Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with a particularly poor prognosis. For decades, the best available systemic therapy was platinum plus etoposide chemotherapy, ...which offered frequent but transient responses. Survival gains were finally realized with the addition of immune checkpoint inhibitors to first-line chemotherapy. The phase III IMpower 133 trial showed that the addition of atezolizumab to chemotherapy improved survival. The subsequent CASPIAN trial demonstrated a similar benefit with durvalumab. These results quickly established chemo-immunotherapy as the preferred initial treatment for advanced SCLC, but outcomes remain poor for most patients. Here, we review the current and evolving role of immunotherapy in SCLC and outline emerging strategies poised to further elevate the standard of care.
The first anion‐templated synthesis of a lanthanide‐containing interlocked molecule is demonstrated by utilizing a nitrite anion to template initial pseudorotaxane formation. Subsequent stoppering of ...the interpenetrated assembly allows for the preparation of a lanthanide‐functionalized 2rotaxane in high yield. Following removal of the nitrite anion template, the europium 2rotaxane host is demonstrated to recognize and sense fluoride selectively.
“European” union: The first anion‐templated synthesis of a lanthanide‐containing interlocked molecule is demonstrated by the unprecedented use of a nitrite anion template. The europium 2rotaxane is formed in high yield and is demonstrated to recognize and sense fluoride selectively.
Purpose
Pituitary apoplexy can be a life threatening and vision compromising event. Antiplatelet and anticoagulation use has been reported as a contributing factor in pituitary apoplexy (PA). ...Utilizing one of the largest cohorts in the literature, this study aims to determine the risk of PA in patients on antiplatelet/anticoagulation (AP/AC) therapy.
Methods
A single center, retrospective study was conducted on 342 pituitary adenoma patients, of which 77 patients presented with PA (23%). Several potential risk factors for PA were assessed, including: patient demographics, tumor characteristics, pre-operative hormone replacement, neurologic deficits, coagulation studies, platelet count, and AP/AC therapy.
Results
Comparing patients with and without apoplexy, there was no significant difference in the proportion of patients taking aspirin (45 no apoplexy vs. 10 apoplexy; p = 0.5), clopidogrel (10 no apoplexy vs. 4 apoplexy; p = 0.5), and anticoagulation (7 no apoplexy vs. 3 apoplexy; p = 0.7). However, male sex (p-value < 0.001) was a predictor for apoplexy while pre-operative hormone treatment was a protective factor from apoplexy (p-value < 0.001). A non-clinical difference in INR was also noted as a predictor for apoplexy (no apoplexy: 1.01 ± 0.09, apoplexy: 1.07 ± 0.15; p < 0.001).
Conclusions
Although pituitary tumors have a high risk for spontaneous hemorrhage, the use of aspirin is not a risk for hemorrhage. Our study did not find an increased risk of apoplexy with clopidogrel or anticoagulation, but further investigation is needed with a larger cohort. Confirming other reports, male sex is associated with an increased risk for PA.
β-Phosphoglucomutase (βPGM) catalyzes isomerization of β- d -glucose 1-phosphate (βG1P) into d -glucose 6-phosphate (G6P) via sequential phosphoryl transfer steps using a β- d -glucose ...1,6-bisphosphate (βG16BP) intermediate. Synthetic fluoromethylenephosphonate and methylenephosphonate analogs of βG1P deliver novel step 1 transition state analog (TSA) complexes for βPGM, incorporating trifluoromagnesate and tetrafluoroaluminate surrogates of the phosphoryl group. Within an invariant protein conformation, the β- d -glucopyranose ring in the βG1P TSA complexes (step 1) is flipped over and shifted relative to the G6P TSA complexes (step 2). Its equatorial hydroxyl groups are hydrogen-bonded directly to the enzyme rather than indirectly via water molecules as in step 2. The (C)O–P bond orientation for binding the phosphate in the inert phosphate site differs by ∼30° between steps 1 and 2. By contrast, the orientations for the axial O–Mg–O alignment for the TSA of the phosphoryl group in the catalytic site differ by only ∼5°, and the atoms representing the five phosphorus-bonded oxygens in the two transition states (TSs) are virtually superimposable. The conformation of βG16BP in step 1 does not fit into the same invariant active site for step 2 by simple positional interchange of the phosphates: the TS alignment is achieved by conformational change of the hexose rather than the protein.
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that are of considerable clinical potential in transplantation and anti-inflammatory therapies due to their capacity for tissue ...repair and immunomodulation. However, MSCs rapidly differentiate once in culture, making their large-scale expansion for use in immunomodulatory therapies challenging. Although the differentiation mechanisms of MSCs have been extensively investigated using materials, little is known about how materials can influence paracrine activities of MSCs. Here, we show that nanotopography can control the immunomodulatory capacity of MSCs through decreased intracellular tension and increasing oxidative glycolysis. We use nanotopography to identify bioactive metabolites that modulate intracellular tension, growth and immunomodulatory phenotype of MSCs in standard culture and during larger scale cell manufacture. Our findings demonstrate an effective route to support large-scale expansion of functional MSCs for therapeutic purposes.
Antibiotic-loaded bone cement (ALBC) is commonly used in the treatment of periprosthetic joint infections (PJIs) to increase the local concentration of antibiotic at the site of infection. Use of ...ALBC has been associated with rare instances of acute kidney injury (AKI) despite low systemic absorption of the nephrotoxic antibiotics; however, the incidence of AKI is unknown. The purpose of this study was to determine the incidence of and risk factors for AKI associated with ALBC.
This single-site, retrospective cohort study compared 162 PJI patients who underwent Stage 1 revision to a spacer with ALBC to 115 PJI patients who underwent debridement, antibiotics, and implant retention (DAIR) without the use of ALBC. Both groups received similar systemic antibiotics postoperatively. Descriptive statistics and multivariable logistic regressions were used to analyze risk factors for AKI.
There was no statistically significant difference in the rate of AKI: 29 patients (17.9%) in the ALBC group and 17 (14.7%) in DAIR group developed AKI (odds ratio 1.43; 95% CI 0.70 to 2.93). There was a trend toward increased severity of AKI in the ALBC group. Chronic kidney disease, systemic vancomycin, and diuretic use were independent factors associated with the risk of AKI.
An AKI occurred in 17% of PJI patients receiving either a spacer with ALBC or a DAIR. The use of ALBC was not associated with a significant increased risk of AKI. However, the use of systemic vancomycin and diuretic use were independent predictors of AKI in this patient population.
Chronic subdural hematoma (CSDH) is an increasingly prevalent disease in the aging population. Patients with CSDH frequently suffer from concurrent vascular disease or develop secondary thrombotic ...complications requiring antithrombotic treatment.
To determine the safety and impact of early reinitiation of antithrombotics after middle meningeal artery embolization for chronic subdural hematoma.
This is a single-institution, retrospective study of patients who underwent middle meningeal artery (MMA) embolizations for CSDH. Patient with or without antithrombotic initiation within 5 days postembolization were compared. Primary outcome was the rate of recurrence within 60 days. Secondary outcomes included rate of reoperation, reduction in CSDH thickness, and midline shift.
Fifty-seven patients met inclusion criteria. The median age was 66 years (IQR 58-76) with 21.1% females. Sixty-six embolizations were performed. The median length to follow-up was 20 days (IQR 14-44). Nineteen patients (33.3%) had rapid reinitiation of antithrombotics (5 antiplatelet, 11 anticoagulation, and 3 both). Baseline characteristics between the no antithrombotic (no-AT) and the AT groups were similar. The recurrence rate was higher in the AT group (no-AT vs AT, 9.3 vs 30.4%, P = .03). Mean absolute reduction in CSDH thickness and midline shift was similar between groups. Rate of reoperation did not differ (4.7 vs 8.7%, P = .61).
Rapid reinitiation of AT after MMA embolization for CSDH leads to higher rates of recurrence with similar rates of reoperation. Care must be taken when initiating antithrombotics after treatment of CSDH with MMA embolization.
Purpose
We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated ...alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant.
Methods
We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis.
Results
WES revealed a pathogenic paternally inherited indel in
ATM
. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single
ATM
variant. WTS revealed in-frame reciprocal fusion transcripts involving
ATM
and
SLC35F2
indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within
ATM
intron 16 and
SLC35F2
intron 7.
Conclusions
We identified a novel
ATM
-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.
Experimental observations of fluoromagnesate and fluoroaluminate complexes of β-phosphoglucomutase (β-PGM) have demonstrated the importance of charge balance in transition-state stabilization for ...phosphoryl transfer enzymes. Here, direct observations of ground-state analog complexes of β-PGM involving trifluoroberyllate establish that when the geometry and charge distribution closely match those of the substrate, the distribution of conformers in solution and in the crystal predominantly places the reacting centers in van der Waals proximity. Importantly, two variants are found, both of which satisfy the criteria for near attack conformers. In one variant, the aspartate general base for the reaction is remote from the nucleophile. The nucleophile remains protonated and forms a nonproductive hydrogen bond to the phosphate surrogate. In the other variant, the general base forms a hydrogen bond to the nucleophile that is now correctly orientated for the chemical transfer step. By contrast, in the absence of substrate, the solvent surrounding the phosphate surrogate is arranged to disfavor nucleophilic attack by water. Taken together, the trifluoroberyllate complexes of β-PGM provide a picture of how the enzyme is able to organize itself for the chemical step in catalysis through the population of intermediates that respond to increasing proximity of the nucleophile. These experimental observations show how the enzyme is capable of stabilizing the reaction pathway toward the transition state and also of minimizing unproductive catalysis of aspartyl phosphate hydrolysis.
Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for ...Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs.
A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs.
The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis n=4, nondisseminated varicella zoster infection n=2, PJP n=1, and Listeria monocytogenes endophthalmitis n=1) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia n=5 each). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs.
Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.
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