Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

Background: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293).

Patients And Methods: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.

Assessment of Factors Associated With Internal Carotid Injury in Expanded Endoscopic Endonasal Skull Base Surgery.

Importance: Injury to the internal carotid artery (ICA) during endoscopic endonasal skull base surgery does not typically occur as an isolated circumstance but often is the result of multiple factors.

Objective: To assess the factors associated with ICA injury in an effort to reduce its occurrence.

Design, Setting, And Participants: This quality improvement study used a multicenter root cause analysis of ICA injuries sustained during endoscopic endonasal skull base surgery performed at 11 tertiary care centers across 4 continents (North America, South America, Europe, and Asia) from January 1, 1993, to December 31, 2018.

Review of Procedures and Outcomes of Video-Assisted Thoracic Surgery for the Treatment of Non-Small Cell Lung Cancer in 45 Patients Undergoing Segmentectomy.

Background: Lung cancer is the leading cause of death due to cancer in the United States and survival is heavily dependent upon the cancer stage at diagnosis. In the treatment of Stage I or Stage II non-small cell lung cancer (NSCLC), cancerous lung nodules are removed through lobectomy or segmentectomy. Lobectomy removes an entire lobe of the lung.

Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders.

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead (A91).

Blood test shows high accuracy in detecting stage I non-small cell lung cancer.

Background: In a previous study (Goebel et. al, Cancer Genomics Proteomics 16:229-244, 2019), we identified 33 biomarkers for an early stage (I-II) Non-Small Cell Lung Cancer (NSCLC) test with 90% accuracy, 80.3% sensitivity, and 95.

Disparities in Risk Reduction Therapy Recommendations for Young Women With Lobular Carcinoma In-Situ.

Background: Endocrine therapy (ET) significantly reduces the risk of breast cancer development in high-risk patients diagnosed with lobular carcinoma in situ (LCIS). However, the variables impacting recommendation and use of ET in young adults (YAs) is not well-studied. We examined the role of provider recommendation and patient acceptance for ET for YAs with LCIS.

Epigenetic hypomethylation and upregulation of GD3s in triple negative breast cancer.

Background: Breast cancer remains a major health problem in the world. Triple-negative breast cancer (TNBC) is an aggressive subtype with very poor prognosis. Up to now, the mechanism behind TNBC's activity is still unclear and no candidate drug target has been identified.

Updates on the Management of Thyroid Cancer.

The diagnostic modalities, stratification tools, and treatment options for patients with thyroid cancer have rapidly evolved since the development of the American Thyroid Association (ATA) guidelines in 2015. This review compiles newer concepts in diagnosis, stratification tools and treatment options for patients with differentiated thyroid cancer (DTC), medullary thyroid carcinoma (MTC) and anaplastic thyroid cancer (ATC). Newer developments apply precision medicine in thyroid cancer patients to avoid over-treatment in low risk disease and under-treatment in high risk disease.

Cellular thermal shift analysis for interrogation of CRISPR-assisted proteomic changes.

CRISPR-Cas9 has proven to be a versatile tool for the discovery of essential genetic elements involved in various disease states. CRISPR-assisted dense mutagenesis focused on therapeutically challenging protein complexes allows us to systematically perturb protein-coding sequences and correlate them with functional readouts. Such perturbations can mimic targeting by therapeutics and serve as a foundation for the discovery of highly specific modulators.

ANG1005, a Brain-Penetrating Peptide-Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases.

Purpose: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown.

Patients And Methods: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted ( = 72 BCBM; = 28 leptomeningeal carcinomatosis subset).

Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer.

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance.

Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease.

Purpose: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development.

Methods: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment.

Stapled Diaphragmatic Plication: Is It Better Than Suture Plication?

Diaphragm dysfunction, which can be due to eventration or an abnormally high-positioned diaphragm, can cause respiratory compromise. Eventration is most commonly due to unilateral diaphragm paralysis, which reduces ventilatory function in adults by about 25%. Since the 1920s, this condition has been treated with diaphragm plication, which itself has evolved to include the use of several different techniques and materials.

Regional Node Basin Recurrence in Melanoma Patients: More Common After Node Dissection for Macroscopic Rather than Clinically Occult Nodal Disease.

Background: Recommended treatment for patients with sentinel lymph node (SLN)-positive melanoma has recently changed. Randomized trials demonstrated equivalent survival with close observation versus completion lymph node dissection (CLND), but increased regional node recurrence. We evaluated factors related to in-basin nodal recurrence after lymphadenectomy (LND) for SLN-positive or macroscopic nodal metastases.

STAT3 Activation-Induced Fatty Acid Oxidation in CD8 T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth.

Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8 T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8 T effector cell functions, leading to inhibition of breast tumor development.

Biological intratumoral therapy for the high-grade glioma part I: intratumoral delivery and immunotoxins.

Management of high-grade gliomas remains a complex challenge. Standard of care consists of microsurgical resection, chemotherapy and radiation, but despite these aggressive multimodality therapies the overall prognosis remains poor. A major focus of ongoing translational research studies is to develop novel therapeutic strategies that can maximize tumor cell eradication while minimizing collateral side effects.

Biological intratumoral therapy for the high-grade glioma part II: vector- and cell-based therapies and radioimmunotherapy.

Management of high-grade gliomas (HGGs) remains a complex challenge with an overall poor prognosis despite aggressive multimodal treatment. New translational research has focused on maximizing tumor cell eradication through improved tumor cell targeting while minimizing collateral systemic side effects. In particular, biological intratumoral therapies have been the focus of novel translational research efforts due to their inherent potential to be both dynamically adaptive and target specific.

Pituitary gland recovery following fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenoma: results of a prospective multicenter study.

Objective: Recovery from preexisting hypopituitarism after transsphenoidal surgery for pituitary adenoma is an important outcome to investigate. Furthermore, pituitary function has not been thoroughly evaluated after fully endoscopic surgery, and benchmark outcomes have not been clearly established. Here, the authors characterize pituitary gland outcomes with a focus on gland recovery following endoscopic transsphenoidal removal of clinically nonfunctioning adenomas.

Diaphragmatic Pacing: Is There a Benefit?

The diaphragm is the primary muscle of respiration and its injury can cause diaphragm dysfunction and respiratory deficits. Respiratory compromise has historically been managed with mechanical ventilation, however, its use has also been shown to result in poor functional outcomes. Therefore, stimulation of the phrenic nerve, called diaphragm pacing, has been used to replace and/or delay the need for mechanical ventilation.

Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy.

Background: Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel.

Methods: Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs.

The Immune Microenvironment Impacts Survival in Western Patients with Gastric Adenocarcinoma.

Background: Expression of CD3+ T cells, CD8+ cytotoxic T cells, CD45RO+ memory T cells, and FOXP3+ regulatory T cells at the invasive margin (IM) and tumor center (TC) has correlated with survival in gastric adenocarcinoma (GA) patients from East Asia, independent of anatomic staging. The reason for improved survival in East Asians compared with Western patients is a subject of debate. This study examined the immune profiles of a cohort of Western patients with GA, and their association with overall survival (OS).

Accuracy of nodal staging is influenced by sidedness in colon cancer.

Background: Adequate lymph node (LN) sampling is critical for accurate nodal staging in colon cancer (CC), particularly for T3N0 disease as current guidelines recommend considering adjuvant chemotherapy when less than 12 LNs are examined. The impact of sidedness on nodal staging accuracy in patients with T3N0 disease has not been previously studied.

Methods: Patients with pathologic T3 CC were identified from a prospective multicenter international trial of ultrastaging in CC.

Parathyroidectomy for Patients With Primary Hyperparathyroidism and Associations With Hypertension.

Importance: Hyperparathyroidism is associated with cardiovascular disease. However, evidence for a beneficial consequence of parathyroidectomy on hypertension is limited.

Objective: To investigate if parathyroidectomy improves hypertension in patients with primary hyperparathyroidism (PHPT).