Multimodal smoking cessation treatment combining repetitive transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol.

Tobacco-related deaths remain the leading cause of preventable death in the United States. Veterans suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies suggest the insula is integrally involved in the neurocircuitry of TUD. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a form of repetitive transcranial magnetic stimulation (rTMS) called intermittent theta burst stimulation (iTBS). iTBS has the advantage of allowing for a patterned form of stimulation delivery that we will administer at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the right post-central gyrus and the right posterior insula, withdrawal symptoms and short-term smoking cessation outcomes will improve. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n = 25) or sham-iTBS + CBT + NRT (n = 25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.

Early to late explantation of Hydrus microstent MIGS device: A case series.

Purpose: The Hydrus microstent was approved by the FDA in August 2018 for use with cataract surgery to reduce IOP in patients with mild to moderate primary open angle glaucoma (POAG). Pivotal clinical trials demonstrated its overall safety and efficacy in lowering IOP. However, malpositioning of the implant can result in uveitis-glaucoma-hyphema (UGH) syndrome necessitating device explantation. Here we report four such cases and their associated challenges. We also highlight the importance of early recognition of post-operative complications for ease of implant removal. Observations: Case 1: A 75-year-old female patient was referred for chronic granulomatous anterior uveitis with cystoid macular edema (CME) and uncontrolled IOP in the left eye after cataract extraction with Hydrus implantation. On gonioscopy, the implant was occluded and embedded in the iris. The patient underwent removal of the Hydrus implant 10 months after the initial surgery with canaloplasty to control IOP.Case 2: A 71-year-old male patient on dual anti-platelet developed intraoperative hyphema during cataract extraction with Hydrus microstent in the right eye. Post-operatively, clopidogrel was stopped, but hyphema persisted with uncontrolled IOP. The Hydrus was noted to be syneched against the iris face. The patient underwent anterior chamber washout with Hydrus explantation and Ahmed glaucoma valve implantation 16 days after the first surgery.Case 3: A 76-year-old patient developed persistent granulomatous anterior uveitis in the left eye after cataract extraction with Hydrus microstent. On gonioscopy, the Hydrus ostium was seen resting on the iris without occlusion, and the patient underwent Hydrus removal with nasal goniotomy 3 months after initial surgery.Case 4: A 63-year-old patient underwent cataract extraction with endoscopic cyclophotocoagulation and a complex Hydrus microstent implantation requiring multiple attempts. Eleven months later, the patient was found to have uveitis-glaucoma-hyphema syndrome and macular edema, and the Hydrus was noted to be insufficiently inserted and posteriorly rotated with contact against the iris. The Hydrus was explanted, and nasal goniotomy was performed. Conclusions and importance: Hydrus microstents that are malpositioned can result in persistent uveitis-glaucoma-hyphema syndrome. Explantation between 2 weeks and 11 months successfully resolved post-operative uveitis and hyphema, but all cases required additional glaucoma-hyphema syndrome. Early recognition is important since late removal was more challenging due to the implant becoming embedded in the iris.

Electroconvulsive Therapy Changes Immunological Markers in Patients With Major Depressive Disorder: A Scoping Review.

ABSTRACT: Major depressive disorder (MDD) is a highly prevalent and disabling condition. As such, understanding the causes of and treatment options for MDD is critical. Electroconvulsive therapy (ECT) remains the gold standard depression treatment, but the molecular mechanisms that underlie its effects are still largely unknown. One such explanation hinges on the immuno-inflammatory correlates of ECT treatment, given mounting evidence supporting the inflammatory hypothesis of depression. This review aims to provide an overview of the suggested immunomodulatory effects of ECT and the predictive value of immune biomarkers in relation to treatment outcomes and side effects. We conducted a preregistered, systematic literature search utilizing MEDLINE (PubMed), Embase (Elsevier), and PsycINFO (EBSCO) databases. We employed keywords related to MDD, ECT, gut microbiome, and the immune system. We only included human subjects research published between 1985 and January 13, 2021. Twenty-six unique studies were included in our analyses. Findings indicate a proinflammatory profile associated with MDD, with immune biomarkers exhibiting acute and chronic changes following ECT. Consistently, lower baseline interleukin 6 levels and higher C-reactive protein levels are correlated with a greater reduction in depressive symptoms following ECT. Furthermore, included studies emphasize the predictive value of peripheral immune changes, specifically interleukin 6 and tumor necrosis factor α, on cognitive outcomes following ECT. Given these results, further exploration of the potential roles of immunomodulatory effects on ECT treatment outcomes, as well as adverse cognitive side effects, is indicated.

Association Between 18F-FDG PET Activity and HER2 Status in Breast Cancer Brain Metastases.

Purpose: The objective of this study was to evaluate whether uptake on 18F-fluorodeoxyglucose (18F-FDG) PET could help differentiate HER2-positive from HER2-negative breast cancer brain metastases. Methods: In this retrospective, cross-sectional study of a cohort of 14 histologically proven breast cancer brain metastases, we analyzed both preoperative 18F-FDG PET/CT and HER2 status of the resected/biopsied brain specimens. The maximum standardized uptake values (SUVmax) of the lesions were normalized to contralateral normal white matter and compared using Mann-Whitney U tests. Results: The study cohort was comprised of 12 women with breast cancer with a mean age of 59 years (range: 43-76 years) with a total of 14 distinct brain metastatic lesions. The SUVmax ratio of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (3.98 vs 1.79, U = 38.00, p = 0.008). Conclusion: The SUVmax ratio may help to identify the HER2 status of breast cancer brain metastases, if validated prospectively.

Effect of chemotherapy on hippocampal volume and shape in older long-term breast cancer survivors.

Purpose: The objective of this study was to assess changes in hippocampal volume and shape in older long-term breast cancer survivors who were exposed to chemotherapy 5-15 years prior. Methods: This study recruited female long-term breast cancer survivors aged 65 years or older with a history of chemotherapy (C+), age-matched breast cancer survivors who did not receive chemotherapy (C-), and healthy controls (HC). The participants were recruited 5-15 years after chemotherapy at time point 1 (TP1) and were followed up for 2 years at time point 2 (TP2). Assessments included hippocampal volume and shape from brain MRI scans and neuropsychological (NP) tests. Results: At TP1, each of the three groups was comprised of 20 participants. The C+ group exhibited a hippocampal volume loss estimated in proportion with total intracranial volume (ICV) in both the left and right hemispheres from TP1 to TP2. Regarding the hippocampal shape at TP1, the C+ group displayed inward changes compared to the control groups. Within the C+ group, changes in right hippocampal volume adjusted with ICV were positively correlated with crystalized composite scores (R = 0.450, p = 0.044). Additionally, in C+ groups, chronological age was negatively correlated with right hippocampal volume adjusted with ICV (R = -0.585, p = 0.007). Conclusion: The observed hippocampal volume reduction and inward shape deformation within the C+ group may serve as neural basis for cognitive changes in older long-term breast cancer survivors with history of chemotherapy treatment.

Multimodal smoking cessation treatment combining transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement therapy in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol.

Tobacco-related deaths exceed those resulting from homicides, suicides, motor vehicle accidence, alcohol consumption, illicit substance use, and acquired immunodeficiency syndrome (AIDS), combined. Amongst U.S. veterans, this trend is particularly concerning given that those suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies have revealed the insula as integrally involved in the neurocircuitry of TUD, specifically showing that individuals with brain lesions involving this region had drastically improved quit rates. Some of these studies show a probability of quitting up to 5 times greater compared to non-insula lesioned regions). Altered activity of the insula may be involved in the disruption of the salience network's (SN) connectivity to the executive control network (ECN), which compromises that patient's ability to switch between interoceptive states focused on cravings to executive and cognitive control. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a patterned form of repetitive transcranial magnetic stimulation (rTMS), intermittent theta burst stimulation (iTBS), at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the SN with the ECN to enhance executive control and by decreasing connectivity with the default mode network (DMN) to reduce interoceptive focus on withdrawal symptoms, we will improve smoking cessation outcomes. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to two conditions: active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n=25) or sham-iTBS + CBT + NRT (n=25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.

Revealing the Impact of Genomic Alterations on Cancer Cell Signaling with an Interpretable Deep Learning Model.

Cancer is a disease of aberrant cellular signaling resulting from somatic genomic alterations (SGAs). Heterogeneous SGA events in tumors lead to tumor-specific signaling system aberrations. We interpret the cancer signaling system as a causal graphical model, where SGAs affect signaling proteins, propagate their effects through signal transduction, and ultimately change gene expression. To represent such a system, we developed a deep learning model called redundant-input neural network (RINN) with a transparent redundant-input architecture. Our findings demonstrate that by utilizing SGAs as inputs, the RINN can encode their impact on the signaling system and predict gene expression accurately when measured as the area under ROC curves. Moreover, the RINN can discover the shared functional impact (similar embeddings) of SGAs that perturb a common signaling pathway (e.g., PI3K, Nrf2, and TGF). Furthermore, the RINN exhibits the ability to discover known relationships in cellular signaling systems.

Laryngeal Amyloidosis: What is the Role of Imaging?

OBJECTIVE/HYPOTHESIS: To review the imaging findings of laryngeal amyloidosis and to identify radiological findings suggestive of this disease. STUDY DESIGN: Retrospective case series. METHODS: A retrospective chart review of patients with pathologically confirmed laryngeal amyloidosis was performed from 2009 to 2022. Clinical and demographic factors were collected. A fellowship-trained head and neck radiologist reviewed all computed tomography (CT) scans and magnetic resonance imaging (MRI) findings within this cohort. RESULTS: 12 patients were identified and a total of 36 imaging studies analyzed. Localized amyloidosis was found in the supraglottic region (n = 6), glottic region (n = 7), and subglottic region (n = 5); six patients had disease spanning two subsites. The most common finding on the CT scan was a homogeneous and well-defined submucosal soft tissue mass. Punctate calcifications were present in three cases. The presence of contrast enhancement was identified in the majority of patients who underwent MRI (4/5). MRI showed consistent signal intensity, hypointense, or isointense on both T1-weighted and T2-weighted images. Diffusion-weighted sequences were obtained in every patient and did not demonstrate diffusion restriction. CONCLUSION: This is the largest series searching for unifying imaging characteristics of laryngeal amyloidosis. This research suggests that characteristics from CT and MR provide both similar and unique features of laryngeal amyloidosis on imaging. Both modalities identify a submucosal mass. CT is the preferred modality to demonstrate punctate calcifications, while MRI identifies enhancement and altered signal characteristics. The main benefit of serial imaging is the correlation with patient symptoms, identification of the extent of disease, and assisting in delineating appropriate timing for surgery.

The retinal deep capillary plexus as a venous outflow system; insights from Sturge Weber Syndrome.

PURPOSE: To report on the venous abnormalities of a patient with Sturge-Weber syndrome (SWS). METHOD: Case report. PATIENT: A 29-year-old woman with a history of SWS since infancy was referred for evaluation of possible diffuse choroidal hemangioma. Multimodal imaging, including ultra-widefield fluorescein, indocyanine green, and optical coherence tomography-angiography (OCTA) were performed. RESULTS: Dilated fundus examination was remarkable for increased cupping of the optic disc in the right eye, venous tortuosity, and marked dilation of the choroidal vessels. Ultra-widefield fluorescein angiography confirmed marked venous tortuosity and dilation, as well as anastomoses of the retinal veins ipsilateral to the port wine stain. Indocyanine green angiography revealed marked engorgement of the vortex veins and choroidal vasculature. OCTA revealed dilated vascular channels in the deep capillary plexus (DCP) that were directly anastomosing to the superficial capillary plexus, but not the intermediate capillary plexus. Engorgement of the ampullae of the DCP vortex system was also observed. The normal contralateral eye was used as comparison for all imaging studies. CONCLUSION: These findings support the notion of generalized venous hypertension state in adult eyes with SWS and corroborate prior evidence that the deep capillary plexus acts as a venous outflow system.

Mobile health contingency management for smoking cessation among veterans experiencing homelessness: A comparative effectiveness trial.

Tobacco cessation is reduced in U.S. military veterans experiencing homelessness. Mobile contingency management (mCM) is a promising treatment for tobacco use among populations experiencing homelessness, but past CM studies have largely been small, have relied on in-person follow-up, and/or lacked long-term biochemically verified abstinence measures. Veterans who smoked and were experiencing homelessness (N = 127) were randomly assigned to mCM treatment (4 weeks of mCM, 5 weeks of telehealth counseling, and the option of 12 weeks of pharmacotherapy) or VA standard care (3 biweekly group sessions and clinically appropriate pharmacotherapy), and all participants were randomly assigned to a $100 longer-term financial incentive for abstinence at 3-month follow-up. Participants were followed at 3-, 6-, and 12-months post-randomization, with the a priori main outcome designated as biochemically verified prolonged abstinence (with lapses) at 6-month follow-up. At 6-months, participants in the mCM group were significantly more likely to meet criteria for prolonged abstinence (OR = 3.1). Across time points, veterans in the mCM group had twice the odds of prolonged abstinence as those in the standard care group. However, by the 12-month follow-up, there was no statistically significant group difference in abstinence. Cost-effectiveness analysis indicated a modest increase in cost ($1,133) associated with an increase of one quality-adjusted life year saved for the intervention compared to standard care. mCM is a cost-effective approach to smoking cessation among veterans experiencing homelessness. Considering waning potency of this and other tobacco cessation interventions at 12-month follow-up, it is crucial to implement strategies to sustain abstinence for individuals experiencing homelessness.

GHR disruption in mature adult mice alters xenobiotic metabolism gene expression in the liver.

BACKGROUND: Lifelong reduction of growth hormone (GH) action extends lifespan and improves healthspan in mice. Moreover, congenital inactivating mutations of GH receptor (GHR) in mice and humans impart resistance to age-associated cancer, diabetes, and cognitive decline. To investigate the consequences of GHR disruption at an adult age, we recently ablated the GHR at 6-months of age in mature adult (6mGHRKO) mice. We found that both, male and female 6mGHRKO mice have reduced oxidative damage, with males 6mGHRKO showing improved insulin sensitivity and cancer resistance. Importantly, 6mGHRKO females have an extended lifespan compared to controls. OBJECTIVE AND METHODS: To investigate the possible mechanisms leading to health improvements, we performed RNA sequencing using livers from male and female 6mGHRKO mice and controls. RESULTS: We found that disrupting GH action at an adult age reduced the gap in liver gene expression between males and females, making gene expression between sexes more similar. However, there was still a 6-fold increase in the number of differentially expressed genes when comparing male 6mGHRKO mice vs controls than in 6mGHRKO female vs controls, suggesting that GHR ablation affects liver gene expression more in males than in females. Finally, we found that lipid metabolism and xenobiotic metabolism pathways are activated in the liver of 6mGHRKO mice. CONCLUSION: The present study shows for the first time the specific hepatic gene expression profile, cellular pathways, biological processes and molecular mechanisms that are driven by ablating GH action at a mature adult age in males and females. Importantly, these results and future studies on xenobiotic metabolism may help explain the lifespan extension seen in 6mGHRKO mice.

Association of lesion contour and lesion composition on MR with HER2 status in breast cancer brain metastases.

BACKGROUND AND PURPOSE: With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 status in breast cancer brain metastases has become increasingly important, particularly given the risks of tissue sampling within the brain and the possibility of a change in receptor expression from the primary tumor to the brain metastasis. The purpose of this study was to evaluate whether lesion contour and composition on MR could help identify the HER2 status of breast cancer brain metastases. MATERIALS AND METHODS: We derived a cohort of 34 women with a mean age of 55 years (range: 31-81 years) with a total of 47 distinct histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MR and HER2 immunohistochemistry and/or fluorescent in-situ hybridization (FISH) of the resected/biopsied brain specimens from 2018 to 2021. Two fellowship-trained neuroradiologists evaluated the lesion contour and lesion composition of each lesion. Logistic regression analyses were performed. RESULTS: In a logistic regression model, an irregular contour had an odds ratio of 170 (p = 0.007) in differentiating HER2-positive from HER2-negative lesions. In a logistic regression model, when compared to a predominantly cystic lesion composition, a solid lesion composition had an odds ratio of 17 (p = 0.016) in differentiating HER2-positive from HER2-negative lesions. CONCLUSION: Lesion contour and lesion composition on MR were significantly associated with the HER2 status of breast cancer brain metastases. Current assessment of HER2 status requires tissue sampling and immunochemical and/or FISH analyses. A non-invasive imaging biomarker that may help predict HER2 status may be of great clinical value.

Association of Relative Cerebral Blood Volume from Dynamic Susceptibility Contrast-Enhanced Perfusion MR with HER2 Status in Breast Cancer Brain Metastases.

RATIONALE AND OBJECTIVES: With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 expression in breast cancer brain metastases has become increasingly important. The purpose of this study was to investigate whether relative cerebral blood volume (rCBV) from dynamic susceptibility contrast-enhanced (DSC) perfusion MR could help identify the HER2 status of breast cancer brain metastases. MATERIALS AND METHODS: With IRB approval for this HIPAA-compliant cross-sectional study and a waiver of informed consent, we queried our institution's electronic medical record to derive a cohort of 14 histologically proven breast cancer brain metastases with preoperative DSC perfusion MR and HER2 analyses of the resected/biopsied brain specimens from 2011-2021. The rCBV of the lesions was measured and compared using Mann-Whitney tests. Receiver operating characteristic analyses were performed to evaluate the performance of rCBV in identifying HER2 status. RESULTS: The study cohort was comprised of 14 women with a mean age of 56 years (range: 32-81 years) with a total of 14 distinct lesions. The rCBV of HER2-positive breast cancer brain metastases was significantly greater than the rCBV of HER2-negative lesions (8.02 vs 3.97, U=48.00, p=0.001). rCBV differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.98 (standard error=0.032, p<0.001). The accuracy-maximizing rCBV threshold (4.8) was associated with an accuracy of 93% (13/14), a sensitivity of 100% (7/7), and a specificity of 86% (6/7). CONCLUSION: rCBV may assist in identifying the HER2 status of breast cancer brain metastases, if validated in a large prospective trial.

Osimertinib-Induced Cutaneous Vasculitis Responsive to Low-Dose Dapsone Without Interruption of Anticancer Therapy: A Case Report and Review of the Literature.

A 45-year-old woman with a history of lung adenocarcinoma treated with osimertinib developed purpuric plaques and vesicles on the lower extremities after 5 months of therapy. Skin biopsy revealed leukocytoclastic vasculitis (LCV). A workup for systemic involvement was unremarkable. The patient was treated with oral dapsone while continuing osimertinib without interruption. Skin lesions cleared within 2 weeks of therapy with no recurrence after titrating off dapsone. To the best of our knowledge, this is the first reported case of LCV induced by a small-molecule EGFR inhibitor in which therapy was not interrupted. This is also the first reported case treated with dapsone rather than systemic corticosteroids. We suggest consideration of dapsone to treat skin-limited LCV induced by EGFR inhibitors in patients with lung cancer without features of systemic vasculitis. In addition, this case highlights that it may not be necessary to stop EGFR inhibitor therapy in the absence of severe features such as ulceration, bullae, necrosis, or severe pain. Dapsone is an effective targeted therapy for cutaneous LCV that does not globally impair the immune system and may allow for uninterrupted treatment of the underlying malignancy.

Intraocular Pressure and Medication Burden With Cataract Surgery Alone, or Cataract Surgery Combined With Trabecular Bypass or Goniotomy.

PRCIS: When compared with cataract surgery in glaucoma patients, trabecular micro-bypass and goniotomy resulted in a large decrease in the incidence of intraocular pressure (IOP) spikes, a modest effect on IOP, and a minimal effect on medication burden. PURPOSE: To compare changes in IOP and ocular hypotensive medications in 3 surgical cohorts: cataract surgery, cataract surgery with trabecular micro-bypass (cataract/trabecular), and cataract surgery with goniotomy (cataract/goniotomy). MATERIALS AND METHODS: We included 138 eyes diagnosed with open-angle glaucoma: (1) 84 eyes with cataract surgery alone, (2) 25 eyes with cataract/trabecular surgery, and (3) 29 eyes with cataract/goniotomy surgery. We compared the groups for postoperative IOP and the number of ocular hypotensive medications. We adjusted for preoperative IOP, and preoperative and postoperative number of ocular hypotensive medications. We defined an IOP spike as IOP ≥21 mm Hg and 10 mm Hg higher than preoperative on postoperative day 1. RESULTS: All 3 surgeries showed a decrease in IOP (P≤0.004) and medication burden (P≤0.001) at 3 and 6 months postoperatively when compared with their own preoperative baselines. When compared with cataract surgery alone, cataract/trabecular and cataract/goniotomy had similar IOP lowering at 1 month postoperatively, and variable results at 3 and 6 months. The change in ocular hypotensive medications was not statistically different between the surgical groups at any postoperative visit. Cataract/trabecular and cataract/goniotomy decreased IOP on postoperative day 1, and had relative risk reduction of ~70% for IOP spikes (P≤0.001 for both). CONCLUSION: Trabecular micro-bypass and goniotomy when added to cataract surgery resulted in a large decrease in IOP spikes, a modest effect on IOP, and a minimal effect on medication burden when compared with cataract surgery alone in glaucoma patients.

Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer.

OBJECTIVES: We quantitatively characterized the change in temporospatial expression of repressive and stimulatory checkpoints across immune cell populations in the tumor microenvironment in a cohort of high grade serous ovarian carcinomas (HGSOC) using matched samples before and after neoadjuvant platinum-based chemotherapy. METHODS: Using retrospectively collected matched tissue samples from 9 patients, cell populations were assessed using multiplex immunofluorescence using the Vectra Multispectral Imaging System (Perkin Elmer). We used multiple panels to assess: tumor (AE1/AE3), T cells (CD3, CD8, FOXP3), macrophages (CD68) as well as immune checkpoints (C3aR, PD-1, PD-L1, LAG3, IDO, ICOS, GITR). IHC staining was performed for folate receptor status. Changes in immune cell populations as well as intensities of associated repressive and stimulatory proteins were assessed pre- to post-treatment. RESULTS: We observed a consistently high pre-treatment stromal macrophage population which is reduced post-chemotherapy with post-treatment enrichment in macrophage PD-L1 expression. While inhibitory checkpoint expression on T cells was heterogeneous post-chemotherapy, we observed a change in the ThICOS+:Treg ratio which resulted in ThICOS+ cells outnumbering Treg cells post-treatment. Spatial analysis revealed the proximity of Treg cells to ThICOS+ T cells decreased post-treatment. We also observed upward shifts in Teff:Treg T cell ratios with retention of immune checkpoints PD-1, LAG3 and GITR. CONCLUSIONS: In this unique dataset of pre and post matched chemotherapy treated HGSOC patients, we observed changes in immune cell subsets expressing repressive or stimulatory proteins resulting in immune compositions more favorable to checkpoint modulations, suggesting novel therapeutic strategies in the recurrent setting.

Mice with gene alterations in the GH and IGF family.

Much of our understanding of GH's action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.

A woman presenting with an unusual cause of fulminant liver failure and sepsis.

We present the case of a 61-year-old woman who presented with acutely worsening right upper quadrant pain and was found to be in acute liver failure with Klebsiella pneumoniae bacteremia. Despite aggressive intensive care management, the patient ultimately died of refractory shock attributed to sepsis and fulminant liver failure. On autopsy, she was found unexpectedly to have diffuse intrahepatic cholangiocarcinoma with metastases to regional lymph nodes and intravascular spread to the lungs. The case highlights a rare instance where intrahepatic cholangiocarcinoma presents with acute liver failure and discusses key intensive care management principles of this clinical syndrome.

Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan.

Studies in multiple species indicate that reducing growth hormone (GH) action enhances healthy lifespan. In fact, GH receptor knockout (GHRKO) mice hold the Methuselah prize for the world's longest-lived laboratory mouse. We previously demonstrated that GHR ablation starting at puberty (1.5 months), improved insulin sensitivity and female lifespan but results in markedly reduced body size. In this study, we investigated the effects of GHR disruption in mature-adult mice at 6 months old (6mGHRKO). These mice exhibited GH resistance (reduced IGF-1 and elevated GH serum levels), increased body adiposity, reduced lean mass, and minimal effects on body length. Importantly, 6mGHRKO males have enhanced insulin sensitivity and reduced neoplasms while females exhibited increased median and maximal lifespan. Furthermore, fasting glucose and oxidative damage was reduced in females compared to males irrespective of Ghr deletion. Overall, disrupted GH action in adult mice resulted in sexual dimorphic effects suggesting that GH reduction at older ages may have gerotherapeutic effects.

Performance of enhancement on brain MRI for identifying HER2 overexpression in breast cancer brain metastases.

PURPOSE: To investigate whether enhancement on MRI could help identify HER2 overexpression in breast cancer brain metastases. METHODS: We derived a cohort of 38 histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MRI and HER2 fluorescent in-situ hybridization of the resected/biopsied brain specimens from 2018 to 2021. Enhancement of the lesions was measured and compared using t-tests. Receiver operating characteristic and logistic regression analyses were performed to evaluate the performance of MRI enhancement in identifying HER2 overexpression. RESULTS: The study cohort was comprised of 29 women with a mean age of 55 years (range: 31-81 years) with a total of 38 distinct lesions. The HER2-positive subcohort was comprised of 17 patients, while the HER2-negative subcohort was comprised of 13 patients. The percent signal intensity change (PSIC) of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (310 v. 153, P = 0.002). The PSIC differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.88 (P < 0.001). In a model controlling for lesion size, lesion location, tumor grade, patient age, scanner magnetic field strength, and contrast agent, the PSIC had an accuracy of 92% (35/38), sensitivity of 96% (23/24), and specificity of 86% (12/14) in differentiating HER2-positive lesions from HER2-negative lesions. CONCLUSION: Enhancement on MRI may assist in identifying HER2 overexpression in breast cancer brain metastases, if validated prospectively.