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Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. In the largest study to date, we report the results of DNA methylation profiling, RNA-Seq and genomic sequencing of 32 RIG tumors, and an in vitro drug screen in two RIG cell lines.

Purpose: : The role of peri-transplant radiation therapy (RT) in children with primary brain tumors is unclear. We characterized our institutional practice patterns and patient outcomes. Methods and Materials: The cohort included all patients treated with high-dose chemotherapy and autologous stem cell transplant for primary brain tumors at our institution from 2011 to 2017. Rates of local control, progression-free survival, overall survival, and radiation-associated injury were assessed. Results: Of the 37 eligible patients, 29 (78%) received peri-transplant RT. Patients treated with RT were more likely to have metastatic (P = .0121) and incompletely resected (P = .056) disease. Of those treated with RT, 13 (45%) received craniospinal irradiation (CSI) and 16 (55%) received focal RT. The median CSI dose was 23.4 Gy (interquartile range [IQR], 18-36 Gy; boost: median, 54 Gy [IQR, 53.7-55.8 Gy]) and focal RT dose was 50.4 Gy [IQR, 50.4-54.5 Gy]). Compared with the focal RT group, patients treated with CSI were older (P = .0499) and more likely to have metastatic disease (P = .0004). For the complete cohort, 2-year local control was 82% (95% confidence interval [CI], 70%-96%), progression-free survival 63% (95% CI, 49%-81%), and overall survival 65% (95% CI, 51%-82%). These rates did not differ significantly between patients treated with and without peri-transplant RT. Two cases of fatal myelopathy were observed after spinal cord doses within the highest tertile (41.4 cobalt Gy equivalent and 36 Gy). Conclusions: Peri-transplant RT was used for high-risk disease. Oncologic outcomes after RT were encouraging. However, 2 cases of grade 5 myelopathy were observed. If used cautiously, RT may contribute to durable remission in patients at high risk of relapse.

Optic pathway glioma (OPG) comprises 10% of pediatric brain tumors and 40% of all pediatric low-grade gliomas (pLGGs). While generally considered benign pathologically, many require interventions with chemotherapy, radiation, or targeted therapies. Management has historically foregone tissue diagnosis given the classical clinical/radiographic presentation of these tumors, inability to safely remove the lesions surgically, and efficacy and safety of available chemotherapy options. Furthermore, when considering such aspects as their delicate location, the role of surgery continues to be heavily debated. More recently, however, a greater understanding of the genetic drivers of OPGs has made operative tissue sampling a critical step in management planning, specifically for patients without Neurofibromatosis, Type I (NF1). Given the need for long-term, complex management of pediatric OPGs, it is crucial that a multidisciplinary approach is employed, and the rapidly expanding role of molecular characterization be incorporated into their management.

Abstract Background Standard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma. Methods Daoy, D283 and D425 medulloblastoma cell lines were characterized by flow cytometry to evaluate HER2 expression. Anti-tumor efficacy of HER2-BBz-CAR T cells in vitro was performed using cytokine release and immune cytotoxicity assays compared to control CD19 CAR T cells. In vivo, Daoy and D283 tumor cells were orthotopically implanted in the posterior fossa of NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice and treated with regional or intravenous HER2-BBz-CAR T cells or control CD19 CAR T cells. Non-human primates (NHPs) bearing ventricular and lumbar reservoirs were treated with target autologous cells bearing extracellular HER2 followed by autologous HER2-CAR T cells intraventricularly. Cerebrospinal fluid and blood were collected serially to measure the persistence of delivered cells and cytokines. Results HER2-BBz-CAR T cells effectively clear medulloblastoma orthotopically implanted in the posterior fossa of NSG mice via both regional and intravenous delivery in xenograft models. Intravenous delivery requires a log higher dose compared to regional delivery. NHPs tolerated intraventricular delivery of autologous cells bearing extracellular HER2 followed by HER2-BBz-CAR T cells without experiencing any systemic toxicity. Conclusions HER2-BBz-CAR T cells show excellent pre-clinical efficacy in vitro and in mouse medulloblastoma models, and their intraventricular delivery is feasible and safe in NHPs. A clinical trial of HER2-BBz-CAR T cells directly delivered into cerebrospinal fluid should be designed for patients with relapsed medulloblastoma.

Adamantinomatous craniopharyngioma (ACP) makes up between 6 and 8% of pediatric brain tumors and is the most common pediatric tumor arising in the sellar/suprasellar region of the brain. The 10-year survival for patients diagnosed with craniopharyngioma ranges between 64 and 92%, but complicating factors such as location, common cyst formation, and potential hypothalamic infiltration cause significant morbidity in this population. There are a number of therapeutic options for children with ACP, including surgery, radiation, and cyst directed therapies such as interferon and bleomycin. Research has raised concerns regarding the efficacy and side effects associated with these conventional therapies, as well as with the difficulty in treating recurrent cystic ACP. Evidence from our group and others has shown that the cystic and solid tumor components of craniopharyngioma have high levels of IL-6R and IL-6, providing a potential target for therapy. Tocilizumab, a humanized monoclonal antibody, acts against soluble and membrane bound IL-6R, and has been widely utilized in pediatric patients. Two patients with recurrent cystic ACP were offered systemically administered tocilizumab or a combination of tocilizumab and bevacizumab on a compassionate use basis. Both patients' tumors had a significant response, with decreased cyst burden, supporting the assertion that tocilizumab with or without bevacizumab may be an option for patients suffering from cystic ACP.

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors.

Diatraea saccharalis F is considered the most important pest of sugarcane in the United States. This article focuses on the history of pest management as it relates to the control of this stem borer in Louisiana sugarcane, and how control practices have become more in tune with integrated pest management paradigms. Various pest management strategies are employed against D. saccharalis and the interactions between each of these provide farmers with the tools needed to curb damaging infestations. However, the invasion of the Mexican rice borer, Eoreuma loftini (Dyar), and other confounding environmental factors have presented farmers, consultants, and researchers with new pest management challenges. We address these challenges and provide an overview of ongoing developments, particularly in the Louisiana sugarcane pest management program.

People with cystic fibrosis (CF) have been reported to make lung T cell responses that are biased towards T helper (Th) 2 or Th17. We hypothesized that CF-related T cell regulatory defects could be detected by analyzing CD4+ lymphocyte subsets in peripheral blood. Peripheral blood mononuclear cells from 42 CF patients (6 months-53 years old) and 78 healthy controls (2-61 years old) were analyzed for Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17+), Treg (FOXP3+), IL-10+ and TGF-β+ CD4+ cells. We observed higher proportions of Treg, IL-10+ and TGF-β+ CD4+ cells in CF adults (≥ 18 years old), but not children/adolescents, compared with controls. Within the CF group, high TGF-β+% was associated with chronic Pseudomonas aeruginosa lung infection (p < 0.006). We observed no significant differences between control and CF groups in the proportions of Th1, Th2 or Th17 cells, and no association within the CF group of any subset with sex, CFTR genotype, or clinical exacerbation. However, high Th17% was strongly associated with poor lung function (FEV1 % predicted) (p = 0.0008), and this association was strongest when both lung function testing and blood sampling were performed within one week. Our results are consistent with reports of CF as a Th17 disease and suggest that peripheral blood Th17 levels may be a surrogate marker of lung function in CF.

A portable analytical chemistry analyzer was used to make field assessments of wild harlequin ducks (Histrionicus histrionicus) in association with telemetry studies of winter survival in Prince William Sound, Alaska. We compared serum chemistry results obtained on-site with results from a traditional laboratory. Particular attention was paid to serum glucose and potassium concentrations as potential indicators of high-risk surgical candidates based on evaluation of the field data. The median differential for glucose values (N=82) between methods was 0.6 mmol/L (quartiles 0.3 and 0.9 mmol/L) with the median value higher when assayed on site. Analysis of potassium on site returned a median of 2.7 mmol/L (N=88 ; quartiles 2.4 and 3.0 mmol/L). Serum potassium values were too low for quantitation by the traditional laboratory. Changes in several serum chemistry values following a three-day storm during the study support the value of on site evaluation of serum potassium to identify presurgical patients with increased anesthetic risk.

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600E mutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors. [ABSTRACT FROM AUTHOR]

Background: Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive, fatal, childhood tumors that arise in the brainstem. DIPGs have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease. New therapeutic targets are needed to develop novel therapy for DIPG.Methods: We examined the expression of PLK1 mRNA in DIPG tumor samples through microarray analysis and found it to be up regulated versus normal pons. Using the DIPG tumor cells, we inhibited PLK1 using a clinically relevant specific inhibitor BI 6727 and evaluated the effects on, proliferation, apoptosis, induction of DNA damage and radio sensitization of the DIPG tumor cells.Results: Treatment of DIPG cell lines with BI 6727, a new generation, highly selective inhibitor of PLK1, resulted in decreased cell proliferation and a marked increase in cellular apoptosis. Cell cycle analysis showed a significant arrest in G2-M phase and a substantial increase in cell death. Treatment also resulted in an increased γH2AX expression, indicating induction of DNA damage. PLK1 inhibition resulted in radiosensitization of DIPG cells.Conclusion: These findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of DIPG that warrants further investigation. [ABSTRACT FROM AUTHOR]

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes 'programmed' or 'regulated' necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics. [ABSTRACT FROM AUTHOR]

Brainstem gangliogliomas ( GGs), often cannot be resected, have a much poorer prognosis than those located in more common supratentorial sites and may benefit from novel therapeutic approaches. Therapeutically targetable BRAF c.1799 T> A (p. V600 E) ( BRAFV600E) mutations are harbored in roughly 50% of collective GGs taken from all anatomical sites. Large numbers of pediatric brainstem GGs, however, have not been specifically assessed and anatomic-and age-restricted assessment of genetic and biological factors are becoming increasingly important. Pediatric brainstem GGs (n = 13), non-brainstem GGs (n = 11) and brainstem pilocytic astrocytomas ( PAs) (n = 8) were screened by standard Sanger DNA sequencing of BRAF exon 15. Five of 13 (38%) pediatric GG harbored a definitive BRAFV600E mutation, with two others exhibiting an equivocal result by this method. BRAFV600E was also seen in five of 11 (45%) non-brainstem GGs and one of eight (13%) brainstem PAs. VE1 immunostaining for BRAFV600E showed concordance with sequencing in nine of nine brainstem GGs including the two cases equivocal by Sanger. The equivocal brainstem GGs were subsequently shown to harbor BRAFV600E using a novel, more sensitive, RNA-sequencing approach, yielding a final BRAFV600E mutation frequency of 54% (seven of 13) in brainstem GGs. BRAFV600E-targeted therapeutics should be a consideration for the high percentage of pediatric brainstem GGs refractory to conventional therapies. [ABSTRACT FROM AUTHOR]

The PULSE@Parkes project has been designed to monitor the rotation of radio pulsars over time spans of days to years. The observations are obtained using the Parkes 64-m and 12-m radio telescopes by Australian and international high school students. These students learn the basis of radio astronomy and undertake small projects with their observations. The data are fully calibrated and obtained with the state-of-the-art pulsar hardware available at Parkes. The final data sets are archived and are currently being used to carry out studies of 1) pulsar glitches, 2) timing noise, 3) pulse profile stability over long time scales and 4) the extreme nulling phenomenon. The data are also included in other projects such as gamma-ray observatory support and for the Parkes Pulsar Timing Array project. In this paper we describe the current status of the project and present the first scientific results from the Parkes 12-m radio telescope. We emphasise that this project offers a straightforward means to enthuse high school students and the general public about radio astronomy while obtaining scientifically valuable data sets. [ABSTRACT FROM AUTHOR]

Mountain ranges, deserts, ice fields and oceans generally act as barriers to the movement of land-dependent animals, often profoundly shaping migration routes. We used satellite telemetry to track the southward flights of bar-tailed godwits (Limosa lapponica baueri), shorebirds whose breeding and non-breeding areas are separated by the vast central Pacific Ocean. Seven females with surgically implanted transmitters flew non-stop 8117–11680km (10153±1043 s.d.) directly across the Pacific Ocean; two males with external transmitters flew non-stop along the same corridor for 7008–7390km. Flight duration ranged from 6.0 to 9.4 days (7.8±1.3 s.d.) for birds with implants and 5.0 to 6.6 days for birds with externally attached transmitters. These extraordinary non-stop flights establish new extremes for avian flight performance, have profound implications for understanding the physiological capabilities of vertebrates and how birds navigate, and challenge current physiological paradigms on topics such as sleep, dehydration and phenotypic flexibility. Predicted changes in climatic systems may affect survival rates if weather conditions at their departure hub or along the migration corridor should change. We propose that this transoceanic route may function as an ecological corridor rather than a barrier, providing a wind-assisted passage relatively free of pathogens and predators. [ABSTRACT FROM AUTHOR]

Abstract   Purpose To identify changes in hepatic parenchymal volume, fibrosis, and induction of portal hypertension following radioembolization with glass microspheres for patients with metastatic disease to the liver. Results In our series of sequential bilobar (n = 17) treatments, a mean decrease in liver volume of 11.8% was noted. In this group, a mean splenic volume increase of 27.9% and portal vein diameter increase of 4.8% were noted. For patients receiving unilobar treatments (n = 15), mean ipsilateral lobar volume decrease of 8.9%, contralateral lobar hypertrophy of 21.2%, and a 5.4% increase in portal vein diameter were also noted. These findings were not associated with clinical toxicities. Conclusion 90Yttrium radioembolization utilizing glass microspheres in patients with liver metastases results in changes of hepatic parenchymal volume and also induced findings suggestive of fibrosis and portal hypertension. Further studies assessing the long-term effects are warranted. [ABSTRACT FROM AUTHOR]

Catheter-directed thrombolysis was used either alone or as an adjunct to percutaneous transluminal angioplasty (PTA) or surgery for peripheral vascular occlusion on 112 occasions in 102 patients. Symptom duration ranged from < one to > twenty-eight days. Thrombolytic therapy using urokinase plasminogen activator thrombolysis (uPAT), including intrathrombic injection when possible, was successful (> 50% lysis) in 99 procedures (88%). Technical failure (< 50% lysis) occurred in 13 procedures (12%). In 9 of the 13 failures, intrathrombic injection of urokinase was not possible, but the duration of occlusion was > twenty-eight days in all but 1. Two other failures were from embolic sources and 2 more occurred in patients with a hypercoagulable state. The uPAT was adjunctive to PTA/surgery in 56 cases (50%). PTA following uPAT was required and successfully performed in 24 of 27 cases (88.9%). Surgery followed lytic therapy in another 32 (including the 3 failed PTAs). In the remaining 56 cases (50%), no additional intervention was required. There were 20 complications (18%), minor in 16 of 20 (80%). Minor complications included small puncture site hematomas and distal embolization resolved by continued lytic therapy Four major complications occurred. One was retroperitoneal hemorrhage directly contributing to the only death in the series. The other 3 were hematuria (2) and femoral neuropathy (1). The authors conclude that catheter-directed lytic therapy alone or as an adjunct to PTA/surgery is a valuable approach to peripheral vascular thromboembolic disease. It is less likely to succeed in chronic occlusion. The incidence of complications is moderate but acceptable. [ABSTRACT FROM AUTHOR]

Smoking prevalence remains high in Europe and widening socioeconomic group differences are driving health inequalities. While plain packaging policies disrupt tobacco industry tactics that sustain smoking, evidence of their equity impact is sparse. This study evaluated the implementation of plain packaging in Ireland in 2018 on consumer responses, overall and by the socioeconomic group. Consecutive nationally representative cross-sectional surveys (2018, n = 7701 and 2019, n = 7382) measured changes in 13 consumer responses among respondents who smoked across three domains: product appeal, health warnings effectiveness, and perceived harmfulness of smoking. Multiple logistic regression-derived adjusted odds ratios with 95% confidence intervals to compare responses post- versus pre-implementation adjusting for age, gender, educational level, and heaviness of smoking. A stratified analysis examined changes by socioeconomic group indexed using educational level. There were statistically significant changes in consumer responses to plain packaging policy implementation across 7/13 outcomes studied. Five changes were aligned with expected policy impacts (2/6 product appeal outcomes and 3/4 health warning effectiveness outcomes). Two responses were also observed which were not expected policy impacts (1 appeal-related and 1 perceived harm-related outcome). There was no change in five outcomes. Differences in consumer responses between educational groups were generally small, mixed in nature, and indistinguishable when interval estimates of effect were compared. Implementation of plain packaging in Ireland had intended impacts on consumer responses. Including plain packaging requirements in revising the European Union's legislative frameworks for tobacco control will help build progress towards a Tobacco-Free Europe without exacerbating smoking inequalities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability., Patients and Methods: Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate., Results: The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each)., Conclusions: FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals., (© The Author(s) 2024. Published by Oxford University Press.)

Osteomyelitis complicates 20% of patients with infected diabetic foot ulcers. In this study, 2 strategies for treating pedal osteomyelitis were compared in a pilot study. This was a retrospective, non-randomized, single center 2 arm cohort study, conducted between 2020 and 2022 involving 53 patients at a tertiary limb salvage unit. All patients were managed with debridement and proximal bone biopsy. Group A was treated with systemic antibiotics for up to 6 weeks. Group B had vancomycin or gentamycin eluting bone void filler implanted into the diseased bone medullary cavity(s) and 1 week of oral antibiotics. Patients were followed independently for the primary endpoint of osteomyelitis treatment failure and secondary endpoints of amputation free survival, wound healing, minor amputation, and treatment-limiting side-effects. Survival analysis demonstrated no significant difference in treatment failure (p = .35) or amputation free survival (p = .46). Limb salvage rates were 88% in Group A and 89% in Group B. Wounds healed in 85% in Group A and 89% in Group B. Minor amputations occurred in 21% in Group A and 11% in Group B. Treatment limiting side effects occurred in 6% in Group A and were absent in Group B. In conclusion, the use of antibiotic eluting bone void filler appeared safe without extended systemic antibiotics in this study. Group B had fewer intravenous lines, requirement for home nursing, and treatment limiting side effects. A larger randomized controlled trial examining longer term clinical and radiological efficacy, treatment costs and side effects is warranted., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery for internal carotid artery (ICA) occlusive disease necessarily requires sufficient external carotid artery (ECA) blood flow. Surgical bypass is therefore precluded if there is common carotid artery (CCA) occlusion. Here we present two such cases: one patient had a CCA occlusion and the other had an ICA occlusion and ECA stenosis. Both had failed medical management, and were therefore treated with angioplasty and stenting of the ECA, followed by STA-MCA bypass. We describe the clinical and radiologic outcomes of these cases, and remark on the potential pitfalls associated with this novel approach., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: The authors have each completed and submitted an ICMJE form for Disclosure of Potential Conflicts of Interest and none was reported.

Objective: Viability of inpatient acupuncture is limited by current hospital reimbursement structuring. Research has primarily focused on length of stay (LOS) instead of cost of stay (COS). This study evaluated acupuncture as an option for inpatient pain control, determined if acupuncture influenced patient satisfaction during hospitalization, and examined any effects on LOS and COS., Materials and Methods: In a quasiexperimental pilot research study, acupuncture was offered free of charge for 3 months on a single floor of an urban medical center. Pre- and postintervention scores, number of treatments, and diagnosis related groups (DRGs) of patients receiving acupuncture were tracked and then compared to a nonintervention, DRGs-matched group with overlapping hospital-floor and admission dates. LOS, COS, and patient satisfaction scores during the months of intervention were compared to the months before and after the intervention., Results: Patients' pain significantly decreased each time they were treated. Consumer Assessment of Healthcare Providers and Systems scores increased to 85, 99, and 97 during the months of intervention and then returned to the lower, preacupuncture levels after acupuncture was no longer available. LOS was higher in the intervention group (+7.8 days), but acupuncture saved the hospital an anticipated $125,770 in the projected COS during that 3-month time alone., Conclusions: Acupuncture was a potent pain-relief alternative for hospitalized patients, providing more satisfaction. Acupuncture resulted in longer LOS, but the aggregate COS was 86% less than expected. Acupuncture may be a financially viable, clinically impactful adjunct to hospital care., Competing Interests: No financial conflicts of interest exist., (Copyright 2024, Mary Ann Liebert, Inc., publishers.)

Competing Interests: Disclosures None.

Introduction: To assess the feasibility of developing World Health Organization (WHO) European Region countries' goals and measures in line with tobacco endgame objectives, information on the current tobacco control context and capacity is needed. The aim of this study was to assess the implementation of the Framework Convention on Tobacco Control (WHO FCTC) and MPOWER measures in the region., Methods: In this cross-sectional study we used data from the WHO FCTC implementation reports and MPOWER from 2020 in 53 WHO European Region countries. Six domains (i.e. capacity, taxation and price policies, other national key regulations, public awareness raising and communication, tobacco use cessation, and monitoring) were formed. Subsequently, available indicators under these domains were scored and the level of implementation was computed for each country. Mann-Whitney tests were carried out to compare the scores between the group of countries with and without official endgame goals., Results: Overall, implementation of the WHO FCTC with the selected indicators at the country level ranged from 28% to 86%, and of MPOWER from 31% to 96%. Full implementation was achieved by 28% of WHO FCTC Parties in the region in taxation and price policies, 12% in public awareness raising and communication, and 42% in monitoring. In capacity, tobacco use cessation and other national key regulations, none of the Parties in the region reached full implementation. Overall median WHO FCTC scores were significantly higher in countries with official endgame goals than in those without (p<0.001)., Conclusions: There is unequal implementation of both WHO FCTC and MPOWER measures among WHO European Region countries. MPOWER and WHO FCTC provide all the measures for the necessary first steps, followed by innovative measures, to accomplish tobacco endgame goals., Competing Interests: The authors have each completed and submitted an ICMJE form for Disclosure of Potential Conflicts of Interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. A. González Marrón, C. Lidón-Moyano, H. Pérez-Martín, O. Ruokolainen, T. Laatikainen and H. Ollila, report that since the initial planning of the work received support by the European Union’s Health Program (2014-2020) under grant agreement N°101035968. H. Koprivnikar, J. Tisza, Z. Cselkó, A. Lambrou, E. Papachristou, M. Vasic, R. Guignard, S. Schoretsaniti and V. Nguyen-Thanh report that since the initial planning of the work their institution received support by European Commission for the Joint action on tobacco control 2 (JATC 2). In addition, M. Mulcahy reports that since the initial planning of the work he received support from the Health Service Executive, Ireland and the Joint action on tobacco control 2 (JATC 2). He also reports that in the past 36 months he received grants, consulting fees, support for attending meetings and travels and receipt of equipment/ materials from the Health Service Executive, Ireland and the Joint action on tobacco control 2 (JATC 2). H. Koprivnikar reports that in the past 36 months she received payment from the Medical Faculty, University of Ljubljana, for lecture to pediatric residents and from Slovene Medical Chamber for lecture to health professionals. E. Nunes reports that since the initial planing of the work she received support from European Commission and from General Directorate of Health, Ministry of Health, Portugal. M. Karekla reports that since the initial planning of the work she received support from Horizon Europe (no payments made to her or her institution). She also reports that in the past 36 months she received support from Horizon Europe for attending meetings of this group and that she is the immediate past president of the Association for Contextual Behavior Science. R. Guignard and V. Nguyen-Thanh report that in past 36 months they received support from the European Commission for travel and accommodation to the JATC 2 consortium meeting in Madrid, Spain, in April 2023., (© 2023 González-Marrón A. et al.)

Background: Forefoot plantar ulcers in patients with diabetic neuropathy are considered to be primarily the result of increased shear forces applied over prominent plantar bony prominences. The purpose of this article is to describe a 2-stage treatment pathway utilizing an outpatient percutaneous tendon-Achilles lengthening (TAL) as the first stage procedure and subsequent proximal metatarsal osteotomy (MTO) as a second stage procedure for a persistent or recurrent ulcer., Methods: A consecutive 112 patients (146 feet), who presented to our Multidisciplinary Diabetic Foot Team clinics since February 2019 with plantar nonischemic forefoot ulcers were included in this study. Excluding the patients who died or were lost to follow-up, 96 feet were followed for a minimum 12 months (range 12-36 months). After TAL, patients were encouraged to walk in a walking cast for 6 weeks and were followed for a minimum 12 months. Patients with persistent or recurrent ulcers were investigated with magnetic resonance imaging scan, and based on intramedullary osteomyelitis and septic destruction of distal metatarsal, we describe a second-stage MTO with the 3 most common clinical presentations., Results: Of 96 feet, none had infection or wound-related problems following TAL. Complete transection of the tendon was noted in 4 patients (4%) and heel callosity in 1 patient. In 92 feet (96%), the ulcers healed within 10 weeks (±4 weeks) after TAL but, in 12 feet (10%), the ulcer failed to heal or recurred. At a minimum 12 months after the second-stage MTO, none in this subgroup had recurrence of ulcer or a transfer lesion., Conclusion: TAL followed with a walking cast as an outpatient procedure was effective in healing forefoot ulcers in 96% of feet. Comparable to the widely practiced hand surgery Wide Awake Local Anesthesia No Tourniquet (WALANT) procedure, our approach involved active control of the degree of ankle dorsiflexion by the patient, and the procedure was proven to be safe and well tolerated. When the second-stage MTO was required to offload the forefoot, in our small cohort, patients had ulcer-free outcome for a minimum 12 months., Level of Evidence: Level IV, retrospective case series., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online.

Purpose: Cancer staging is the foundation for all cancer management decisions. For real-time use, stage must be embedded in the electronic health record as a discrete data element. The objectives of this quality improvement (QI) initiative were to (1) identify barriers to utilization of an existing discrete cancer staging module, (2) identify health information technology (HIT) solutions to support discrete capture of cancer staging data, and (3) increase capture across the oncology enterprise in our diverse health system., Methods: Six sigma QI methodologies were used to define barriers and solutions to improve discrete cancer staging. Design thinking principles informed solution development to test prototypes. Two multidisciplinary teams of disease-specific clinicians within GI and genitourinary conducted phased testing pilots to determine health system solutions. Solutions were expanded to all oncology specialties across our health system., Results: Baseline average discrete staging capture across our health system was 31%. Poor workflow efficiency, limited accountability, and technical design gaps were key barriers to timely, complete staging. Implementation of more than 25 design enhancements to a HIT solution and passive user alerts led to a postimplementation capture rate of 58% across 55 outpatient clinics involving more than 400 clinicians., Conclusion: We identified key barriers to discrete data capture and designed solutions through iterative use of QI methodologies and disease-specific pilots. After implementation, discrete capture of cancer staging nearly doubled across our diverse health system. This approach is scalable and transferable to other initiatives to develop and implement clinically relevant HIT solutions across a diverse health system.

Background: We previously reported activity of pelareorep, pembrolizumab and chemotherapy. Patients developed new T-cell clones and increased peripheral T-cell clonality, leading to an inflamed tumour. To evaluate a chemotherapy-free regimen, this study assesses if pelareorep and pembrolizumab has efficacy by inducing anti-tumour immunological changes (NCT03723915)., Methods: PDAC patients who progressed after first-line therapy, received iv pelareorep induction with pembrolizumab every 21-days. Primary objective is overall response rate. Secondary objectives included evaluation of immunological changes within tumour and blood., Results: Clinical benefit rate (CBR) was 42% amongst 12 patients. One patient achieved partial response (PR) and four stable disease (SD). Seven progressed, deemed non-responders (NR). VDAC1 expression in peripheral CD8 +  T cells was higher at baseline in CBR than NR but decreased in CBR upon treatment. On-treatment peripheral CD4 +  Treg levels decreased in CBR but not in NR. Analysis of tumour demonstrated PD-L1 +  cells touching CD8 +  T cells, and NK cells were more abundant post-treatment vs. baseline. A higher intensity of PD-L1 in tumour infiltrates at baseline, particularly in CBR vs. NR. Finally, higher levels of soluble (s)IDO, sLag3, sPD-1 observed at baseline among NR vs. CBR., Conclusion: Pelareorep and pembrolizumab showed modest efficacy in unselected patients, although potential immune and metabolic biomarkers were identified to warrant further evaluation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Materials & methods: We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment indication was explored as part of a single institution retrospective case series of HER2 positive esophageal adenocarcinoma LM (n = 2). Results: One patient received intrathecal trastuzumab (80 mg twice weekly) as part of their treatment regimen with durable long-term response and clearance of circulating tumor cells in the cerebral spinal fluid. The other patient demonstrated rapid progression and death as previously described in the literature. Conclusion: Intrathecal trastuzumab is a well-tolerated and reasonable therapeutic option worthy of further exploration for patients with HER2 positive esophageal carcinoma LM. An associative, but not a causal relationship, can be made regarding therapeutic intervention.

The perinatal period is one of increased vulnerability to parents experiencing the onset of, or an increase of existing, obsessive-compulsive disorder (OCD) symptoms. Existing OCD and perinatal mental health best practice guidelines do not detail specific considerations relevant to OCD in the perinatal period ('Perinatal OCD'). Perinatal OCD risks being undiagnosed or misdiagnosed, and subsequently untreated or mistreated, with potential negative impacts for individuals and families experiencing this problem, highlighting the importance of specific guidance. This study employed a modified Delphi survey methodology to establish recommended best practice for the assessment and treatment of perinatal OCD. A literature review identified 103 initial best practice recommendations, and participants suggested 18 further recommendations. These recommendations were rated for importance over three survey rounds by two expert panels, comprising of 15 professionals with clinical or research expertise in perinatal OCD and 14 consumers with lived experience of perinatal OCD. One-hundred and two statements were endorsed for inclusion in the final set of recommendations for clinical best practice with perinatal OCD. These recommendations inform practice across eight themes; psychoeducation, screening, assessment, differential diagnosis, case care considerations, treatment, partners & families, and culture & diversity. This novel study is the first to collate and outline a set of clinical best practice recommendations, developed using the consensus perspectives of both individuals with lived experience and professionals with relevant expertise, for supporting individuals with perinatal OCD and their families. Differences between panel perspectives, and directions for future research are also discussed., (© 2023. The Author(s).)

Background: Large territory middle cerebral artery (MCA) ischaemic strokes account for around 10% of all ischaemic strokes and have a particularly devastating prognosis when associated with malignant oedema. Progressive cerebral oedema starts developing in the first 24 to 48 hours of stroke ictus with an associated rise in intracranial pressure. The rise in intracranial pressure may eventually overwhelm compensatory mechanisms leading to a cascading secondary damage to surrounding unaffected parenchyma. This downward spiral can rapidly progress to death or severe neurological disability. Early decompressive craniectomy to relieve intracranial pressure and associated tissue shift can help ameliorate this secondary damage and improve outcomes. Evidence has been accumulating of the benefit of early surgical decompression in stroke patients. Earlier studies have excluded people above the age of 60 due to associated poor outcomes; however, newer trials have included this patient subgroup. This review follows a Cochrane Review published in 2012., Objectives: To assess the effectiveness of surgical decompression in people with malignant oedema after ischaemic stroke with regard to reduction in mortality and improved functional outcome. We also aimed to examine the adverse effects of surgical decompression in this patient cohort., Search Methods: We searched the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2022, Issue 7 of 12), MEDLINE Ovid, Embase Ovid, Web of Science Core Collection, Scopus databases, ClinicalTrials.gov, and the WHO ICTRP to July 2022. We also reviewed the reference lists of relevant articles., Selection Criteria: We included randomised controlled trials (RCTs) comparing decompressive craniectomy with medical management to best medical management alone for people with malignant cerebral oedema after MCA ischaemic stroke., Data Collection and Analysis: Two review authors independently screened the search results, assessed study eligibility, performed risk of bias assessment, and extracted the data. The primary outcomes were death and death or severe disability (modified Rankin Scale (mRS) &gt; 4) at 6 to 12 months follow-up. Other outcomes included death or moderate disability (mRS &gt; 3), severe disability (mRS = 5), and adverse events. We assessed the certainty of the evidence using the GRADE approach, categorising it as high, moderate, low, or very low., Main Results: We included nine RCTs with a total of 513 participants included in the final analysis. Three studies included patients younger than 60 years of age; two trials accepted patients up to 80 years of age; and one trial only included patients 60 years or older. The majority of included trials (six) mandated a time from stroke ictus to treatment of &lt; 48 hours, whilst in two of them this was &lt; 96 hours. Surgical decompression was associated with a reduction in death (odds ratio (OR) 0.18, 95% confidence interval (CI) 0.12 to 0.27, 9 trials, 513 participants, P &lt; 0.001; high-certainty evidence); death or severe disability (mRS &gt; 4, OR 0.22, 95% CI 0.15 to 0.32, 9 trials, 513 participants, P &lt; 0.001; high-certainty evidence); and death or moderate disability (mRS &gt; 3, OR 0.34, 95% CI 0.22 to 0.52, 9 trials, 513 participants, P &lt; 0.001; moderate-certainty evidence). Subgroup analysis did not reveal any significant effect on treatment outcomes when analysing age (&lt; 60 years versus ≥ 60 years); time from stroke ictus to intervention (&lt; 48 hours versus ≥ 48 hours); or dysphasia. There was a significant subgroup effect of time at follow-up (6 versus 12 months, P = 0.02) on death as well as death or severe disability (mRS &gt; 4); however, the validity of this finding was affected by fewer participant numbers in the six-month follow-up subgroup. There was no consistent reporting of per-participant adverse event rates in any of the included studies, which prevented further analysis., Authors' Conclusions: Surgical decompression improves outcomes in the management of malignant oedema after acute ischaemic stroke, including a considerable reduction in death or severe disability (mRS &gt; 4) and a reduction in death or moderate disability (mRS &gt; 3). Whilst there is evidence that this positive treatment effect is present in patients &gt; 60 years old, it is important to take into account that these patients have a poorer prospect of functional survival independent of this treatment effect. In interpreting these results it must also be considered that the data demonstrating benefit are drawn from a unique patient subset with profound neurological deficit, reduced level of consciousness, and no pre-morbid disability or severe comorbidity., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker for baseline characterization and longitudinal monitoring of a tumor throughout disease management. The aim of this study was to evaluate the utility of ctDNA across a wide spectrum of tumor types., Methods: We retrospectively identified 1,763 patients with advanced cancers who had next-generation sequencing of ctDNA or tumor tissue completed by a designated commercial assay at Northwestern University., Results: ctDNA identified at least one gene alteration in 90% of patients. The number of detected alterations (NDA) and mutant allele frequency (MAF) of the most frequently mutated genes varied significantly across tumor types, with the highest MAF observed in gastric, colorectal, and breast cancers and the highest NDA observed in colorectal, lung squamous, and ovarian/endometrial cancers. TP53 was the most mutated gene in all tumor types. PIK3CA, ERBB2, BRCA1 , and FGFR1 alterations were associated with breast cancer, and ESR1 mutations were exclusively detected in this tumor type. Colorectal cancer was characterized by alterations in KRAS and APC mutations, whereas KRAS, EGFR, PIK3CA , and BRAF mutations were common in lung adenocarcinoma. Concordance between blood and tissue sequencing was notably observed for truncal gene alterations (eg, APC and KRAS ), whereas low concordance was often observed in genes associated with treatment resistance mechanisms (eg, RB1 and NF1 ). Tumor mutational burden (TMB) varied significantly across tumor types, and patients with high MAF or NDA had a significantly higher TMB score with one of the investigated platforms., Conclusion: The study provided new insights into the ctDNA mutational landscape across solid tumors, suggesting new hypotheses-generating data and caveats for future histotype-agnostic workflows integrated with tissue-based biomarkers such as TMB.

Patients with a history of malignancy have been shown to be at an increased risk of COVID-19-related morbidity and mortality. Poorer clinical outcomes in that patient population are likely due to the underlying systemic illness, comorbidities, and the cytotoxic and immunosuppressive anti-tumor treatments they are subjected to. We identified 416 cancer patients with SARS-CoV-2 infection being managed for their malignancy at Northwestern Medicine in Chicago, Illinois, between March and July of 2020. Seventy-five (18.0%) patients died due to COVID-related complications. Older age (>60), male gender, and current treatment with immunotherapy were associated with shorter overall survival. Laboratory findings showed that higher platelet counts, ALC, and hemoglobin were protective against critical illness and death from COVID-19. Conversely, elevated inflammatory markers such as ferritin, d-dimer, procalcitonin, CRP, and LDH led to worse clinical outcomes. Our findings suggest that a thorough clinical and laboratory assessment of infected patients with cancer might help identify a more vulnerable population and implement more aggressive proactive strategies.