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Background To better understand how the COVID-19 pandemic has affected surgical trainees’ and early-career surgeons’ professional and personal experiences, a survey of the membership of the American College of Surgeons (ACS) Resident and Associate Society (RAS) and Young Fellows Association (YFA) was performed. Study Design An anonymous online survey was disseminated to members of RAS and YFA. Descriptive analyses were performed, and factors associated with depression and burnout were examined with univariate and multivariable stepwise logistic regression. Results Of the RAS/YFA membership of 21,385, there were 1,160 respondents. The majority (96%) of respondents reported the COVID-19 pandemic having a negative impact on their clinical experience, with 84% residents reporting >50% reduction in operative volume and inability to meet minimum case requirements. Respondents also reported negative impacts on personal wellness. Nearly one third reported inadequate access to personal protective equipment (PPE), and depression and burnout were pervasive (≥21% of respondents reported yes to every screening symptom). On multivariable analysis, female gender (OR 1.54 for depression, OR 1.47 for burnout) and lack of wellness resources (OR 1.55 for depression, OR 1.44 for burnout) predicted depression and burnout. Access to adequate PPE was protective against burnout (OR 0.52). Conclusion These data demonstrate a significant impact of the COVID-19 pandemic upon the lives of resident and early-career surgeons. Actionable items from these data include mitigation of burnout and depression through increasing PPE access and provision of wellness programs, with a particular focus on high-risk groups., Graphical abstract

The presentation and treatment of ductal carcinoma in situ (DCIS) has changed substantially over the years. While previously an incidental pathologic finding in more advanced, palpable tumors, the institution of screening mammography has repositioned this disease entity as one largely diagnosed as a non-palpable lesion, often prior to any invasive disease. As DCIS is a precursor to invasive carcinoma, evolution in the approach to treatment has followed in the footsteps of that for invasive disease, including breast conservation therapy, adjuvant radiation, and use of antihormonal therapy. Survival outcomes for DCIS are very high and more recent literature has investigated tailoring therapeutic approaches to avoid overtreatment. Two important areas of ongoing clinical debate concerning overtreatment include use of preoperative MRI and the role of adjuvant radiation. The heterogeneity of the disease makes it difficult to differentiate lesions that would benefit from more aggressive treatment from those in which overtreatment could be avoided. Clinical characteristics, such as histologic appearance, age at diagnosis, and margin status at tumor excision have been established as moderate predictors of disease recurrence, but none has provided strong enough evidence as to guide consensus decisions on adjuvant therapy. Continuing research seeks to define the genetic and molecular characteristics that can predict disease course and serve as the potential targets for novel therapeutic agents. While several markers have shown promise in differentiating tumor aggressiveness, there is still much to be discovered about the precise mechanisms of disease progression and how this can be applied clinically to optimize treatment.

The presentation and treatment of ductal carcinoma in situ (DCIS) has changed substantially over the years. While previously an incidental pathologic finding in more advanced, palpable tumors, the institution of screening mammography has repositioned this disease entity as one largely diagnosed as a non-palpable lesion, often prior to any invasive disease. As DCIS is a precursor to invasive carcinoma, evolution in the approach to treatment has followed in the footsteps of that for invasive disease, including breast conservation therapy, adjuvant radiation, and use of antihormonal therapy. Survival outcomes for DCIS are very high and more recent literature has investigated tailoring therapeutic approaches to avoid overtreatment. Two important areas of ongoing clinical debate concerning overtreatment include use of preoperative MRI and the role of adjuvant radiation. The heterogeneity of the disease makes it difficult to differentiate lesions that would benefit from more aggressive treatment from those in which overtreatment could be avoided. Clinical characteristics, such as histologic appearance, age at diagnosis, and margin status at tumor excision have been established as moderate predictors of disease recurrence, but none has provided strong enough evidence as to guide consensus decisions on adjuvant therapy. Continuing research seeks to define the genetic and molecular characteristics that can predict disease course and serve as the potential targets for novel therapeutic agents. While several markers have shown promise in differentiating tumor aggressiveness, there is still much to be discovered about the precise mechanisms of disease progression and how this can be applied clinically to optimize treatment.

OBJECTIVES/SPECIFIC AIMS: Drug repositioning has the potential to accelerate translation of novel cancer chemotherapeutics from bench to bedside. The goal of this study was to determine the effects of ciclopirox olamine (CPX) on esophageal tumor cells. METHODS/STUDY POPULATION: We tested the effect of CPX on four esophageal cancer cell lines, assessing cell proliferation and viability by hexosaminidase and clonogenicity assay, respectively. We analyzed the effects of CPX on three-dimensional (3D) esophageal tumor cell spheroids. We also analyzed effects on cell cycle by flow cytometry. For mechanism, we performed western blots for proteins involved in cell cycle regulation, apoptosis and the Wnt/β-catenin pathway. For in vivo effects, we performed a murine xenograft model with intraperitoneal administration of CPX (100 mg/Kg body weight daily). RESULTS/ANTICIPATED RESULTS: CPX inhibited growth of all cell lines in a time and concentration-dependent manner. CPX also inhibited growth of esophageal spheroids. Cell cycle analysis demonstrated G0/G1 arrest in cells treated with CPX. Western blot analyses demonstrated decreased expression of cyclinD1, CDK4, CDK6, and transcriptionally active β-catenin, supporting the role of CPX in cell cycle inhibition and decreased β-catenin activity. Finally, treatment of nude mice with CPX significantly decreased tumor xenograft volume. DISCUSSION/SIGNIFICANCE OF IMPACT: CPX demonstrates anti-tumor properties in esophageal cancer cell lines. The current results justify further research into the mechanism of this inhibition. Additionally, given its established safety in humans, CPX is a potential candidate for repositioning as an adjunct treatment for esophageal cancer.

Herpes simplex virus 1 (HSV-1) capsids leave the nucleus by a process of envelopment and de-envelopment at the nuclear envelope (NE) that is accompanied by structural alterations of the NE. As capsids translocate across the NE, transient primary enveloped virions form in the perinuclear space. Here, we provide evidence that torsinA (TA), a ubiquitously expressed ATPase, has a role in HSV-1 nuclear egress. TA resides within the lumen of the endoplasmic reticulum (ER)/NE and functions in maintaining normal NE architecture. We show that perturbation of TA normal function by overexpressing torsinA wild type (TAwt) inhibits HSV-1 production. Ultrastructural analysis of infected cells overexpressing TAwt revealed reduced levels of surface virions in addition to accumulation of novel, double-membrane structures called virus-like vesicles (VLVs). Although mainly found in the cytoplasm, VLVs resemble primary virions in their size, by the appearance of the inner membrane, and by the presence of pUL34, a structural component of primary virions. Collectively, our data suggest a model in which interference of TA normal function by overexpression impairs de-envelopment of the primary virions leading to their accumulation in a cytoplasmic membrane compartment. This implies novel functions for TA at the NE.

Esophageal carcinoma continues to carry a poor prognosis due presentation at advanced stages. Current chemotherapeutics often only prolong survival for months to a few years. Drug repositioning is an important pharmacologic strategy that involves investigation and implementation of known drugs for treatment of new diseases. This method significantly reduces the costs required for establishing the safety of a drug and is associated with higher rates of drug approval. Ciclopirox olamine (CPX) is an antifungal agent that has been on the market since the 1970s. The mechanism of action is believed to include disruptions of DNA repair and cell division signals. Recently, however, this drug has been studied for its antitumor properties demonstrated in human rhabdomyosarcoma, breast carcinoma, colon adenocarcinoma, bladder carcinoma, and hematologic malignancies. To date, there are no studies related to the effect of CPX on esophageal cancer. Here, we show that ciclopirox olamine causes growth inhibition of four esophageal cell lines: TE-10, SKGT4, FLO1 and ESO1. This growth inhibition is demonstrated by hexosaminidase assay performed after incubation with the drug for 24-72 h. The IC50 values range between 5-20µM depending on the cell line used. Cell death was also demonstrated by immunofluorescent staining with Hoschst and propidium iodide, which shows a decrease in the number of viable cells with increasing concentrations of CPX. Clonogenicity assay was also performed with each cell line and demonstrates a decrease in the ability of cells to form colonies after 24 and 48 hour treatment with CPX and subsequent incubation in standard media for 5-7 days. Cell cycle analysis demonstrates G0/G1 arrest in cells treated with CPX. The effects of CPX on the cell cycle are further supported by Western blot analysis showing a decrease in in CDK4 and CDK6, which are necessary for cell cycle progression from the G0/G1 phase. We have also found that treatment with CPX results in a decrease in β-catenin in TE10 cells, suggesting that the drug is affecting this pathway to cause growth inhibition of tumor cells. Finally, we used our ESO1 mouse esophageal squamous cell carcinoma cell line for a xenograft study in which tumor cells were injected into the flanks of mice. Mice treated with intraperitoneal injections of 300 mg/m2 of CPX had smaller tumor volumes compared to untreated controls. In summary, we have shown that CPX inhibits growth of esophageal tumor cells both in vitro and in vivo. Our data suggest that CPX induces cell cycle arrest of tumor cells. The mechanism of tumor cell inhibition may be related to downregulation of the WNT/β-catenin signaling pathway. In future studies, we plan to analyze the effects of CPX on other components in the WNT family from in vitro cells as well as tumor xenografts. Citation Format: Randi J. Ryan, Prabhu Ramamoorthy, Dharmalingam Subramaniam, Shrikant Anant, Scott Weir. Ciclopirox olamine: A common antifungal agent that inhibits growth of esophageal tumor cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2865.

Background Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment for patients with metastatic neuroendocrine tumors (NETs). However, delivering sufficient radiation dose to the tumor to result in a high percentage of long-term tumor remissions remains challenging because of the limits imposed on administered activity levels by radiation damage to normal tissues. The goal of this study was to evaluate the dosimetric advantages of adding 131I meta-iodobenzylguanidine (131I-MIBG) to 90Y DOTA Phe1-Tyr3-octreotide (90Y-DOTATOC) in patients with advanced stage midgut NETs. Methods Ten patients were imaged simultaneously with 131I-MIBG and 111In-pentetreotide (as a surrogate for 90Y-DOTATOC) on days 1, 2, and 3 post-administration. Blood samples were obtained at the same time points. Using dosimetry measures from this data and our previously published methodology for calculating optimal combined administered activity levels for therapy, we determined the amount of 131I-MIBG that could be added to 90Y-DOTATOC without exceeding normal organ dose limits (marrow and kidneys) along with the expected increase in associated tumor dose, if any. Results We found that a median value of 34.6 GBq of 131I-MIBG could be safely added to 90Y-DOTATOC (delivered over multiple cycles) by reducing the maximum total deliverable 90Y-DOTATOC by a median value of 24.5%. Taking this treatment approach, we found that there would be a median increase in deliverable tumor dose of 4,046 cGy in six of the ten subjects. Of note, there were a small number of metastases that were positive for only one or the other of these radiopharmaceuticals within the same subject. Conclusions We conclude that approximately half of the patients with midgut NETs that are eligible for PRRT could reasonably be expected to benefit from the addition of 131I-MIBG to 90Y-DOTATOC.