Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.

Self-reported knowledge of tetrahydrocannabinol and cannabidiol concentration in cannabis products among cancer patients and survivors.

PURPOSE: Cannabis use may introduce risks and/or benefits among people living with cancer, depending on product type, composition, and nature of its use. Patient knowledge of tetrahydrocannabinol (THC) or cannabidiol (CBD) concentration could provide information for providers about cannabis use during and after treatment that may aide in risk and benefit assessments. This study aimed to examine knowledge of THC or CBD concentration among patients living with cancer who consume cannabis, and factors associated with knowledge of cannabinoid concentrations. METHODS: People living with cancer who consumed cannabis since their diagnosis (n = 343) completed an anonymous, mixed-mode survey. Questions assessed usual mode of delivery (MOD), knowledge of THC/CBD concentration, and how source of acquisition, current cannabis use, and source of instruction are associated with knowledge of THC/CBD concentration. Chi-square and separate binary logistic regression analyses were examined and weighted to reflect the Roswell Park patient population. RESULTS: Less than 20% of people living with cancer had knowledge of THC and CBD concentration for the cannabis products they consumed across all MOD (smoking- combustible products, vaping- vaporized products (e-cigarettes), edibles-eating or drinking it, and oral- taking by mouth (pills)). Source of acquisition (smoking-AOR:4.6, p < 0.01, vaping-AOR:5.8, p < 0.00, edibles-AOR:2.6, p < 0.04), current cannabis use (edibles-AOR:5.4, p < 0.01, vaping-AOR: 11.2, p < 0.00, and oral-AOR:9.3, p < 0.00), and source of instruction (vaping only AOR:4.2, p < 0.05) were found to be variables associated with higher knowledge of THC concentration. CONCLUSION: Self-reported knowledge of THC and CBD concentration statistically differed according to MOD, source of acquisition, source of instruction, and current cannabis use.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Palliative Management of Inoperable Malignant Bowel Obstruction: Prospective, Open Label, Phase 2 Study at an NCI Comprehensive Cancer Center.

CONTEXT: Malignant bowel obstruction (MBO) is a common complication of intra-abdominal cancer, frequently seen in advanced gastrointestinal and gynecologic cancer. Management of MBO can be challenging, particularly if the patient is not a surgical candidate. No consensus exists on how best to manage these patients medically. Retrospective studies suggest that the combination of dexamethasone, octreotide and metoclopramide may lead to relief of obstruction and improvement in symptoms associated with the obstruction. OBJECTIVES: This study seeks to prospectively evaluate the combination of drug "triple therapy" dexamethasone 4 mg BID, metoclopramide 10 mg Q6 and octreotide 300 mcg TID to assess tolerability, safety, and effect on symptoms and deobstruction. METHODS: Adults admitted at Roswell Park Comprehensive Cancer Center with malignant bowel obstruction were eligible. Eligible patients who constented to the study were started on the triple therapy with close monitoring of symptoms and for adverse effects. RESULTS: A total of 15 patients enrolled in the study. Two patients experienced bradycardia as adverse effect and there was no incidence of bowel perforation. All patients who completed the study had complete resolution of their nausea, and improvement in other symptoms including pain, constipation, tolerance of oral intake and resumption of bowel movements. Only two of the 15 patients were alive to complete the six-month post study follow up. CONCLUSION: "Triple therapy" with dexamethasone, metoclopramide, and octreotide for management of nonsurgical MBO in this small sample size appears safe and well tolerated however a diagnosis of inoperable MBO remains associated with poor prognosis and death within months.

Vitreous metastasis from cutaneous melanoma: diagnosis and management / Metástase vítrea de melanoma cutâneo: diagnóstico e tratamento

ABSTRACT Purpose: To report the clinical findings, treatments, and outcomes in a series of patients with vitreous metastasis from cutaneous melanoma. Methods: This single-center, retrospective, interventional case series included patients with biopsy-confirmed vitreous metastasis from cutaneous melanoma diagnosed between 1997 and 2020. Standard 23- or 25-gauge pars plana vitrectomy was performed for diagnostic sampling. Sclerotomies were treated with double or triple freeze-thaw cryotherapy. Perioperative intravitreal injections of melphalan (32 µg/0.075 mL) were administered, when indicated. Visual acuity, intraocular pressure, and systemic and ocular treatment responses were reported. Results: Five eyes of five patients with unilateral vitreous metastasis from cutaneous melanoma were identified. The median age at diagnosis was 84 (range, 37-88) years. The median follow-up after ophthalmic diagnosis was 28 (8.5-36) months; one patient did not have a follow-up. The initial visual acuity ranged from 20/30 to hand motions. Baseline clinical findings included pigmented or non-pigmented cellular infiltration of the vitreous (5/5), anterior segment (4/5), and retina (3/5). Four patients had secondary glaucoma. Systemic therapy included checkpoint inhibitor immunotherapy (n=3, all with partial/complete response), systemic chemotherapy (n=2), surgical resection (n=3), and radiation (n=2). The median time from primary diagnosis to vitreous metastasis was 2 (2-15) years. One patient had an active systemic disease at the time of vitreous metastasis. The final visual acuity ranged from 20/40 to no light perception. Ophthalmic treatment included vitrectomy in all five patients, intravitreal administration of melphalan in three, and intravitreal administration of methotrexate in one. One patient required enucleation, and histopathology revealed extensive invasion by melanoma cells. Conclusions: Vitreous metastasis from cutaneous melanoma can present as a diffuse infiltration of pigmented or non-pigmented cells into the vitreous and may be misdiagnosed as uveitis. Diagnostic pars plana vitrectomy and periodic intravitreal chemotherapy may be indicated.

RESUMO Objetivo: Descrever os achados clínicos, tratamentos, e desfechos em uma série de pacientes com me tástases vítreas de melanoma cutâneo. Métodos: Série retrospectiva de casos de único centro com intervenção. Pacientes incluídos tiveram seu diagnóstico de MVMC confirmado por biópsia entre 1997 e 2020. Vitrectomia via pars plana com 23 ou 25 gauge foram realizadas para obter espécimens. Esclerotomias foram tratadas com crioterapia em duplo ou triplo congelamento. Injeção intravítrea perioperatória de melfalano (32 ug/0,075 mL) foi administrada quando necessário. Foram relatados acuidade visual, pressão intraocular, resposta terapêutica sistêmica e ocular. Resultados: Cinco olhos de 5 pacientes com metástases vítreas de melanoma cutâneo unilateral foram identificados. Idade média de diagnóstico foi 84 anos (variando de 37-88). Seguimento médio após diagnóstico oftalmológico foi 28 (8,5-36) meses; 1 paciente não teve acompanhamento. Acuidade visual inicial variou de 20/30 a movimentos de mão. Achados clínicos iniciais incluíram infiltração de células pigmentadas e não-pigmentadas no vítreo (5/5), segmento anterior (4/5), e retina (3/5). Quatro pacientes tiveram glaucoma secundário. Tratamento sistêmico incluiu imunoterapia com inibidores da via de sinalização (3 - todos com resposta parcial/completa), quimioterapia sistêmica (2), ressecção cirúrgica (3), e irradiação (2). Intervalo médio entre diagnóstico primário e metástases vítreas foi 2 (2-15) anos. Um paciente teve doença sistêmica ativa simultânea as metástases vítreas. Acuidade visual final variou entre 20/40 e SPL. Tratamento oftalmológico incluiu vitrectomia nos 5 pacientes, melfalano intravítreo em 3 e metotrexato intravítreo em 1. Um paciente precisou de enucleação. A histopatologia revelou invasão celular extensa de melanoma. Conclusões: Metástases vítreas de melanoma cutâneo pode se manifestar como uma infiltração difusa de células pigmentadas e não-pigmentadas no vítreo e erroneamente diagnosticada como uveites. Vitrectomia diagnóstica e quimioterapia intravítrea periódica podem estar indicadas.

Metal-Free Electrochemical Reduction of Disulfides in an Undivided Cell under Mass Transfer Control.

Electroorganic synthesis is generally considered to be a green alternative to conventional redox reactions. Electrochemical reductions, however, are less advantageous in terms of sustainability, as sacrificial metal anodes are often employed. Divided cell operation avoids contact of the reduction products with the anode and allows for convenient solvent oxidation, enabling metal free greener electrochemical reductions. However, the ion exchange membranes required for divided cell operation on a commercial scale are not amenable to organic solvents, which hinders their applicability. Herein, we demonstrate that electrochemical reduction of oxidatively sensitive compounds can be carried out in an undivided cell without sacrificial metal anodes by controlling the mass transport to a small surface area electrode. The concept is showcased by an electrochemical method for the reductive cleavage of aryl disulfides. Fine tuning of the electrode surface area and current density has enabled the preparation of a wide variety of thiols without formation of any oxidation side products. This strategy is anticipated to encourage further research on greener, metal free electrochemical reductions.

Real-world study of disease-free survival & patient characteristics associated with disease-free survival in early-stage non-small cell lung cancer: A retrospective observational study.

INTRODUCTION/ BACKGROUND: Surgical resection remains standard of care for patients with early-stage non-small cell lung cancer (NSCLC), but research shows that adjuvant therapy can reduce the risk of disease recurrence. Our objective was to characterize disease-free survival (DFS) using real-world data. MATERIALS AND METHODS: This was a retrospective study using the COTA real-world database derived from electronic health records in the United States (US). Adults diagnosed with stage IB-IIIA NSCLC from 2013 to 2018 who underwent complete surgical resection (index date) for NSCLC were included. DFS was analyzed using the Kaplan-Meier method. A multivariable Cox-Proportional Hazard (PH) model stratified by year of diagnosis was developed to evaluate covariates associated with DFS. RESULTS: 703 patients met the study criteria (mean age 66.2 years, female (56%), White (82%), and median follow-up time was 37.4 months from index date. Approximately 48% of patients experienced recurrence or death with a median DFS of 42.9 months (95% CI: 37.4-52.2). Patients who received adjuvant therapy, neoadjuvant and adjuvant therapy, neoadjuvant therapy, and surgery only experienced a median DFS of 43.7, 32.3, 33.7, and 49.4 months, respectively. After adjustment, stage at diagnosis and adjuvant therapy status were significantly associated with DFS events. CONCLUSIONS: Higher stage at diagnosis and lack of adjuvant therapy were associated with greater risk of recurrence. Future research should focus on the adoption and effect of adjuvant/ neoadjuvant therapies on disease recurrence, including in patients with oncogenic driver mutations.

Out-of-pocket costs and catastrophic healthcare expenditure for families of children requiring surgery in sub-Saharan Africa.

BACKGROUND: Out-of-pocket healthcare costs leading to catastrophic healthcare expenditure pose a financial threat for families of children undergoing surgery in Sub-Saharan African countries, where universal healthcare coverage is often insufficient. METHODS: A prospective clinical and socioeconomic data collection tool was used in African hospitals with dedicated pediatric operating rooms installed philanthropically. Clinical data were collected via chart review and socioeconomic data from families. The primary indicator of economic burden was the proportion of families with catastrophic healthcare expenditures. Secondary indicators included the percentage who borrowed money, sold possessions, forfeited wages, and lost a job secondary to their child's surgery. Descriptive statistics and multivariate logistic regression were performed to identify predictors of catastrophic healthcare expenditure. RESULTS: In all, 2,296 families of pediatric surgical patients from 6 countries were included. The median annual income was $1,000 (interquartile range 308-2,563), whereas the median out-of-pocket cost was $60 (interquartile range 26-174). Overall, 39.9% (n = 915) families incurred catastrophic healthcare expenditure, 23.3% (n = 533) borrowed money, 3.8% (n = 88%) sold possessions, 26.4% (n = 604) forfeited wages, and 2.3% (n = 52) lost a job because of the child's surgery. Catastrophic healthcare expenditure was associated with older age, emergency cases, need for transfusion, reoperation, antibiotics, and longer length of stay, whereas the subgroup analysis found insurance to be protective (odds ratio 0.22, P = .002). CONCLUSION: A full 40% of families of children in sub-Saharan Africa who undergo surgery incur catastrophic healthcare expenditure, shouldering economic consequences such as forfeited wages and debt. Intensive resource utilization and reduced insurance coverage in older children may contribute to a higher likelihood of catastrophic healthcare expenditure and can be insurance targets for policymakers.

Real-world outcomes of frontline venetoclax-based therapy in older adults with acute myeloid leukemia: an analysis utilizing EHR data.

Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low-dose cytarabine has become the standard of care for patients with acute myeloid leukemia (AML) who are ineligible to receive intensive induction chemotherapy. Clinical trials are performed in a controlled setting that can be difficult to emulate in the real world. We sought to investigate outcomes of patients treated with VEN-based therapy in the real world. Patients with an age of ≥65 years who received frontline VEN-based therapy were identified using the COTA database (n = 112). The majority of patients (91%) were treated in the community setting and had adverse-risk AML (63%). The real-world overall response rate (rwORR) was 55% with a median real-world overall survival (rwOS) of 13 months after VEN/HMA. The rwORR was lower and median rwOS was shorter than those reported in the VIALE-A trial, underscoring the importance of studying novel therapies using real-world data.

Fast detection of liver fibrosis with collagen-binding single-nanometer iron oxide nanoparticles via T1-weighted MRI.

SNIO-CBP, a single-nanometer iron oxide (SNIO) nanoparticle functionalized with a type I collagen-binding peptide (CBP), was developed as a T1-weighted MRI contrast agent with only endogenous elements for fast and noninvasive detection of liver fibrosis. SNIO-CBP exhibits 6.7-fold higher relaxivity compared to a molecular gadolinium-based collagen-binding contrast agent CM-101 on a per CBP basis at 4.7 T. Unlike most iron oxide nanoparticles, SNIO-CBP exhibits fast elimination from the bloodstream with a 5.7 min half-life, high renal clearance, and low, transient liver enhancement in healthy mice. We show that a dose of SNIO-CBP that is 2.5-fold lower than that for CM-101 has comparable imaging efficacy in rapid (within 15 min following intravenous injection) detection of hepatotoxin-induced liver fibrosis using T1-weighted MRI in a carbon tetrachloride-induced mouse liver injury model. We further demonstrate the applicability of SNIO-CBP in detecting liver fibrosis in choline-deficient L-amino acid-defined high-fat diet mouse model of nonalcoholic steatohepatitis. These results provide a platform with potential for the development of high relaxivity, gadolinium-free molecular MRI probes for characterizing chronic liver disease.

Serous Choroidal Detachment and Scleritis Associated with Necrotic Choroidal Tumors.

Purpose: The aim of the study was to describe choroidal detachments and concurrent scleritis associated with necrotic choroidal metastasis or melanoma. Methods: We conducted a retrospective case series. Results: We report 4 patients with scleritis and choroidal detachment with an underlying malignant choroidal tumor. All patients underwent fine-needle aspiration biopsy for cytopathologic characterization of their choroidal tumor, and they all demonstrated evidence of tumor necrosis. Two patients were diagnosed with choroidal metastasis from lung and esophageal adenocarcinoma. Both patients ultimately expired from systemic metastasis. The remaining 2 patients were diagnosed with choroidal melanoma and were successfully treated with plaque radiotherapy. Conclusion: Choroidal detachment with concurrent scleritis can occur as a rare sequelae of tumor necrosis of an underlying choroidal malignancy.

Assessing Efficacy and Use Patterns of Medical Cannabis for Symptom Management in Elderly Cancer Patients.

OBJECTIVES: Our study sought to further characterize patterns of medical cannabis use in elderly cancer patients. Furthermore, we sought to assess efficacy of medical cannabis for the treatment of pain, nausea, anorexia, insomnia and anxiety in elderly cancer patients. BACKGROUND: Medical cannabis use is growing for symptom management in cancer patients, but limited data exists on the safety or efficacy of use in elderly patients. METHODS: A retrospective chart review assessing changes in numerical symptom scores reported at clinic visits before and after medical cannabis initiation. RESULTS: There was no statistically significant difference in pain, nausea, appetite, insomnia or anxiety scores reported before and after initiation of medical cannabis. Oil was the most common form used, followed by vape, and the most common ratios used were high tetrahydrocannabinol (THC) to cannabidiol (CBD) and equal parts THC/CBD products. CONCLUSION: This study did not find a statistically significant change in symptom scores with medical cannabis use, although further study is warranted given the limitations of the present study. Elderly patients most commonly are using equal parts THC/CBD or high THC ratio products initially.

IRIS METASTASIS FROM BREAST CANCER SUCCESSFULLY TREATED WITH ABEMACICLIB AND LETROZOLE.

PURPOSE: To describe a patient with an unusual presentation of iris metastasis from breast cancer and her response to systemic therapy. METHODS: Retrospective chart review of one patient. RESULTS: A 57-year-old woman presented with a superonasal translucent vascularized iris stromal mass with fish egg-like structures budding from the surface. High-frequency anterior segment ultrasonography demonstrated a solid iris stromal mass measuring 6.0 mm × 3.3 mm × 1.9 mm. On optical coherence tomography, the egglike structures appeared as hyperreflective spheres, some of which were detached from the main iris stromal tumor. Oncologic evaluation revealed metastatic breast cancer involving the brain and lung. She was treated with oral abemaciclib and letrozole, as well as external beam radiotherapy to the brain. The iris mass had completely regressed within 4 months and remained undetectable through the 8-month follow-up. The other metastatic lesions responded well to therapy. CONCLUSION: A case of iris metastasis was reported as the presenting sign of cancer dissemination that was successfully treated with targeted systemic therapy without ocular radiotherapy.

COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT EPITHELIUM AT PEDIATRIC AGE: Surgical Versus Conservative Approach.

PURPOSE: To report outcomes of pediatric patients with combined hamartoma of the retina and the retina pigment epithelium followed up conservatively or after pars plana vitrectomy. METHODS: This retrospective multicenter study included 62 eyes of 59 pediatric patients with combined hamartoma of the retina and the retina pigment epithelium from 13 different international centers with an average age of 7.7 ± 4.7 (0.3-17) years at the time of the diagnosis and having undergone pars plana vitrectomy or followed conservatively. At baseline and each visit, visual acuity values, optical coherence tomography for features and central foveal thickness, and tumor location were noted. Lesions were called as Zone 1, if it involves the macular and peripapillary areas, and the others were called as Zone 2 lesions. RESULTS: Twenty-one eyes of 20 patients in the intervention group and 41 eyes of 39 patients in the conservative group were followed for a mean of 36.2 ± 40.4 (6-182) months. Best-corrected visual acuity improved in 11 (68.8%) of 16 eyes in the intervention group and 4 (12.9%) of 31 eyes in the conservative group ( P < 0.001). The mean central foveal thickness decreased from 602.0 ± 164.9 µ m to 451.2 ± 184.3 µ m in the intervention group, while it increased from 709.5 ± 344.2 µ m to 791.0 ± 452.1 µ m in Zone 1 eyes of the conservative group. Posterior location of tumor, irregular configuration of the foveal contour and ellipsoid Zone defect in optical coherence tomography, subretinal exudate and prominent vascular tortuosity were associated with poor visual acuity. CONCLUSION: Vitreoretinal surgery is safe and effective in improving vision and reducing retinal distortion in Zone 1 combined hamartoma of the retina and the retina pigment epithelium in children.

Enabling Suzuki-Miyaura coupling of Lewis-basic arylboronic esters with a nonprecious metal catalyst.

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh2Me)2NiCl2 as an inexpensive and air-stable precatalyst that addresses this challenge. Under activation by n-BuMgCl, this complex can catalyze the coupling of synthetically important heteroaryl pinacolborons with heteroaryl halides. Mildly basic conditions (aqueous K3PO4) allow the reaction to tolerate sensitive functional groups that were incompatible with other Ni-SMC methods. Experimental and computational studies suggest that catalyst inhibition by substitution of PPh2Me from Ni(ii) intermediates by Lewis basic reactants and products is disfavored relative to more commonly employed ligands in the Ni-SMC, which allows it to operate efficiently in the presence of Lewis bases such as unhindered pyridines.

Cyst-like recurrence of retinoblastoma diagnosed by multimodal imaging.

Purpose: To illustrate the diagnosis and management of an atypical, cyst-like recurrence of retinoblastoma. Observations: A 4-month-old boy was diagnosed with Group B retinoblastoma in the right eye, consisting of a 10 x 9 × 3.6 mm retinal tumor temporal to the macula. He was treated with one session of intra-arterial ophthalmic artery chemotherapy using melphalan, followed by three sessions of diode laser transpupillary thermotherapy (TTT), after which complete tumor regression was achieved. 45 weeks after initial treatment, a cystic lesion was detected adjacent to superior margin of the regressed tumor scar. The differential diagnosis included pigment epithelial detachment, retinal gliosis, secondary retinoschisis, and local tumor recurrence. Multimodal imaging including OCT angiography confirmed the diagnosis of local recurrence manifesting as a vascularized cyst-like lesion. Two additional sessions of TTT achieved sustained tumor regression through 16 months of additional follow-up. Conclusions and Importance: Recurrence of retinoblastoma following chemotherapy typically manifests as enlargement of a previously regressed tumor, or seeding into the vitreous or subretinal space. An unusual cyst-like recurrence of retinoblastoma at the margin of a previously regressed tumor was diagnosed by multimodal imaging. Focal diode laser transpupillary thermotherapy was curative.

Lymphatic cells do not functionally integrate into 3D organotypic brain slice cultures, but aggregate around penetrating blood vessels.

Brain slice culture (BSC) is a well-known three-dimensional model of the brain. In this study, we use organotypic slices for studying neuro-lymphatic physiology, to directly test the longstanding assumption that the brain is not a hospitable milieu for typical lymphatic vessels. An additional objective is to model fluid egress through brain perivascular space systems and to visualize potential cellular interactions among cells in the leptomeninges including alterations of cellular geometry and number of processes. Immortalized lymphatic rat cell lines were used to seed organotypic brain slices. The brain slice model was characterized by monitoring morphologies, growth rates, degree of apoptosis, and transport properties of brain slices with or without a lymphatic component. The model was then challenged with fibroblast co-cultures, as a control cell that is not normally found in the brain. Immortalized lymphatic cells penetrated the brain slices within 2-4 days. Typical cell morphology is spindly with bipolar and tripolar forms well represented. Significantly more indigo carmine marker passed through lymphatic seeded BSCs compared to arachnoid BSCs. Significantly more indigo carmine passed through brain slices co-cultured with fibroblast compared to lymphatic and arachnoid BSCs alone. We have developed an organotypic model in which lymphatic cells are able to interact with parenchymal cells in the cerebrum. Their presence appears to alter the small molecule transport ability of whole-brain slices. Lymphatic cells decreased dye transport in BSCs, possibly by altering the perivascular space. Given their direct contact with the CSF, they may affect convectional and diffusional processes. Our model shows that a decrease in lymphatic cell growth may reduce the brain slice's transport capabilities.

Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

BACKGROUND: TGF-ß is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-ß blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-ß type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. METHODS: This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4-54·0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. FINDINGS: Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. INTERPRETATION: The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. FUNDING: Eli Lilly via ExIST program, The Providence Foundation.

Family Conflict Non-negotiation and HIV Disclosure Associated With ART Adherence in a Disadvantaged Population.

Adherence to antiretroviral therapy (ART) is vital for reducing racial and gender disparities in morbidity and mortality among people living with HIV/AIDS (PLWH). Little research attention has been given to aspects of family functioning affecting ART adherence among PLWH vulnerable to disparities. Data were from n = 313 participants (93% African American) in the BEACON study, which recruited injection-drug-using PLWH on ART. Using factor analysis and longitudinal structural equation modeling, we found that current substance use and negative family conflict tactics (i.e., non-negotiation) predicted PLWH's lower probability of ART adherence at 12-month follow-up; and greater HIV disclosure to support network members predicted a higher probability of adherence. These findings suggest the importance of family and other support network members in this vulnerable population's ART adherence. Social network-focused interventions promoting prosocial response to conflict and negotiation skills are important for improving vulnerable PLWH's HIV outcomes and reducing health disparities.