Liquid-liquid interfaces enable tunable cell confinement to recapitulate surrounding tissue deformations during neutrophil interstitial migration in vivo.

Cell migration is regulated by an interplay between both chemical and mechanical cues. Immune cells navigate through interstitial spaces and generate forces to deform surrounding cells, which in turn exert opposing pressures that regulate cell morphology and motility mechanisms. Current in vitro systems to study confined cell migration largely utilize rigid materials orders of magnitude stiffer than surrounding cells, limiting insights into how these local physical interactions regulate interstitial cell motility. Here, we first characterize mechanical interactions between neutrophils and surrounding cells in larval zebrafish and subsequently engineer in vitro migration channels bound by a deformable liquid-liquid interface that responds to cell generated pressures yielding a gradient of confinement across the length of a single cell. Tuning confining pressure gradients replicates mechanical interactions with surrounding cells during interstitial migration in vivo . We find that neutrophils favor a bleb-based mechanism of force generation to deform a barrier applying cell-scale confining forces. This work introduces a biomimetic material interface that enables new avenues of exploring the influence of mechanical forces on cell migration.

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.

Risk of death at home or on hospital readmission after discharge with pediatric tracheostomy.

OBJECTIVE: To evaluate outcomes of patients discharged home following tracheostomy, including the timing and place of death for non-survivors. STUDY DESIGN: We retrospectively reviewed medical records of infants undergoing tracheostomy between 2006 and 2017, within the first year of life for congenital or acquired neonatal conditions. RESULTS: Of the 224 patients discharged after tracheostomy, 127 (57%) required home mechanical ventilation (MV). Overall, 40 (18%) patients died (65% were on MV); 38% of the deaths occurred at home and 63% at a subsequent hospitalization. Having tube feeding was identified as significantly associated with increased mortality on multivariate analysis. Having a tracheostomy for upper airway obstruction was the only variable significantly associated with increased risk of death at home on multivariate analysis. CONCLUSIONS: Having tube feeding was associated with increased risk of death overall and having the tracheostomy for obstructive airway conditions was associated with death occurring at home.

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.

Hospital Admissions in Pediatric Patients With Tracheostomies Based on Rurality and Insurance Status.

OBJECTIVE: Determine whether rurality or public insurance status is associated with greater 30-day readmission after tracheostomy in pediatric patients. STUDY DESIGN: Retrospective cohort. SETTING: Pediatric Health Information System (PHIS) Database. METHODS: Patients within PHIS who underwent tracheostomy from 2013 to 2017 were included. Rural status was defined by rural-urban commuting area codes. Insurance status was based on the primary payer. All-cause 30-day readmissions and tracheostomy-related readmissions were recorded. Multivariate logistic regression was performed to test for differences in readmissions between cohorts. RESULTS: Among patients, 1092 were rural, and 4329 were publicly insured, with no significant association between rurality and insurance. Compared to nonrural patients, rural patients were more frequently white, less frequently ventilator dependent, and more likely discharged home rather than to a care facility. Publicly insured patients were more frequently non-white. Twenty-eight percent of patients were readmitted within 30 days of discharge. Odds of 30-day readmission were lower in rural patients (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.68-0.95, p = .01) but higher in publicly insured (OR: 1.24, 95% CI: 1.09-1.42, p = .001) controlling for age at tracheostomy, sex, race, and ventilator dependence. The odds of tracheostomy-related admission did not differ by rurality but were higher in publicly insured children (1.39, 95% CI: 1.03-1.88, p = .03). CONCLUSION: Readmission within 30 days following tracheostomy was more likely in publicly insured patients and less likely in rural patients. These findings help identify at-risk patients when considering discharge planning and follow-up. More work is needed to understand long-term tracheostomy outcomes in these groups.

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.

Reduction in inpatient readmissions following implementation of a dedicated tracheostomy care team.

OBJECTIVE: Pediatric tracheostomy patients are at risk for lengthy hospitalizations and multiple readmissions with rare but potentially disastrous tracheostomy-related complications. Several centers have formed multidisciplinary teams for pediatric tracheostomy patients to coordinate care and enhance caregiver education to aid in safe care delivery. Current literature has shown encouraging change in pediatric tracheostomy care with these interventions, but there remains an opportunity to better gauge alterations of morbidity. We aimed to review our institution's experience before and after development of a pediatric tracheostomy care team. METHODS: Pediatric tracheostomy patients (<19 years) who underwent tracheostomy between January 2010 and June 2020 were included. A pediatric tracheostomy care team including a nurse practitioner and registered nurse was established in July 2017. Rates of readmission, outpatient visits, decannulation rates, and mortality are examined before and after implementation of the care team. Bivariate and multivariable analyses were utilized. RESULTS: 296 patients were included with 128 patients in the pre-intervention group, 82 in the post-intervention group, and 86 completing cross-over care. The groups were comparable in age at tracheostomy, tracheostomy indication, and underlying comorbidities. Mean outpatient visits per tracheostomy-year in the post-intervention group were higher than the pre-intervention group (2.3 vs. 2.2, p = .02). Fewer mean inpatient admissions per tracheostomy-year (0.02 vs. 0.11, p = .03) were observed after intervention. Time to decannulation did not differ significantly between the two groups (p = .57). CONCLUSION: Implementation of a dedicated tracheostomy care team may help decrease inpatient admissions for tracheostomy-specific complications.

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.

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.

Early-Stage Non-Small Cell Lung Cancer Stereotactic Body Radiation Therapy (SBRT) Outcomes in an Equal Access Military Setting.

Introduction Lung stereotactic body radiation therapy (SBRT) is a first-line treatment for early-stage lung cancer in non-surgical candidates or those who refuse surgery. We compared our institutional outcomes from a unique patient population with decreased barriers to care with a recently published prospective series. Materials and methods  We retrospectively reviewed all patients who received definitive lung SBRT at the Walter Reed National Military Medical Center from 2015 to 2020. All patients underwent a positron emission tomography-computed tomography (PET-CT) and all were presented at a multidisciplinary tumor board. Patients were treated on a Trubeam linear accelerator (LINAC)-based system with daily cone-beam CT. The results were qualitatively compared to outcomes from prospective studies including RTOG 0236 and RTOG 0618. Results A total of 105 patients with 114 lesions were included. Median age was 77 years and 54.7% had ≥ 40-pack year smoking history. 36.8% did not have pathologic confirmation. With a median follow-up of 24 months, three-year local control (LC), disease-free survival (DFS) and overall survival (OS) rates were 92.4%, 81.0%, and 80.0%, respectively. Rates of Grade 1 and 2 toxicity were 21.9% and 6.7% and no patients experienced Grade ≥ 3 toxicity. Conclusions In our military setting with universal coverage and routine multidisciplinary care, lung SBRT provides outcomes comparable to prospective studies conducted at high-volume academic centers. More than one-third of patients were treated empirically without pathologic confirmation of disease, demonstrating a difference between clinical trials and community practice. Further investigation is warranted to integrate multidisciplinary management and achieve equal access to care to bridge existing health disparities in the community setting.

Pattern of failure in prostate cancer previously treated with radical prostatectomy and post-operative radiotherapy: a secondary analysis of two prospective studies using novel molecular imaging techniques.

BACKGROUND: Prostate Membrane Specific Antigen (PSMA) positron emission tomography (PET) and multiparametric MRI (mpMRI) have shown high accuracy in identifying recurrent lesions after definitive treatment in prostate cancer (PCa). In this study, we aimed to outline patterns of failure in a group of post-prostatectomy patients who received adjuvant or salvage radiation therapy (PORT) and subsequently experienced biochemical recurrence, using 18F-PSMA PET/CT and mpMRI. METHODS: PCa patients with biochemical failure post-prostatectomy, and no evident site of recurrence on conventional imaging, were enrolled on two prospective trials of first and second generation 18F-PSMA PET agents (18F-DCFBC and 18F-DCFPyL) in combination with MRI between October 2014 and December 2018. The primary aim of our study is to characterize these lesions with respect to their location relative to previous PORT field and received dose. RESULTS: A total of 34 participants underwent 18F-PSMA PET imaging for biochemical recurrence after radical prostatectomy and PORT, with 32/34 found to have 18F-PSMA avid lesions. On 18F-PSMA, 17/32 patients (53.1%) had metastatic disease, 8/32 (25.0%) patients had locoregional recurrences, and 7/32 (21.9%) had local failure in the prostate fossa. On further exploration, we noted 6/7 (86%) of prostate fossa recurrences were in-field and were encompassed by 100% isodose lines, receiving 64.8-72 Gy. One patient had marginal failure encompassed by the 49 Gy isodose. CONCLUSIONS: 18F-PSMA PET imaging demonstrates promise in identifying occult PCa recurrence after PORT. Although distant recurrence was the predominant pattern of failure, in-field recurrence was noted in approximately 1/5th of patients. This should be considered in tailoring radiotherapy practice after prostatectomy. Trial registration www.clinicaltrials.gov , NCT02190279 and NCT03181867. Registered July 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02190279 and June 8 2017, https://clinicaltrials.gov/ct2/show/NCT03181867 .

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.

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.

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.