Early Access to Electronic Health Records May Influence the Patient Experience.

In a recent Hot Topics column, Mehmet Sitki Copur, MD, FACP, et al discussed the pros and cons of patients receiving test results early through electronic medical records.

Complete Pathologic Response to Neoadjuvant Chemoimmunotherapy and Oxaliplatin-Induced Fever Associated With IL-6 Release in a Patient With Locally Advanced Colon Cancer

Neoadjuvant systemic therapy is a preferred treatment approach for a number of tumor types due to many potential advantages over upfront surgery, including tumor downstaging, early treatment of micrometastatic disease, and providing an in vivo test of tumor biology. For colon cancer, current standard of care is upfront surgery followed by adjuvant systemic therapy in high-risk patients. Concerns about inaccurate radiological staging and tumor progression during preoperative treatment, as well the lack of randomized data demonstrating benefit, are among the reasons for the limited use of neoadjuvant therapy in this disease. Locally advanced colon cancer, defined as primary colon cancer with direct invasion into the adjacent structures or extensive regional lymph node involvement, is not always amenable to pathological complete resection, and when attempted it comes with high incidence of postoperative morbidity and mortality because of the required multivisceral resection. Clinical trials of neoadjuvant chemotherapy for colon cancer to date have been promising with downstaging of disease and higher rates of R0 resection. Here, we report a case of a patient with locally advanced, unresectable, mismatch repair deficient sigmoid colon cancer who was treated with neoadjuvant chemoimmunotherapy followed by surgical resection leading to a complete pathologic response after preoperative systemic chemoimmunotherapy.

GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome.

OBJECTIVE: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. METHODS: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. RESULTS: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. INTERPRETATION: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332-347.

A 64-Year-Old Man With Germline BRCA2-Mutated Breast Cancer: Known and Unknown Aspects of Male Breast Cancer.

Male breast cancer is a rather uncommon and understudied disease. It accounts for less than 1% of all breast cancers, but in recent decades its frequency has been on the rise. Clinical trials of breast cancer have traditionally excluded men. Due to the lack of large-scale prospective studies, most published data come from single-institution, small-cohort studies, and treatment recommendations are based on the extrapolation of data from clinical trials enrolling only women. Although to some extent etiology, diagnosis, and treatment characteristics can be similar, male breast cancer exhibits some distinct features. Men tend to be diagnosed with breast cancer at an older age and at a more advanced stage. A better understanding of the biologic features, clinically relevant differences, effective treatments, and outcomes of male breast cancer is crucial to appropriately manage these patients. We present a male breast cancer case with a germline BRCA2 mutation and discuss the epidemiologic, pathologic, and clinical characteristics along with treatment and follow-up recommendations in view of our recent understanding of this disease.

Mucinous Adenocarcinoma of the Appendix With Histologic Response to Neoadjuvant Chemotherapy: Review of Histologic and Clinical Spectrum of Epithelial Neoplastic Mucinous Lesions of the Appendix.

Appendiceal mucinous neoplasms are a rare and heterogeneous group of diseases with challenging clinical management decisions. They account for less than 1% of all cancers but their incidence is on the rise. Treatment is based on their stage and histology. Appendiceal neoplasms frequently metastasize inside the abdomen; this leads to tumor cell growth in the abdominal cavity, known as peritoneal carcinomatosis, and buildup of mucinous material, known as pseudomyxoma peritonei. While low-grade, early-stage tumors can be effectively treated with limited surgical resection, patients with low-grade, advanced-stage disease require peritoneal debulking and hyperthermic intraperitoneal chemotherapy. Therapeutic options for high-grade, advanced-stage mucinous tumors of the appendix have not been well established. Debulking surgery with hyperthermic intraperitoneal chemotherapy preceded and/or followed by systemic chemotherapy has been utilized based on some prospective but not randomized data. We present a case of mucinous adenocarcinoma of the appendix treated with neoadjuvant chemotherapy followed by cytoreductive surgery/hyperthermic intraperitoneal chemotherapy and adjuvant chemotherapy. Preoperative chemotherapy provided a favorable histologic response by converting initial mucinous appendiceal adenocarcinoma histology to a high-grade mucinous appendiceal neoplasm.

Splitting up to heal: mitochondrial shape regulates signaling for focal membrane repair.

Mitochondria are central to the health of eukaryotic cells. While commonly known for their bioenergetic role, mitochondria also function as signaling organelles that regulate cell stress responses capable of restoring homeostasis or leading the stressed cell to eventual death. Damage to the plasma membrane is a potentially fatal stressor incurred by all cells. Repairing plasma membrane damage requires cells to mount a rapid and localized response to injury. Accumulating evidence has identified a role for mitochondria as an important facilitator of this acute and localized repair response. However, as mitochondria are organized in a cell-wide, interconnected network, it is unclear how they collectively sense and respond to a focal injury. Here we will discuss how mitochondrial shape change is an integral part of this localized repair response. Mitochondrial fragmentation spatially restricts beneficial repair signaling, enabling a localized response to focal injury. Conservation of mitochondrial fragmentation in response to cell and tissue damage across species demonstrates that this is a universal pro-survival adaptation to injury and suggests that mitochondrial fragmentation may provide cells a mechanism to facilitate localized signaling in contexts beyond repairing plasma membrane injury.

Mitochondrial dysfunction and role of harakiri in the pathogenesis of myositis.

The etiology of myositis is unknown. Although attempts to identify viruses in myositis skeletal muscle have failed, several studies have identified the presence of a viral signature in myositis patients. Here we postulate that in individuals with susceptible genetic backgrounds, viral infection alters the epigenome to activate the pathological pathways leading to disease onset. To identify epigenetic changes, methylation profiling of Coxsackie B infected human myotubes and muscle biopsies from polymyositis (PM) and dermatomyositis (DM) patients were compared to changes in global transcript expression induced by in vitro Coxsackie B infection. Gene and protein expression analysis and live cell imaging were performed to examine the mechanisms. Analysis of methylation and gene expression changes identified that a mitochondria-localized activator of apoptosis - harakiri (HRK) - is upregulated in myositis skeletal muscle cells. Muscle cells with higher HRK expression have reduced mitochondrial potential and poor ability to repair from injury as compared to controls. In cells from myositis patient toll-like receptor 7 (TLR7) activates and sustains high HRK expression. Forced over expression of HRK in healthy muscle cells is sufficient to compromise their membrane repair ability. Endurance exercise that is associated with improved muscle and mitochondrial function in PM and DM patients decreased TLR7 and HRK expression identifying these as therapeutic targets. Increased HRK and TLR7 expression causes mitochondrial damage leading to poor myofiber repair, myofiber death and muscle weakness in myositis patients and exercise induced reduction of HRK and TLR7 expression in patients is associated with disease amelioration. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Locally Advanced Rectal Cancer, What is the Standard of Care?

Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one-third of newly diagnosed cases. A comprehensive trimodality approach involving neoadjuvant chemoradiotherapy, total mesorectal excision, and systemic chemotherapy has been the standard of care for medically operable patients with nonmetastatic, locally advanced rectal cancer. Despite a marked reduction in local recurrence rates with good local control, systemic recurrence rates of as high as 35% constitute the leading cause of death in this population. This has led to increasing interest in neoadjuvant systemic therapy before or after neoadjuvant chemoradiation a new approach called total neoadjuvant therapy. This case study will review the current status of clinical stage II or III locally advanced rectal cancer (T3/4, N0, or node-positive) treatment regarding neoadjuvant therapy.

Recurrent Small Cell Carcinoma of the Lung With Cutaneous Metastasis in Breast.

Lung cancer remains the leading cause of cancer-related deaths and the second leading cause of new cancer cases in the United States. Although more commonly involving hilar nodes, the liver, adrenal glands, bones, and the brain, lung cancer can metastasize to almost any organ. Metastases, although rare in the skin may be the first sign of a lung cancer or cutaneous metastases may present as a sign of recurrent disease. The incidence of cutaneous metastases from lung cancer has been reported in approximately 1% to 12 % of cases and was associated with poor prognosis. Although cutaneous metastasis from small cell lung cancer is a rare occurrence, cutaneous metastasis involving the breast is even less common. Here, we present a case of recurrent small cell lung cancer presenting with a firm purplish cutaneous metastatic nodule in the right breast.

Recurrent EGFR-Mutated Non-Small Cell Lung Cancer Discovered by Abnormal Mammogram: Adjuvant/Frontline Metastatic Management Options.

Breast metastasis from extramammary malignancy is rare, with a reported incidence rate of 0.4% to 1.3% in the published literature. The primary malignancies that most commonly metastasize to the breast are leukemia, lymphoma, and malignant melanoma. Here, we report a very rare case of metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in the breast detected by screening mammography. The patient had initially been diagnosed with a clinical stage IIIA NSCLC and had been treated with neoadjuvant chemoradiation followed by curative-intent surgery. Several interesting aspects of the case, along with a discussion of evolving adjuvant and frontline metastatic management options in EGFR-mutated NSCLC, will be presented.

Membrane Repair Deficit in Facioscapulohumeral Muscular Dystrophy.

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies.

Cellular mechanisms and signals that coordinate plasma membrane repair.

Plasma membrane forms the barrier between the cytoplasm and the environment. Cells constantly and selectively transport molecules across their plasma membrane without disrupting it. Any disruption in the plasma membrane compromises its selective permeability and is lethal, if not rapidly repaired. There is a growing understanding of the organelles, proteins, lipids, and small molecules that help cells signal and efficiently coordinate plasma membrane repair. This review aims to summarize how these subcellular responses are coordinated and how cellular signals generated due to plasma membrane injury interact with each other to spatially and temporally coordinate repair. With the involvement of calcium and redox signaling in single cell and tissue repair, we will discuss how these and other related signals extend from single cell repair to tissue level repair. These signals link repair processes that are activated immediately after plasma membrane injury with longer term processes regulating repair and regeneration of the damaged tissue. We propose that investigating cell and tissue repair as part of a continuum of wound repair mechanisms would be of value in treating degenerative diseases.

Structural and signaling role of lipids in plasma membrane repair.

The plasma membrane forms the physical barrier between the cytoplasm and extracellular space, allowing for biochemical reactions necessary for life to occur. Plasma membrane damage needs to be rapidly repaired to avoid cell death. This relies upon the coordinated action of the machinery that polarizes the repair response to the site of injury, resulting in resealing of the damaged membrane and subsequent remodeling to return the injured plasma membrane to its pre-injury state. As lipids comprise the bulk of the plasma membrane, the acts of injury, resealing, and remodeling all directly impinge upon the plasma membrane lipids. In addition to their structural role in shaping the physical properties of the plasma membrane, lipids also play an important signaling role in maintaining plasma membrane integrity. While much attention has been paid to the involvement of proteins in the membrane repair pathway, the role of lipids in facilitating plasma membrane repair remains poorly studied. Here we will discuss the current knowledge of how lipids facilitate plasma membrane repair by regulating membrane structure and signaling to coordinate the repair response, and will briefly note how lipid involvement extends beyond plasma membrane repair to the tissue repair response.

Outpatient versus observation/inpatient parotidectomy: patient factors and perioperative complications.

The objective of this manuscript is to review a single institution's experience with superficial or total parotidectomy in outpatient and observation/inpatient groups. All patients who underwent superficial or total parotidectomy between 2009 and 2015 were identified. Patients were excluded if they had undergone concurrent surgery such as neck dissection, had prior radiation treatment or surgery at the operative site. Main outcomes were perioperative complications in both groups. 215 consecutive patients were included in the study, 116 (54%) patients in the inpatient group and 99 (46%) in the outpatient group. Aside from a higher observed rate of cardiac disease in the outpatient group (24.2 vs. 11.2%, p = 0.014) and larger mean body mass index (BMI) in the inpatient group (32.448 vs. 30.034, p = 0.017), there were no significant differences for age, sex or smoking status. Average operative time differed between groups with 2 h 42 min for inpatients and 2 h 18 min for outpatients (p < 0.001). There were 26 complications in the inpatient group (22.4%, including two hematomas) and 8 in the outpatient group (8.1%). The rate of seroma/sialocele formation was significantly higher in the inpatient group at 15.5% (n = 18) compared with the outpatient group at 3% (n = 3, p = 0.001). Our study shows that parotidectomy, superficial or total, was performed safely as an outpatient procedure without significant increase in complications when compared to patients observed for at least one night after surgery.

A Rare Case of Ruptured Tailgut Cyst Leading to Carcinomatosis.

Tailgut cysts are congenital cysts arising in the retrorectal space. They are thought to be benign with variable malignancy risks. We report a case with previous surgical intervention decades prior that had undergone a tailgut cyst excision with surgical complications leading to carcinomatosis. An elderly female (70s) presented with tailbone/pelvic pain. She underwent cyst excision that was complicated by an intraoperative rupture. The cyst was pathologically proven to be a tailgut cyst with adenocarcinoma. She presented 13 months postoperatively to the emergency department with worsening abdominal pain. Imaging was concerning for diffuse omental nodules and narrowing of the proximal sigmoid colon. She was not deemed to be a surgical candidate and was transitioned to hospice care, where she passed away shortly afterward. This case report highlights the utility of complete excision of tailgut cysts and possible complications.

Damage-induced basal epithelial cell migration modulates the spatial organization of redox signaling and sensory neuron regeneration.

Epithelial damage leads to early reactive oxygen species (ROS) signaling, which regulates sensory neuron regeneration and tissue repair. How the initial type of tissue injury influences early damage signaling and regenerative growth of sensory axons remains unclear. Previously we reported that thermal injury triggers distinct early tissue responses in larval zebrafish. Here, we found that thermal but not mechanical injury impairs sensory axon regeneration and function. Real-time imaging revealed an immediate tissue response to thermal injury characterized by the rapid Arp2/3-dependent migration of keratinocytes, which was associated with tissue-scale ROS production and sustained sensory axon damage. Osmotic regulation induced by isotonic treatment was sufficient to limit keratinocyte movement, spatially-restrict ROS production and rescue sensory function. These results suggest that early keratinocyte dynamics regulate the spatial and temporal pattern of long-term signaling in the wound microenvironment during tissue repair.

A Validated 3D Printed Laryngeal Suturing Simulator for Endoscopic Laryngeal Cleft Repair.

OBJECTIVES: Endoscopic laryngeal cleft repair (ELCR) with endolaryngeal suturing is an advanced surgical skill. This study objective was to assess the validity of 3-dimensionally (3D) printed laryngeal suturing simulator for ELCR. STUDY DESIGN: Development and validation of a simulator for ELCR. METHODS: An ELCR model was developed using 3D printed and readily available materials. Participants were surveyed before and after a simulation session using five-point Likert scale questions. Performance data was assessed using blinded expert video review and rated using a novel objective structured assessment of technical skills (OSATS) for endoscopic laryngeal suturing. RESULTS: Twenty-one participants ranging from residents to attendings completed the simulation session. Survey respondents reported on a five-point Likert scale that the model was "easy to use" and "quite realistic" (both mean of 4). Confidence improved significantly in 86% of participants (p < 0.01). Overall OSATS scores (out of a total of 55) showed a median improvement in technical skills of 11.7 points (p = 0.004). OSATS demonstrated good intra-rater (κ = 0.689 and 0.677) and moderate inter-rater (κ = 0.573) reliability. Completion times improved from the first to the last suture by a median time of 512 to 350 s (decrease of 202 s, p = 0.002). Participants with no prior ELCR experience improved more than those with in vivo experience. CONCLUSION: This study demonstrates the validity of a simulator utilizing 3D printed larynges for ELCR. A novel OSATS for endoscopic laryngeal suturing was successfully implemented. Confidence, technical skills, and completion times improved with the use of the model across a variety of participants. Laryngoscope, 133:785-791, 2023.