Nomograms and prognosis for superficial esophageal squamous cell carcinoma.

In recent years, endoscopic resection, particularly endoscopic submucosal dissection, has become increasingly popular in treating non-metastatic superficial esophageal squamous cell carcinoma (ESCC). In this evolving paradigm, it is crucial to identify factors that predict higher rates of lymphatic invasion and poorer outcomes. Larger tumor size, deeper invasion, poorer differentiation, more infiltrative growth patterns (INF-c), higher-grade tumor budding, positive lymphovascular invasion, and certain biomarkers have been associated with lymph node metastasis and increased morbidity through retrospective reviews, leading to the construction of comprehensive nomograms for outcome prediction. If validated by future prospective studies, these nomograms would prove highly applicable in guiding the selection of treatment for superficial ESCC.

Endoscopic ultrasound-guided radiofrequency ablation of pancreatic tumors.

PURPOSE OF REVIEW: Surgery is a cornerstone in the management of pancreatic cancer and precancerous pancreatic lesions. However, many patients are not suitable candidates for surgery at the time of diagnosis for various reasons. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) appears to be a promising treatment option for patients who are ineligible for surgery for management of pancreatic adenocarcinoma (PDAC), and pancreatic neuroendocrine tumors (PNETs), and pancreatic cystic lesions (PCLs). RECENT FINDINGS: EUS-RFA may serve as an adjunct to chemotherapy or palliative measures for inoperable cases of PDAC. Given its feasibility and efficacy, EUS-RFA has an evolving niche as a minimally invasive and potentially definitive treatment for PNETs and high-risk PCLs such as intraductal papillary mucinous neoplasms (IPMNs). EUS-RFA is a generally well tolerated procedure, with abdominal pain and acute pancreatitis being the most common adverse effects, though the risk can be mitigated through prophylactic measures. SUMMARY: There is an increasing body of evidence to support the use of EUS-RFA in managing pancreatic lesions, either as definitive, adjunctive, or palliative treatment, depending on lesion type.

Endoscopic Ultrasound-Guided Needle-Based Confocal Endomicroscopy as a Diagnostic Imaging Biomarker for Intraductal Papillary Mucinous Neoplasms.

Pancreatic cancer is on track to become the second leading cause of cancer-related deaths by 2030, yet there is a lack of accurate diagnostic tests for early detection. Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer and are increasingly being detected. Despite the development and refinement of multiple guidelines, diagnosing high-grade dysplasia or cancer in IPMNs using clinical, radiologic, endosonographic, and cyst fluid features still falls short in terms of accuracy, leading to both under- and overtreatment. EUS-guided needle-based confocal laser endomicroscopy (nCLE) is a novel technology that allows real-time optical biopsies of pancreatic cystic lesions. Emerging data has demonstrated that EUS-nCLE can diagnose and risk stratify IPMNs more accurately than conventional diagnostic tools. Implementing EUS-nCLE in clinical practice can potentially improve early diagnosis of pancreatic cancer, reduce unnecessary surgeries of IPMNs with low-grade dysplasia, and advance the field of digital pathomics. In this review, we summarize the current evidence that supports using EUS-nCLE as a diagnostic imaging biomarker for diagnosing IPMNs and for risk stratifying their degree of neoplasia. Moreover, we will present emerging data on the role of adding artificial intelligence (AI) algorithms to nCLE and integrating novel fluid biomarkers into nCLE.

Revisiting degron motifs in human AURKA required for its targeting by APC/CFZR1.

Mitotic kinase Aurora A (AURKA) diverges from other kinases in its multiple active conformations that may explain its interphase roles and the limited efficacy of drugs targeting the kinase pocket. Regulation of AURKA activity by the cell is critically dependent on destruction mediated by the anaphase-promoting complex (APC/CFZR1) during mitotic exit and G1 phase and requires an atypical N-terminal degron in AURKA called the "A-box" in addition to a reported canonical D-box degron in the C-terminus. Here, we find that the reported C-terminal D-box of AURKA does not act as a degron and instead mediates essential structural features of the protein. In living cells, the N-terminal intrinsically disordered region of AURKA containing the A-box is sufficient to confer FZR1-dependent mitotic degradation. Both in silico and in cellulo assays predict the QRVL short linear interacting motif of the A-box to be a phospho-regulated D-box. We propose that degradation of full-length AURKA also depends on an intact C-terminal domain because of critical conformational parameters permissive for both activity and mitotic degradation of AURKA.

Selective targeting of non-centrosomal AURKA functions through use of a targeted protein degradation tool.

Targeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (PROteolysis Targeting Chimeras, PROTACs) that recruit ubiquitin ligases to targets of interest, leading to ubiquitination and destruction of the targets. Several PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate centrosome- and chromatin- based microtubule spindle assembly pathways. In interphase cells PROTAC-mediated clearance of non-centrosomal AURKA modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential sensitivity of subcellular pools of substrate, governed by substrate conformation or localization-dependent accessibility to PROTAC action, a phenomenon not previously described for this new class of degrader compounds.

AURKA destruction is decoupled from its activity at mitotic exit but is essential to suppress interphase activity.

Activity of AURKA is controlled through multiple mechanisms including phosphorylation, ubiquitin-mediated degradation and allosteric interaction with TPX2. Activity peaks at mitosis, before AURKA is degraded during and after mitotic exit in a process strictly dependent on the APC/C coactivator FZR1. We used FZR1 knockout cells (FZR1KO) and a novel FRET-based AURKA biosensor to investigate how AURKA activity is regulated in the absence of destruction. We found that AURKA activity in FZR1KO cells dropped at mitotic exit as rapidly as in parental cells, despite absence of AURKA destruction. Unexpectedly, TPX2 was degraded normally in FZR1KO cells. Overexpression of an N-terminal TPX2 fragment sufficient for AURKA binding, but that is not degraded at mitotic exit, caused delay in AURKA inactivation. We conclude that inactivation of AURKA at mitotic exit is determined not by AURKA degradation but by degradation of TPX2 and therefore is dependent on CDC20 rather than FZR1. The biosensor revealed that FZR1 instead suppresses AURKA activity in interphase and is critically required for assembly of the interphase mitochondrial network after mitosis.This article has an associated First Person interview with the first authors of the paper.

Rhombencephalitis in cocaine-induced nasal septal perforation and skull base erosion.

Rhombencephalitis is a rare and potentially fatal condition involving the brainstem, with infectious, autoimmune, and paraneoplastic etiologies. We present a patient presenting with left-extremity weakness and dysphonia who had brainstem imaging findings suggestive of rhombencephalitis. We suspect that the case was due to inoculation of the brainstem from nasopharyngeal adenoviral infection. Due to heavy cocaine use, extensive basiocciput erosion led to direct contact between the brainstem and the nasopharyngeal mucosa. The patient's milder clinical course might have been due to some degree of pre-existing immunity against adenovirus. Additionally, clinicians need to be aware of the proximity of the brainstem to the nasopharynx when there is basiocciput erosion, due to the potential risk of injury during instrumentation.

Pattern of Childhood Uveitis in Egypt.

Purpose: To report the pattern of childhood-onset uveitis observed in Egypt from May 2010 to May 2017 Methods: Retrospective evaluation of the data of all patients with uveitis diagnosed before the age of 16 and visiting uveitis referral clinics in 5 Egyptian Governorates (Alexandria, Cairo, Al Bohayra (Damanhour), Al Gharbeya (Tanta), and Sohag) between May 2010 and May 2017. Results: A total of 413 uveitis patients were enrolled. These included 219 male and 194 female patients. Uveitis was bilateral in 68.3% of the patients. The most frequently observed ocular complications were cataract, glaucoma, and cystoid macular edema. The percentage of children with a visual acuity ≥1.00 logMAR in at least one eye by the final visit was 21.8%. Conclusion: Pediatric uveitis is a vision-threatening condition which caused more than one-fifth of the children in this study to lose vision in one or both eyes.

Constitutive regulation of mitochondrial morphology by Aurora A kinase depends on a predicted cryptic targeting sequence at the N-terminus.

Aurora A kinase (AURKA) is a major regulator of mitosis and an important driver of cancer progression. The roles of AURKA outside of mitosis, and how these might contribute to cancer progression, are not well understood. Here, we show that a fraction of cytoplasmic AURKA is associated with mitochondria, co-fractionating in cell extracts and interacting with mitochondrial proteins by reciprocal co-immunoprecipitation. We have also found that the dynamics of the mitochondrial network are sensitive to AURKA inhibition, depletion or overexpression. This can account for the different mitochondrial morphologies observed in RPE-1 and U2OS cell lines, which show very different levels of expression of AURKA. We identify the mitochondrial fraction of AURKA as influencing mitochondrial morphology, because an N-terminally truncated version of the kinase that does not localize to mitochondria does not affect the mitochondrial network. We identify a cryptic mitochondrial targeting sequence in the AURKA N-terminus and discuss how alternative conformations of the protein may influence its cytoplasmic fate.

Retained Wooden Foreign Body in the Second Metatarsal.

The foot is considered the second most common location for foreign bodies. The most common foreign bodies include needles, metal, glass, wood, and plastic. Although metallic foreign bodies are readily seen on plain film radiographs, radiolucent bodies such as wood are visualized poorly, if at all. Although plain radiography is known to be ineffective for demonstrating radiolucent foreign bodies, it is often the first imaging modality used. In such cases, complete surgical extraction cannot be guaranteed, and other imaging modalities should be considered. We present a case of a retained toothpick of the second metatarsal in a young male patient who presented with pain in the right foot of a few weeks' duration. Plain radiography showed an oval cyst at the base of the second metatarsal of the right foot. Magnetic resonance imaging revealed a toothpick penetrating the second metatarsal. The patient recalled stepping on a toothpick 8 years previously. Surgical exploration revealed a 2-cm toothpick embedded inside the second metatarsal.

Dedifferentiated parosteal osteosarcoma of the calvaria.

Dedifferentiated parosteal osteosarcoma is a rare tumor and is even rarer when involving the skull bones. We present a case of a 57-year-old man with a partially ossified progressive enlarging left skull mass in the left temporoparietal region, with erosion of the outer table. Radiological diagnosis of dedifferentiated parosteal osteosarcoma was suggested, and histopathology confirmed the diagnosis.

Idiopathic Giant Hepatic Artery Pseudoaneurysm.

Hepatic artery pseudoaneurysm (HAP) incidence is rising due to more common use of endoscopic and percutaneous hepatic interventions. HAP is potentially fatal, as it could lead to sudden life-threatening hemorrhage. HAP can be intrahepatic or extrahepatic. On computed tomography angiogram (CTA) and magnetic resonance angiogram (MRA), HAP follows blood pool on multiphasic examination, with brisk arterial enhancement that washes out, similar to the abdominal aorta on later phases. We present a case of idiopathic giant HAP in an 82-year-old male. Currently, angioembolization is replacing surgery as the initial modality of choice for management of this condition.

Usefulness of radium-223 in patients with bone metastases.

Castration-resistant prostate osseous metastases can be challenging to treat. There is a new era of clinical advancement with the Food and Drug Administration approval of radium-223 for use in these patients. Radium-223 is the only clinically used therapeutic radiopharmaceutical that emits alpha particles, making it extremely safe for therapeutic purposes for the patient as well as close contacts. This review discusses radium-223's mechanism of action, pharmacokinetics, indications, and safety profile, as well as findings of concluded clinical trials.

Acute Calcific Tendinitis of the Longus Colli Muscle: Report of Two Cases and Review of the Literature.

Acute calcific tendinitis (ACT) of the longus colli muscle is a rare cause of debilitating neck pain. The ACT is presumed to be an aseptic inflammatory process of the superior oblique tendons of the longus colli muscle. It is often confused with other more concerning conditions including trauma, epidural abscess, disc herniation, and neoplasm. We present two cases of ACT and a brief literature review to stress the risk of misdiagnosis. A 38-year-old male presented with neck pain and stiffness accompanied by dysphagia. Computed tomography (CT) scan was done and the diagnosis was secured by demonstrating calcifications at the C1-C2 level as well as the retropharyngeal effusion. A 53-year-old female was also complaining of neck pain and dysphagia. The CT scan demonstrated similar findings and the diagnosis was again clinched. Awareness of this unusual entity is essential to prevent unnecessary interventions.