Use of ultrasound and MRI to stage the axilla for breast cancer before and after neoadjuvant chemotherapy prior to targeted sentinel lymphadenectomy.

PURPOSE: Prior data from this Center demonstrated that for patients who had biopsy-proven axillary metastases, were ycN0 after neoadjuvant chemotherapy (NAC), and had a wire-directed (targeted) sentinel lymphadenectomy (WD-SLND), 60% were node negative. The hypothesis of this study was that results of axillary imaging either before or after NAC would be predictive of final pathologic status after WD-SLND. METHODS: For patients treated with NAC between 2015 and 2023, ultrasound and MRI images of the axilla were retrospectively reviewed by radiologists specializing in breast imaging, who were blinded to the surgical and pathology results. RESULTS: Of 113 patients who fit the clinical criteria, 66 (58%) were ypN0 at WD-SLND and 34 (30%) had a pathologic complete response to NAC. There was no correlation between the number of abnormal lymph nodes on pre-NAC ultrasound or MRI imaging and the final pathologic status of the lymph nodes. The positive predictive value (PPV) of abnormal post-NAC axillary imaging was 48% for ultrasound and 53% for MRI. The negative predictive value (NPV) for normal post-NAC axillary imaging was 67% for ultrasound and 68% for MRI. CONCLUSION: The results of axillary imaging were not adequate to identify lymph nodes after NAC that were persistently pathologically node positive or those which had become pathologically node negative.

Exposure-Response Relationships for Pralsetinib in Patients with RET-Altered Thyroid Cancer or RET Fusion-Positive Nonsmall Cell Lung Cancer.

Pralsetinib is a highly potent oral kinase inhibitor of oncogenic RET (rearranged during transfection) fusions and mutations. Pralsetinib received approval from the United States Food and Drug Administration for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), and received accelerated approval for the treatment of patients with RET fusion-positive thyroid cancer. Exposure-response (ER) analyses of efficacy were performed separately in patients with thyroid cancer and in patients with NSCLC, but data for all patients were pooled for the safety analysis. ER models were developed with time-varying exposure; the effect of covariates was also examined. For patients with NSCLC, a higher starting dose was associated with improved progression-free survival (PFS), but this improvement did not correlate with a higher exposure overall. Significant covariates included sex and baseline Eastern Cooperative Oncology Group (ECOG) score. For patients with thyroid cancer, a higher exposure was associated with improved PFS. Significant covariates included prior systemic cancer therapy and ECOG score. For safety, higher exposure was associated with a greater risk of grade ≥3 anemia, pneumonia, and lymphopenia. Patients with an ECOG score of ≥1 had an increased risk of grade ≥3 pneumonia. Non-White patients had a lower risk of grade ≥3 lymphopenia. ER analysis revealed that higher pralsetinib exposure was associated with improved PFS in thyroid cancer, but not in NSCLC. However, a higher starting dose (ie, 400 vs ≤300 mg daily) was correlated with better PFS for all indications. Higher exposure was also associated with an increased risk of grade ≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400 mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment.

Background: Immunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates. Results: 21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease. Conclusions: On spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.

Differential Impact of Smoking on Methylome and Transcriptome in Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Smoking is an environmental factor that differentially impacts Crohn's disease (CD) and ulcerative colitis (UC). The mechanism of impact of smoking on disease risk and clinical outcomes remains to be established. METHODS: This study used a prospective cohort of patients with CD or UC. Self-reported smoking status was validated using serum cotinine measurement. We profiled methylation changes in peripheral blood using the Illumina Methylation BeadChip. Transcriptomic profiling was performed on ileal and colonic tissue using an Illumina TruSeq platform. We compared the methylation and transcriptional changes in current, former, and never smokers stratified by disease type. RESULTS: Our cohort included 200 patients with CD or UC with methylation profiles and 160 with transcriptomic data. The mean serum cotinine level was higher in current compared with former or never smokers. Epigenetic changes common to both CD and UC included hypomethylation at AHRR. Smoking-associated MGAT3 hypomethylation was associated with severe disease course only in UC, while IER3 hypomethylation was associated with worse course only in CD. Smoking downregulated several inflammatory pathways in UC. Current smoking in CD but not in UC was associated with upregulation of several genes mediating Paneth cell function. Genes with opposite direction of effects in CD and UC include HSD3B2 and GSTA1. CONCLUSIONS: Our findings suggest both common and differential effects of cigarette smoking on CD and UC. Paneth cell dysfunction may mediate adverse impact of smoking on CD. Bile acid and oxidative stress pathways may be relevant for the differential effect of smoking on CD and UC.

Smoking is a key environmental risk factor for the development of inflammatory bowel disease. Smoking induces changes differential epigenetic changes in the peripheral blood in Crohn's disease and ulcerative colitis. Smoking also induces down regulation of expression of various proinflammatory genes in the colon in ulcerative colitis.

Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2R413X reduced Wnt/ß-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/ß-catenin signaling, improved cytoskeletal organization, restored cell junction integrity in cell pairs, and improved calcium wave velocity in engineered tissues. Together, these findings highlight the therapeutic potential of modulating Wnt/ß-catenin signaling in a human model of ACM.

[68 Ga]-DOTATATE PET/MR-based evaluation of physiologic somatostatin receptor 2 expression in the adult pituitary gland as a function of age and sex in a prospective cohort.

PURPOSE: The pituitary gland has the fourth highest physiologic avidity of [68 Ga]-DOTATATE. In order to guide our understanding of [68 Ga]-DOTATATE PET in clinical contexts, accurate characterization of the normal pituitary gland is first required. This study aimed to characterize the normal pituitary gland using dedicated brain [68 Ga]-DOTATATE PET/MRI as a function of age and sex. METHODS: A total of 95 patients with a normal pituitary gland underwent brain [68 Ga]-DOTATATE PET examinations for the purpose of diagnosing CNS SSTR2 positive tumors (mean age: 58.9, 73% female). Maximum SUV of the pituitary gland was obtained in each patient. SUV of superior sagittal sinus was obtained to calculate normalized SUV score (SUVR) of the gland. The anatomic size of the gland was collected as maximum sagittal height (MSH). Correlations with age and sex were analyzed. RESULTS: The mean SUV and SUVR of the pituitary gland were 17.6 (range: 7-59.5, SD = 7.1) and 13.8 (range: 3.3-52.6, SD = 7.2), respectively. Older females had significantly higher SUV of the pituitary gland compared to younger females. When stratified by age and sex, both older and younger females had significantly higher pituitary SUV than older males. SUVR did not differ significantly by age or sex. MSH of the pituitary gland in younger females was significantly greater than in younger males at all age cutoffs. CONCLUSION: This study provides an empiric profiling of the physiological [68 Ga]-DOTATATE avidity of the pituitary gland. The findings suggest that SUV may vary by age and sex and can help guide the use of [68 Ga]-DOTATATE PET/MRI in clinical and research settings. Future studies can build on these findings to investigate further the relationship between pituitary biology and demographic factors.

Destabilization of the SHP2 and SHP1 protein tyrosine phosphatase domains by a non-conserved "backdoor" cysteine.

Protein tyrosine phosphatases (PTPs) are critical regulators of cellular signal transduction that catalyze the hydrolytic dephosphorylation of phosphotyrosine in substrate proteins. Among several conserved features in classical PTP domains are an active-site cysteine residue that is necessary for catalysis and a "backdoor" cysteine residue that can serve to protect the active-site cysteine from irreversible oxidation. Curiously, two biologically important phosphatases, Src homology domain-containing PTPs 2 and 1 (SHP2 and SHP1), each contain an additional backdoor cysteine residue at a position of the PTP domain that is occupied by proline in almost all other classical PTPs (position 333 in human SHP2 numbering). Here we show that the presence of cysteine 333 significantly destabilizes the fold of the PTP domains in the SHPs. We find that replacement of cysteine 333 with proline confers increased thermal stability on the SHP2 and SHP1 PTP domains, as measured by temperature-dependent activity assays and differential scanning fluorimetry. Conversely, we show that substantial destabilization of the PTP-domain fold is conferred by introduction of a non-natural cysteine residue in a non-SHP PTP that contains proline at the 333 position. It has previously been suggested that the extra backdoor cysteine of the SHP PTPs may work in tandem with the conserved backdoor cysteine to provide protection from irreversible oxidative enzyme inactivation. If so, our current results suggest that, during the course of mammalian evolution, the SHP proteins have developed extra protection from oxidation at the cost of the thermal instability that is conferred by the presence of their PTP domains' second backdoor cysteine.

Evaluating diagnostic accuracy and determining optimal diagnostic thresholds of different approaches to [68Ga]-DOTATATE PET/MRI analysis in patients with meningioma.

Multiple approaches with [68Ga]-DOTATATE, a somatostatin analog PET radiotracer, have demonstrated clinical utility in evaluation of meningioma but have not been compared directly. Our purpose was to compare diagnostic performance of different approaches to quantitative brain [68Ga]-DOTATATE PET/MRI analysis in patients with suspected meningioma recurrence and to establish the optimal diagnostic threshold for each method. Patients with suspected meningioma were imaged prospectively with [68Ga]-DOTATATE brain PET/MRI. Lesions were classified as meningiomas and post-treatment change (PTC), using follow-up pathology and MRI as reference standard. Lesions were reclassified using the following methods: absolute maximum SUV threshold (SUV), SUV ratio (SUVR) to superior sagittal sinus (SSS) (SUVRsss), SUVR to the pituitary gland (SUVRpit), and SUVR to the normal brain parenchyma (SUVRnorm). Diagnostic performance of the four methods was compared using contingency tables and McNemar's test. Previously published pre-determined thresholds were assessed where applicable. The optimal thresholds for each method were identified using Youden's J statistics. 166 meningiomas and 41 PTC lesions were identified across 62 patients. SUV, SUVRsss, SUVRpit, and SUVRnorm of meningioma were significantly higher than those of PTC (P < 0.0001). The optimal thresholds for SUV, SUVRsss, SUVRpit, and SUVRnorm were 4.7, 3.2, 0.3, and 62.6, respectively. At the optimal thresholds, SUV had the highest specificity (97.6%) and SUVRsss had the highest sensitivity (86.1%). An ROC analysis of SUV, SUVRsss, SUVRpit, and SUVRnorm revealed AUC of 0.932, 0.910, 0.915, and 0.800, respectively (P < 0.0001). Developing a diagnostic threshold is key to wider clinical translation of [68Ga]-DOTATATE PET/MRI in meningioma evaluation. We found that the SUVRsss method may have the most robust combination of sensitivity and specificity in the diagnosis of meningioma in the post-treatment setting, with the optimal threshold of 3.2. Future studies validating our findings in different patient populations are needed to continue optimizing the diagnostic performance of [68Ga]-DOTATATE PET/MRI in meningioma patients.Trial registration: ClinicalTrials.gov Identifier: NCT04081701. Registered 9 September 2019. https://clinicaltrials.gov/ct2/show/NCT04081701 .

Liver Transplant for Nonhepatocellular Malignancies: A Review for Radiologists.

Although liver transplant is traditionally only performed for hepatocellular carcinoma (HCC), the last decade has seen a resurgence in its use for non-HCC malignancies, likely due to improvements in neoadjuvant treatment regimens and the establishment of well-defined eligibility criteria. Given promising survival results, patients with perihilar cholangiocarcinoma, neuroendocrine liver metastases, and hepatic hemangioendothelioma are eligible to receive Model for End-Stage Liver Disease (MELD) exception points for tumors that meet well-defined criteria. Patients with additional tumors such as colorectal cancer liver metastases, intrahepatic cholangiocarcinoma, and hepatocellular cholangiocarcinoma may undergo transplant at specialized centers with well-defined protocols, although these patients are not yet eligible for MELD exception. Transplant eligibility criteria commonly incorporate imaging findings; however, because of the relatively novel and evolving nature of liver transplant for non-HCC malignancies, radiologists may be unaware of relevant criteria or the implications of their imaging interpretations. Knowledge of the allocation process, previous studies, and liver transplant selection criteria facilitates radiologists' active participation in multidisciplinary discussion, leading to better and more equitable care for transplant candidates with non-HCC malignancy. This review provides an overview of transplant allocation and selection criteria in patients with non-HCC malignancy, with an emphasis on imaging features and the role of the radiologist.

Dynamic 68Ga-DOTATATE PET/MRI in the Diagnosis and Management of Intracranial Meningiomas.

Purpose To evaluate dynamic gallium 68 (68Ga) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) brain PET/MRI as an adjunct modality in meningioma, enabling multiparametric standardized uptake value (SUV) and Patlak net binding rate constant (Ki) imaging, and to optimize static acquisition period. Materials and Methods In this prospective study (ClinicalTrials.gov no. NCT04081701, DOMINO-START), 68Ga-DOTATATE PET/MRI-derived time-activity curves (TACs) were measured in 84 volumes of interest in 19 participants (mean age, 63 years; range, 36-89 years; 13 women; 2019-2021) with meningiomas. Region- and voxel-specific Ki were determined using Patlak analysis with a validated population-based reference tissue TAC model built from an independent data set of nine participants. Mean and maximum absolute and relative-to-superior-sagittal-sinus SUVs were extracted from the entire 50 minutes (SUV50) and last 10 minutes (SUV10) of acquisition. SUV versus Ki Spearman correlation, SUV and Ki meningioma versus posttreatment-change Mann-Whitney U tests, and SUV50 versus SUV10 Wilcoxon matched-pairs signed rank tests were performed. Results Absolute and relative maximum SUV50 demonstrated a strong positive correlation with Patlak Ki in meningioma (r = 0.82, P < .001 and r = 0.85, P < .001, respectively) and posttreatment-change lesions (r = 0.88, P = .007 and r = 0.83, P = .02, respectively). Patlak Ki images yielded higher lesion contrast by mitigating nonspecific background signal. All SUV50 and SUV10 metrics differed between meningioma and posttreatment-change regions (P < .001). Within the meningioma group, SUV10 attained higher mean scores than SUV50 (P < .001). Conclusion Combined SUV and Patlak Ki68Ga-DOTATATE PET/MRI enabled multiparametric evaluation of meningioma, offering the potential to enhance lesion contrast with Ki imaging and optimize the SUV measurement postinjection window. Keywords: Molecular Imaging-Clinical Translation, Neuro-Oncology, PET/MRI, Dynamic, Patlak ClinicalTrials.gov registration no. NCT04081701 © RSNA, 2022.

Nasolabial Sulcus Rejuvenation: Paranasal Augmentation Using a Folded Dermal Graft.

BACKGROUND: Nasolabial sulcus rejuvenation is steadily gaining popularity among Asians. Though many treatment options using synthetic grafts and autografts have been introduced, none of them has yet been accepted as an ideal technique. This study describes the operative procedure and evidence-based clinical outcomes of paranasal augmentation using dermal grafts. METHODS: From March 2015 to August 2019, 56 patients underwent paranasal augmentation. The dermal graft, harvested from the buttock, was folded into 4 to 6 layers and inserted into the supraperiosteal pocket through a gingivobuccal incision. Ultrasonographic evaluation was performed at postoperative months 1, 6, 12, and 18 to appraise the change in the thickness of the graft. RESULTS: No major complications, including foreign body sensation and graft extrusion, occurred. The average dermal thickness was 10.31 mm at postoperative month 1 and 6.30 mm, 5.21 mm, and 5.17 mm at postoperative months 6, 12 and 18, respectively. The average absorption rates were 38.72%, 49.36%, and 49.92% at postoperative months 6, 12, and 18, respectively. CONCLUSIONS: Paranasal augmentation using a folded dermal graft serves as a useful method to rejuvenate the midface with durable and aesthetically satisfactory outcomes. By virtue of biocompatibility, complications occurred rarely compared with the artificial implants. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

[68Ga]-DOTATATE PET/MRI in the diagnosis and management of recurrent head and neck paraganglioma with spinal metastasis.

Most head and neck paragangliomas (PGLs) are biochemically silent and often present with recurrence and metastases in association with hereditary syndromes. Whole-body functional imaging is increasingly used to detect tumor extent and guide treatment planning of PGLs. [68Ga]-DOTATATE, which targets somatostatin receptor 2 (SSTR2) overexpression, has emerged as a sensitive functional imaging modality in PGLs. We present a patient with metastatic glomus caroticum PGL in whom [68Ga]-DOTATATE PET/MRI provided a more accurate characterization of metastatic extent, as compared to gadolinium-enhanced MRI of the neck and whole body [18F]-FDG PET/CT. We then review the current literature and discuss the imaging implications of [68Ga]-DOTATATE PET/MRI in PGLs.

PET/MR Imaging of Somatostatin Receptor Expression and Tumor Vascularity in Meningioma: Implications for Pathophysiology and Tumor Outcomes.

BACKGROUND AND PURPOSE: Meningiomas, the most common primary intracranial tumor, are vascular neoplasms that express somatostatin receptor-2 (SSTR2). The purpose of this investigation was to evaluate if a relationship exists between tumor vascularity and SSTR2 expression, which may play a role in meningioma prognostication and clinical management. MATERIALS AND METHODS: Gallium-68-DOTATATE PET/MRI with dynamic contrast-enhanced (DCE) perfusion was prospectively performed. Clinical and demographic patient characteristics were recorded. Tumor volumes were segmented and superimposed onto parametric DCE maps including flux rate constant (Kep), transfer constant (Ktrans), extravascular volume fraction (Ve), and plasma volume fraction (Vp). Meningioma PET standardized uptake value (SUV) and SUV ratio to superior sagittal sinus (SUVRSSS) were recorded. Pearson correlation analyses were performed. In a random subset, analysis was repeated by a second investigator, and intraclass correlation coefficients (ICCs) were determined. RESULTS: Thirty-six patients with 60 meningiomas (20 WHO-1, 27 WHO-2, and 13 WHO-3) were included. Mean Kep demonstrated a strong significant positive correlation with SUV (r = 0.84, p < 0.0001) and SUVRSSS (r = 0.81, p < 0.0001). When stratifying by WHO grade, this correlation persisted in WHO-2 (r = 0.91, p < 0.0001) and WHO-3 (r = 0.92, p = 0.0029) but not WHO-1 (r = 0.26, p = 0.4, SUVRSSS). ICC was excellent (0.97-0.99). CONCLUSION: DOTATATE PET/MRI demonstrated a strong significant correlation between tumor vascularity and SSTR2 expression in WHO-2 and WHO-3, but not WHO-1 meningiomas, suggesting biological differences in the relationship between tumor vascularity and SSTR2 expression in higher-grade meningiomas, the predictive value of which will be tested in future work.

Inhibition of mTOR Signaling Enhances Maturation of Cardiomyocytes Derived From Human-Induced Pluripotent Stem Cells via p53-Induced Quiescence.

BACKGROUND: Current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells (iPSCs) are capable of generating highly pure cardiomyocyte populations as determined by expression of cardiac troponin T. However, these cardiomyocytes remain immature, more closely resembling the fetal state, with a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared with adult cardiomyocytes. Immaturity of iPSC-derived cardiomyocytes may be a significant barrier to clinical translation of cardiomyocyte cell therapies for heart disease. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of rapamycin (mTOR)-signaling pathway plays a key role in nutrient sensing and growth. We hypothesized that transient inhibition of the mTOR-signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation. METHODS: Cardiomyocytes were differentiated from 3 human iPSC lines using small molecules to modulate the Wnt pathway. Torin1 (0 to 200 nmol/L) was used to inhibit the mTOR pathway at various time points. We quantified contractile, metabolic, and electrophysiological properties of matured iPSC-derived cardiomyocytes. We utilized the small molecule inhibitor, pifithrin-α, to inhibit p53 signaling, and nutlin-3a, a small molecule inhibitor of MDM2 (mouse double minute 2 homolog) to upregulate and increase activation of p53. RESULTS: Torin1 (200 nmol/L) increased the percentage of quiescent cells (G0 phase) from 24% to 48% compared with vehicle control (P<0.05). Torin1 significantly increased expression of selected sarcomere proteins (including TNNI3 [troponin I, cardiac muscle]) and ion channels (including Kir2.1) in a dose-dependent manner when Torin1 was initiated after onset of cardiomyocyte beating. Torin1-treated cells had an increased relative maximum force of contraction, increased maximum oxygen consumption rate, decreased peak rise time, and increased downstroke velocity. Torin1 treatment increased protein expression of p53, and these effects were inhibited by pifithrin-α. In contrast, nutlin-3a independently upregulated p53, led to an increase in TNNI3 expression and worked synergistically with Torin1 to further increase expression of both p53 and TNNI3. CONCLUSIONS: Transient treatment of human iPSC-derived cardiomyocytes with Torin1 shifts cells to a quiescent state and enhances cardiomyocyte maturity.

Upregulation of ZIP14 and Altered Zinc Homeostasis in Muscles in Pancreatic Cancer Cachexia.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from decreased tolerance to anti-cancer therapies and often succumb to premature death due to respiratory and cardiac muscle wasting. Yet, there are no approved therapies available to alleviate cachexia. We previously found that upregulation of the metal ion transporter, Zip14, and altered zinc homeostasis are critical mediators of cachexia in metastatic colon, lung, and breast cancer models. Here, we show that a similar mechanism is likely driving the development of cachexia in PDAC. In two independent experimental metastasis models generated from the murine PDAC cell lines, Pan02 and FC1242, we observed aberrant Zip14 expression and increased zinc ion levels in cachectic muscles. Moreover, in advanced PDAC patients, high levels of ZIP14 in muscles correlated with the presence of cachexia. These studies underscore the importance of altered ZIP14 function in PDAC-associated cachexia development and highlight a potential therapeutic opportunity for improving the quality of life and prolonging survival in PDAC patients.

Prescription Drug Price Paradox: Cost Analysis of Canadian Online Pharmacies versus US Medicare Beneficiaries for the Top 100 Drugs.

BACKGROUND AND OBJECTIVES: Despite the introduction of Medicare Part D (MPD) and 2012 Affordable Care Act (ACA), patients have a cost burden due to increases in drug prices. To overcome cost barriers, some patients purchase their medications from Canadian online pharmacies as Canadian prescription drug prices are believed to be lower than US prescription drug prices. The objective of this study was to determine which top 100 Medicare drugs can be imported to the USA legally, and to determine which type of prescription drug would be more beneficial to be purchased from Canadian online pharmacies. Moreover, we also deemed it important to compare MPD beneficiary annual expenses with expenses patients would have when obtaining their prescriptions from Canadian online pharmacies. METHODS: We conducted a cost analysis from a patient perspective. A list of the top 100 Medicare drugs was compiled and information on drug prices was collected from three Canadian online pharmacies and four MPD plans in Virginia. The annual cost of each Medicare drug and percent change between Canadian online pharmacies and MPD were compared. RESULTS: A total of 78 drugs from the top 100 Medicare drugs were included in the final analysis. Seventy-six prescription drugs (97.4%) that could be purchased from Canadian online pharmacies showed a significantly lower average drug price percent change of -72.71% (P < 0.0001). The heart health/blood pressure subgroup had the highest number of drugs that could be purchased from Canadian online pharmacies. CONCLUSION: The majority of prescription drugs can be purchased at lower prices from Canadian online pharmacies when compared to Medicare beneficiaries' potential expenses. Purchasing medications from Canadian online pharmacies may be a viable option to address cost barriers.

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight.

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

Cutaneous Metastasis of Rectal Cancer: A Case Report and Literature Review.

Cutaneous metastasis of rectal cancer is rare. It typically indicates widespread disease and poor prognosis. We report an exceedingly rare case of rectal cancer with metastasis to the skin and review the literature on cutaneous metastasis of rectal cancer. A 47-year-old man presented with stage IV unresectable adenocarcinoma of the rectum and received palliative chemoradiation for local pain control. About a year later he developed extensive skin lesions involving the genital area, bilateral groin, and perineum. Biopsy specimen showed mucinous adenocarcinoma compatible with rectal origin. Palliative treatment with radiation therapy was initiated. The patient responded well to treatment and is still alive more than a year after diagnosis of cutaneous metastasis. Surgeons should maintain strong suspicion of cutaneous metastases when patients with rectal cancer have new or evolving skin lesions.

Primary Epithelial Neuroendocrine Tumors of the Retroperitoneum.

Neuroendocrine tumors are either epithelial or neural in origin. Neuroendocrine tumors of the retroperitoneum are mostly metastatic. Primary epithelial neuroendocrine tumors of the retroperitoneum are exceedingly rare. We describe a case of a retroperitoneal tumor that was discovered incidentally during exploratory laparotomy for small-bowel obstruction. Histopathologic and immunochemical analyses of the biopsied mass were consistent with an epithelial neuroendocrine tumor. The tumor was subsequently removed and final analyses confirmed the initial diagnosis. No evidence of lymph nodes or paraganglia were found within the tumor on histologic examination. Extensive evaluation did not reveal any other primary or metastatic lesions. Therefore, the diagnosis of primary epithelial neuroendocrine tumor of the retroperitoneum was made. The literature is reviewed and discussed. To date, this is only the fifth reported case of primary epithelial retroperitoneal neuroendocrine tumor. Although extremely rare, the possibility of such diagnosis should be included in the differential diagnosis of a retroperitoneal tumor.

Functional differences between kindlin-1 and kindlin-2 in keratinocytes.

Integrin-ß1-null keratinocytes can adhere to fibronectin through integrin αvß6, but form large peripheral focal adhesions and exhibit defective cell spreading. Here we report that, in addition to the reduced avidity of αvß6 integrin binding to fibronectin, the inability of integrin ß6 to efficiently bind and recruit kindlin-2 to focal adhesions directly contributes to these phenotypes. Kindlins regulate integrins through direct interactions with the integrin-ß cytoplasmic tail and keratinocytes express kindlin-1 and kindlin-2. Notably, although both kindlins localize to focal adhesions in wild-type cells, only kindlin-1 localizes to the integrin-ß6-rich adhesions of integrin-ß1-null cells. Rescue of these cells with wild-type and chimeric integrin constructs revealed a correlation between kindlin-2 recruitment and cell spreading. Furthermore, despite the presence of kindlin-1, knockdown of kindlin-2 in wild-type keratinocytes impaired cell spreading. Our data reveal unexpected functional consequences of differences in the association of two homologous kindlin isoforms with two closely related integrins, and suggest that despite their similarities, different kindlins are likely to have unique functions.