outcomes of neurologic complications in patients with KFS with matched controls. Methods We performed an independent 1:2 case–control retrospective radiographic and chart review of a consecutive series of adults with KFS who underwent surgical intervention. The control group consisted of consecutive non-KFS surgical patients. Patients were matched in 1:2 case–control manner. Their charts were reviewed and the clinical characteristics were compared. Axial T2-weighted magnetic resonance imaging (MRI) was used to measure the anteroposterior and mediolateral axial spinal cord and spinal canal at the operative levels and measurements were compared. Results A total of 22 patients with KFS and 44 controls were identified. The KFS group had a tendency of more myeloradiculopathy, and the control group had a tendency toward more radiculopathy. Both tendencies, however, were not significantly different. MRIs of 10 patients from the KFS group and 22 controls were available. There was no difference in the area of both spinal cord and canal at the operative levels. Conclusion Contrary to the finding in previous reports on pediatric patients, there were no differences between KFS and well-matched control groups in terms of age of onset, presentation, revision rate, complication rate, surgical outcome, and cross-sectional spinal cord and canal dimensions at the operative level

Malic enzyme 1 absence in synovial sarcoma shifts antioxidant system dependence and increases sensitivity to ferroptosis induction with ACXT-3102

PURPOSE: To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. EXPERIMENTAL DESIGN: ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo. RESULTS: ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls. CONCLUSIONS: These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients. See related commentary by Subbiah and Gan, p. 3408

Pheromone Trail Following in Three Dimensions by the Freshwater Copepod \u3cem\u3eHesperodiaptomus shoshone\u3c/em\u3e

Finding mates can pose a particular problem for obligately sexual planktonic organisms, resulting in a variety of adaptations to ensure sufficient mating. Several types of mate-finding behavior have been observed in marine copepods, but the one most effective at low population density, following a pheromone trail, has not been observed in freshwater copepods. Using three-dimensional (3D) videography, we show that males of the large-bodied alpine species Hesperodiaptomus shoshone follow pheromones in the female\u27s trail. Using a trail mimic comprised of female-conditioned water, we found that males followed female scent without the presence of the female. This behavior was reduced when the female scent was diluted, suggesting that the male\u27s behavior can be modified by the intensity of the chemical signal. Analyses of the 3D trajectories of copepods that formed mating pairs indicate that the male does not make a direct approach to the female, as might be expected if he relied purely on hydrodynamic or visual cues. Instead, males that are \u3e0.5 cm from females react to crossing female trails by making an abrupt turn and spending more than 2 s following the female\u27s trail. Furthermore, flow field analysis showed that at this distance it was unlikely that copepods could distinguish the hydrodynamic signal from the background flow. This is the first demonstration of chemical trail following in a freshwater copepod and has important implications for encounter rates and viable population densities in similar species

CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade

Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role of CD4+ T cells in ICB-induced antitumor activity is not well defined; however, CD4+ T cells are speculated to play a supportive role in the development of CD8+ T cells that kill tumor cells after recognition of tumor antigens presented by MHC class I. To investigate the mechanisms of ICB-induced activity against UC, we developed mouse organoid-based transplantable models that have histologic and genetic similarity to human bladder cancer. We found that ICB can induce tumor rejection and protective immunity with these systems in a manner dependent on CD4+ T cells but not reliant on CD8+ T cells. Evaluation of tumor infiltrates and draining lymph nodes after ICB revealed expansion of IFN-γ-producing CD4+ T cells. Tumor cells in this system express MHC class I, MHC class II, and the IFN-γ receptor (Ifngr1), but none were necessary for ICB-induced tumor rejection. IFN-γ neutralization blocked ICB activity, and, in mice depleted of CD4+ T cells, IFN-γ ectopically expressed in the tumor microenvironment was sufficient to inhibit growth of tumors in which the epithelial compartment lacked Ifngr1. Our findings suggest unappreciated CD4+ T cell-dependent mechanisms of ICB activity, principally mediated through IFN-γ effects on the microenvironment

Mycotic Aneurysm after Bacillus Calmette-Guérin Treatment: Case Report and Review of the Literature

Background. Intravesicular Bacillus Calmette-Guérin (BCG) is an effective adjunctive therapy for superficial bladder cancer that has been shown to delay recurrence and progression of disease. Serious side effects are relatively rare but are difficult to diagnosis and commonly overlooked. Case Presentation. We report the case of a patient who was found to have mycotic aortic aneurysms secondary to treatment with BCG after a prolonged course with multiple intervening hospitalizations. Conclusion. Through this report, we discuss our present understanding of BCG infection following treatment and review the literature regarding this particular rare manifestation

Ovarian complete hydatidiform mole: case study with molecular analysis and review of the literature

Ectopic complete molar pregnancy in the ovary is an exceptionally rare event. Here we present a case of ovarian complete hydatidiform mole in a 20-year-old gravida 2 para 1 woman. At presentation, the patient underwent excision of a hemorrhagic left ovarian cyst, with routine sections demonstrating a hemorrhagic corpus luteum with a single microscopic focus of detached atypical trophoblast, without chorionic villi. Subsequent left salpingo-oophorectomy for persistently elevated human chorionic gonadotropin led to a final diagnosis of complete hydatidiform mole arising in the ovary. The fallopian tube was unremarkable. Zygosity was determined using short tandem repeat analysis, confirming the diagnosis of monospermic complete mole. In the clinical setting of a markedly elevated human chorionic gonadotropin level and an ovarian mass, histopathologic examination is critical in distinguishing ectopic pregnancy from choriocarcinoma. Short tandem repeat analysis can be a useful adjunct to histologic diagnosis in challenging cases

Clinicopathologic consensus study of gray zone lymphoma with features intermediate between DLBCL and classical HL

Accurate GZL diagnosis remains challenging, with >60% of patients with presumed GZL having the diagnosis reclassified on consensus review. Treatment with DLBCL-based therapy appears most effective for GZL (including R-CHOP); however, new therapies are needed to improve outcomes. Gray zone lymphoma (GZL) is described as sharing features with classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). However, there remains complexity in establishing diagnosis, delineating prognosis, and determining optimum therapy. Sixty-eight cases diagnosed as GZL across 15 North American academic centers were evaluated by central pathology review to achieve consensus. Of these, only 26 (38%) were confirmed as GZL. Morphology was critical to GZL consensus diagnosis (eg, tumor cell richness); immunohistochemistry showed universal B-cell derivation, frequent CD30 expression, and rare Epstein-Barr virus (EBV) positivity (CD20 + , 83%; PAX5 + , 100%; BCL6 + , 20%; MUM1 + , 100%; CD30 + , 92%; EBV + , 4%). Forty-two cases were reclassified: nodular sclerosis (NS) cHL, n = 27 (including n = 10 NS grade 2); lymphocyte predominant HL, n = 4; DLBCL, n = 4; EBV + DLBCL, n = 3; primary mediastinal large BCL n = 2; lymphocyte-rich cHL and BCL–not otherwise specified, n = 1 each. GZL consensus-confirmed vs reclassified cases, respectively, more often had mediastinal disease (69% vs 41%; P = .038) and less likely more than 1 extranodal site (0% vs 25%; P = .019). With a 44-month median follow-up, 3-year progression-free survival (PFS) and overall survival for patients with confirmed GZL were 39% and 95%, respectively, vs 58% and 85%, respectively, for reclassified cases ( P = .19 and P = .15, respectively). Interestingly, NS grade 2 reclassified patients had similar PFS as GZL consensus-confirmed cases. For prognostication of GZL cases, hypoalbuminemia was a negative factor (3-year PFS, 12% vs 64%; P = .01), whereas frontline cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab (CHOP±R) was associated with improved 3-year PFS (70% vs 20%; P = .03); both factors remained significant on multivariate analysis. Altogether, accurate diagnosis of GZL remains challenging, and improved therapeutic strategies are needed