Put Yourself out There! A Strategy for Effective Self-Promotion in Academic Medicine.

Introduction: Trainees and faculty in academic medicine often struggle with self-promotion. Barriers may be more formidable for women and other groups underrepresented in medicine. Experience-based stories illustrating personal strengths are preferable when engaging in self-promotion activities. Methods: We developed a 90- to 120-minute workshop utilizing approaches such as iterative journaling and peer discussion to teach the development of problem-action-result (PAR) stories for self-promotion efforts in interviews and written applications to new positions. Participants provided Likert-scale (1 = strongly disagree, 5 = strongly agree) and free-response evaluations, which we analyzed for workshop strengths and areas for improvement. Results: We presented the workshop in person to 28 pediatric residents and subsequently to 22 residents, fellows, and faculty at an in-person national meeting. Sixty-one percent of the resident group and 100% of the national workshop group completed the evaluation. Both groups reported high satisfaction with the workshop's format (M = 4.7) and content (M = 4.7) and indicated intention to use the skills learned (M = 4.7). Strengths included the PAR format, interactivity, journaling, opportunity for reflection, and tips for interviewing and writing. Areas to improve included offering the workshop earlier in the academic year and providing more written examples of PAR stories. Discussion: This workshop used strategies of personal reflection, journaling, and peer feedback to help participants understand behavior-based recruiting practices and the PAR framework as a strategy for successful self-promotion. Learners can use these strategies to develop greater confidence and efficacy and to address barriers to effective self-promotion they encounter.

Moving Beyond Hemangioma: Interactive, Multidisciplinary, Case-Based Teaching in Vascular Anomalies for Pediatric Residents.

Introduction: Vascular anomalies are a spectrum of disorders, including vascular tumors and malformations, that often require multispecialty care. The rarity and variety of these lesions make diagnosis, treatment, and management challenging. Despite the recognition of the medical complexity and morbidity associated with vascular anomalies, there is a general lack of education on the subject for pediatric primary care and subspecialty providers. A needs assessment and the lack of an available standardized teaching tool presented an opportunity to create an educational workshop for pediatric trainees using the POGIL (process-oriented guided inquiry learning) framework. Methods: We developed a 2-hour workshop consisting of an introductory didactic followed by small- and large-group collaboration and case-based discussion. The resource included customizable content for learning assessment and evaluation. Residents completed pre- and posttest assessments of content and provided written evaluations of the teaching session. Results: Thirty-four learners in pediatrics participated in the workshop. Session evaluations were positive, with Likert responses of 4.6-4.8 out of 5 on all items. Pre- and posttest comparisons of four content questions showed no overall statistically significant changes in correct response rates. Learners indicated plans to use the clinical content in their practice and particularly appreciated the interactive teaching forum and the comprehensive overview of vascular anomalies. Discussion: Vascular anomalies are complex, potentially morbid, and often lifelong conditions; multispecialty collaboration is key to providing comprehensive care for affected patients. This customizable resource offers a framework for trainees in pediatrics to appropriately recognize, evaluate, and refer patients with vascular anomalies.

RAS-RAF-miR-296-3p signaling axis increases Rad18 expression to augment radioresistance in pancreatic and thyroid cancers.

Oncogenic RAS and RAF signaling has been implicated in contributing to radioresistance in pancreatic and thyroid cancers. In this study, we sought to better clarify molecular mechanisms contributing to this effect. We discovered that miRNA 296-3p (miR-296-3p) is significantly correlated with radiosensitivity in a panel of pancreatic cancer cells, and miR-296-3p is highly expressed in normal cells, but low in cancer cell lines. Elevated expression of miR-296-3p increases radiosensitization while decreasing the expression of the DNA repair enzyme RAD18 in both pancreatic and thyroid cancer cells. RAD18 is overexpressed in both pancreatic and thyroid tumors compared to matched normal controls, and high expression of RAD18 in tumors is associated with poor prognostic features. Modulating the expression of mutant KRAS in pancreatic cancer cells or mutant BRAF in thyroid cancer cells demonstrates a tight regulation of RAD18 expression in both cancer types. Depletion of RAD18 results in DNA damage and radiation-induced cell death. Importantly, RAD18 depletion in combination with radiotherapy results in marked and sustained tumor regression in KRAS mutant pancreatic cancer orthotopic tumors and BRAF mutant thyroid heterotopic tumors. Overall, our findings identify a novel coordinated RAS/RAF-miR-296-3p-RAD18 signaling network in pancreatic and thyroid cancer cells, which leads to enhanced radioresistance.

Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1-deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1-proficient PDAC cells, but not in Cav-1-deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.

Retrospective Analysis of Direct-Acting Oral Anticoagulants (DOACs) Initiation Timing and Outcomes After Thrombolysis in High- and Intermediate-Risk Pulmonary Embolism.

Direct-acting oral anticoagulants (DOACs) are prescribed in the treatment of venous thromboembolism, including pulmonary embolism (PE). Evidence is limited regarding the outcomes and optimal timing of DOACs in patients with intermediate- or high-risk PE treated with thrombolysis. We conducted a retrospective analysis of outcomes among patients with intermediate- and high-risk PE who received thrombolysis, by choice of long-term anticoagulant agent. Outcomes of interest included hospital length of stay (LOS), intensive care unit LOS, bleeding, stroke, readmission, and mortality. Descriptive statistics were used to examine characteristics and outcomes among patients, by anticoagulation group. Patients receiving a DOAC (n = 53) had shorter hospital LOS compared to those in warfarin (n = 39) and enoxaparin (n = 10) groups (mean LOS 3.6, 6.3 and 4.5 days, respectively; P < .0001). This single institution retrospective study suggests DOAC initiation <48 h from thrombolysis may result in shorter hospital LOS compared to DOAC initiation ≥48 h (P < .0001). Further larger studies with more robust research methodology are needed to address this important clinical question.

Comparison of Efficiency and Effectiveness Between a Slap Hammer and Rigid C-Frame Device for Extraction of an Intramedullary Nail.

BACKGROUND: Removal of orthopaedic intramedullary implants can be difficult and time-consuming. Instrumentation for implant removal is frequently deficient for effective removal. The purpose of this study was to compare the efficiency of a C-type jig with a standard slap hammer attachment. We hypothesize that a C-type jig will be a more energy-efficient method for implant removal. METHODS: An intramedullary (IM) nail removal was simulated in a series of 10 tests using 40 PCF Sawbones bone blocks with drilled holes and custom-made IM nails. Each attachment was secured to a Shukla Medical threaded connector from their IM nail revision product. A camera recorded each hammer swing, and a caliper recorded the distance the nail traveled out of the bone block. The data were then analyzed to determine extraction rate and efficiency. RESULTS: The c-frame hammer exerted a greater force, had a greater extraction efficiency, and required 37.4% less energy expenditure than the slap hammer to extract the nail the same distance. The c-frame hammer also removed the nail 38.1% faster with the same energy expenditure and possessed greater usable kinetic energy, whereas the slap hammer had more "lost" energy. CONCLUSIONS: The c-frame hammer attachment was found to have a considerably higher extraction rate and efficiency than the slap hammer. It will be a more useful method of implant extraction, especially for cases involving larger bones or larger implants. However, the slap hammer may be more suitable for smaller tools or bones for which larger impact loading would be detrimental.

Outcomes of a Peer Mentoring Circle: An Innovation to Improve Academic Physician Career Advancement in a Community Hospital Setting.

PROBLEM: Faculty retention is a prominent topic in academic medicine. Investment in faculty career development supports faculty vitality, advancement, and retention. Academic physicians in community-based settings far from their academic affiliate may find identifying local career advancement mentorship challenging. APPROACH: In June 2018, a career advancement in-service day at The Children's Hospital of San Antonio and Baylor College of Medicine in Houston was convened to design a peer mentoring circle (PMC). Using self-determination theory, this program aimed to help PMC members develop goals; schedule and attend regular meetings; format, review, and critique member curricula vitae and portfolios; and hold one another accountable to submitting award and promotion applications. OUTCOMES: Eleven inaugural PMC cohort members attended regular monthly meetings from July 2018 to June 2019 (median, 6 members per meeting). All members were competent in accessing the PMC repository of materials. Statistically significant improvement ( P < .01) was seen in self-reported knowledge and skills relevant to award or academic promotion support and resources. Compared with no patient care or teaching awards and 1 academic promotion among non-PMC faculty, 5 PMC members (45.5%) earned a patient care award, 4 (36.4%) earned a teaching award, and 5 of 10 faculty members (50.0%) achieved academic promotion ( P < .001 for all). On the retrospective pre-post survey, members endorsed several PMC strengths, including personal and emotional support, professional support, and accountability. NEXT STEPS: Next steps include establishing a local faculty development office, convening a second cohort, revising evaluation methods, expanding membership, and offering 1-on-1 career counseling. Community-based academicians who aim to replicate this program should organize a career advancement and faculty development in-service day, identify local faculty members to manage meetings, retain a repository of resources, set deadlines and hold one another accountable to them, and celebrate achievements and support one another in failure.

Discovery of the inhibitor of DNA binding 1 as a novel marker for radioresistance in pancreatic cancer using genome-wide RNA-seq.

Purpose/Objective(s): Discovery of genetic drivers of radioresistance is critical for developing novel therapeutic strategies to combine with radiotherapy of radioresistant PDAC. In this study, we used genome-wide RNA-seq to identify genes upregulated in generated radioresistant PDAC cell lines and discovered the Inhibitor of DNA Binding 1 (ID1) gene as a potential regulator of radioresistance in PDAC. Materials/Methods: Radioresistant clones of the PDAC cell lines MIA PaCa-2 and PANC-1 were generated by delivering daily ionizing irradiation (IR) (2 Gy/day) in vitro over two weeks (total 20 Gy) followed by standard clonogenic assays following one week from the end of IR. The generated RR and parental cell lines were submitted for RNA-seq analysis to identify differentially expressed genes. The Limma R package was used to calculate differential expression among genes. Log2 fold change values were calculated for each sample compared to the control. Genes with an absolute fold change > 1 were considered significant. RNA sequencing expression data from the Cancer Genome Atlas (TCGA) database was analyzed through the online databases GEPIA, cBioPortal, and the Human Protein Atlas. Results: Following exposure to two weeks of 2 Gy daily IR in vitro, the two PDAC cell lines showed significantly greater clonogenic cell survival than their parental cell lines, indicating enhanced RR in these cells. RNA-seq analysis comparing parental and RR cell lines found upregulated seven genes (TNS4, ZDHHC8P1, APLNR, AQP3, SPP1, ID1, ID2) and seven genes downregulated (PTX3, ITGB2, EPS8L1, ALDH1L2, KCNT2, ARHGAP9, IFI16) in both RR cell lines. Western blotting confirmed increased expression of the ID1 protein in the RR cell lines compared to their parental cell lines. We found that ID1 mRNA was significantly higher in PDAC tumors compared to matched normal and high ID1 expression correlated with significantly worse disease-free survival (DFS) in PDAC patients (HR = 2.2, log rank P = 0.009). ID1 mRNA expression was also strongly correlated in tumors with TP53 mutation, a known driver of radioresistance. Conclusion: Our analysis indicates a novel role of ID1 in PDAC radioresistance. ID1 expression is higher in tumor tissue compared to normal, and high expression correlates with both worse DFS and association with the TP53 mutation, suggesting that targeting ID1 prior to IR is an attractive strategy for overcoming radioresistance in PDAC.

Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation. METHODS: We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS). RESULTS: We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34; 95%CI 1.27-11.38; p = 0.017) and OS (HR = 2.89; 95%CI 1.10-4.76; p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39; 95%CI 1.03-5.54; p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71; 95%CI 1.14-6.48; p = 0.025), DR (HR = 1.93; 95%CI 1.10-3.38; p = 0.022), and OS (HR = 1.97; 95%CI 1.17-3.34; p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p < 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS. CONCLUSIONS: RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.

BRAF mutation correlates with worse local-regional control following radiation therapy in patients with stage III melanoma.

BACKGROUND: In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve tumor control. Melanomas harbor BRAF mutations (BRAF+) in 40-50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF+ and BRAF- melanoma. METHODS: This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006 to 2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF+ and BRAF- groups using Fisher's exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local-regional lymph node control, distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). RESULTS: Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF+ patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p < 0.05). The 5 year local-regional control in the BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3-15.5, p = 0.02). There were no significant differences in 5-year DMFS, RFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for local-regional lymph node control, RFS, and OS in multivariate analysis. CONCLUSIONS: Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of local recurrence or regional lymph node recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance.

Disseminated histoplasmosis leading to end stage liver failure in immunocompetent patient: case report and review of literature.

Histoplasmosis is the fungal infection caused by Histoplasma capsulatum fungus. It is commonly found in a few endemic areas in the United States, where there is a large number of birds or bats and can spread through their droppings. Disseminated histoplasmosis is a severe manifestation of the fungal infection which is commonly seen in individuals with underlying immunosuppression. Our case is an unusual case of disseminated histoplasmosis in a 60-year-old, immunocompetent male patient with a history of significant alcohol abuse, which led to end stage liver failure. While the patient showed some signs of improvement initially upon beginning the treatment, he ultimately continued to deteriorate despite treatment due to an overwhelming histoplasmosis infection. This case demonstrates the importance of keeping a high index of suspicion even amongst immunocompetent patients with no obvious exposure to risk factors. It also shows that timely diagnosis with a high index of suspicion is required with an integrated treatment approach.

Teaching Sexual Orientation and Gender Identity in Pediatric Clinical Settings: A Training Workshop for Faculty and Residents.

Introduction: Health disparities for the lesbian, gay, bisexual, transgender, queer, intersex, asexual, all other genders, sexes, and sexualities (LGBTQIA+) population are striking. Yet, deliberate efforts to integrate sexual orientation and gender identity in pediatric education settings remain lacking. The type of formal training that pediatric educators currently have for teaching of sexual orientation and gender identity is unclear and limited, which led to the development and implementation of this curriculum. Methods: A 2-hour workshop was developed to address gaps in knowledge, equip faculty and resident educators with skills to apply key concepts in teaching activities, and motivate them to examine challenges and opportunities in teaching sexual orientation and gender identity principles in their routine duties in pediatric settings across the undergraduate and graduate education spectrum. Learning strategies of the workshop included learner activation, a didactic, and clinical cases with role-play opportunities. Participants completed evaluations at the end of the workshop. Results: The workshop was implemented in three varied educational settings in 2019. All 65 participants enrolled in the workshop completed the evaluations. Evaluations ranged from 4.6 to 4.9 on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree). Participants reported workshop strengths and anticipated impact on their own teaching and clinical practice. Discussion: Stark health disparities for the LGBTQIA+ population and gaps in relevant curricula demand a training intervention for pediatric educators. We demonstrated the successful implementation of a training workshop, with evidence of feasibility and generalizability, that addressed knowledge gaps and teaching and clinical skills.

Predictors of Response, Progression-Free Survival, and Overall Survival in Patients With Lung Cancer Treated With Immune Checkpoint Inhibitors.

Monoclonal antibodies that target immune checkpoint proteins, so-called immune checkpoint inhibitors, prevent tumor evasion of the immune system and are often effective in the treatment of lung cancer. Studies have revealed improved objective response rates, progression-free survival, and overall survival with immune checkpoint inhibitors when used in both first and subsequent-line settings. Unfortunately, only a subset of unselected patients with lung cancer responds to these therapies. An important area of ongoing research is to identify biomarkers that can predict which patients are most likely to derive clinical benefit. This review will discuss established and emerging biomarkers from some of the clinical trials that have demonstrated the efficacy of immune checkpoint inhibitors for the treatment of both NSCLC and SCLC.

Increasing neutrophil-to-lymphocyte ratio following radiation is a poor prognostic factor and directly correlates with splenic radiation dose in pancreatic cancer.

PURPOSE: Neutrophil-to-lymphocyte ratio has been correlated with clinical outcomes in many cancers. We investigated whether the delta-NLR (ΔNLR) following radiation therapy (RT) could predict achieving surgical resection and the overall survival (OS) of patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC), and whether the splenic radiation dose impacted ΔNLR. METHODS/MATERIALS: 101 patients with biopsy-proven BRPC or LAPC who received induction chemotherapy followed by RT were retrospectively enrolled. Following contouring of spleens, dose-volume histograms (DVHs) for splenic dosimetric parameters were calculated. Pre- and post-RT complete blood counts (CBC) within two weeks were recorded. Delta (Δ) values were calculated by subtracting the post-RT value from the pre-RT value. Cox regression survival analysis for pre and postradiation CBC values and OS was performed. Receiver operating curves (ROC) were generated and optimal cutoff points for highest sensitivity and specificity were identified. Kaplan-Meier curves for OS were generated. RESULTS: On univariate Cox regression analysis, the only significant CBC value associated with OS was ΔNLR (HR 1.06, CI 1.03-1.09, p < 0.001). On multivariate analysis, ΔNLR, age, and completed resection all significantly predicted for worse OS (p < 0.05). ΔNLR significantly predicted achieving surgical resection (p = 0.04) and the optimal cutoff point for ΔNLR was 2.5. Patients with ΔNLR < 2.5 had significantly longer OS (log rank p = 0.046). Spleen radiation dose parameters were all significantly higher in patients with a ΔNLR ≥ 2.5. Optimal radiation cutoff points to predict a ΔNLR ≥ 2.5 were splenic Dmean of 308 cGy and V5 of 10.3%. CONCLUSIONS: Among patients with BRPC or LAPC who have received induction chemotherapy, elevated ΔNLR after RT significantly predicts worse OS and decreased odds of achieving resection. Furthermore, ΔNLR is correlated with higher splenic doses, suggesting the spleen may be an important organ at risk.

A Case of Myelofibrosis and Myelodysplasia Identified Following Exposure to Isotretinoin.

A 15-year-old male individual treated with isotretinoin for acne vulgaris presented with persistent pancytopenia and circulating myeloblasts after discontinuation of the drug. Marrow assessment revealed myelofibrosis (MF) and myeloblasts exhibiting monosomy 7, diagnostic of myelodysplastic syndrome (MDS). Although a popular website seems to associate isotretinoin with MF, no published cases of MF or MDS attributable to this drug were identified. Although we expect that he would eventually have developed MDS and MF, this patient was perhaps identified sooner due to cytopenias accelerated by isotretinoin. This case illustrates that patients exhibiting cytopenias persisting following isotretinoin therapy merit evaluation for underlying hematopoietic disorders.

Morphologic changes associated with neoadjuvant-treated pancreatic ductal adenocarcinoma and comparison of two tumor regression grading systems.

Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with an overall five-year survival rate of 9%, and few patients are candidates for pancreatectomy at presentation. The role of neoadjuvant therapy (NAT) is evolving, especially for high-risk potentially resectable tumors. Owing to the increasing number of NAT resection specimens, we aim to characterize the histologic changes associated with NAT and to compare two tumor regression grading schemes. One hundred eighteen resections for PDAC were selected from the cases between 2011 and 2018, 59 not treated and 59 treated with NAT. All H&E stained tumor slides were reviewed for histologic changes and graded using the four-tier modified Ryan score (recommended by College of American Pathologists) and the three-tier MD Anderson (MDA) score. The histologic changes evaluated included blue/grey fibrosis, islet cell hyperplasia, dystrophic calcification, amyloid deposition, cholesterol clefts, nerve hypertrophy, elastotic stromal/vascular change, abscess formation, and eosinophilic tumor cell changes. There were statistically significant differences for dystrophic calcification, eosinophilic tumor cell changes, elastotic stromal/vascular change, islet cell hyperplasia, and nerve hypertrophy between the two groups, with these features seen more frequently in NAT cases. Blue/grey stromal fibrosis was present in all cases regardless of NAT, except few complete regression cases and one treated case with intraneural invasion only. Blue/grey fibrosis is a useful histologic visual clue to suggest the possibility of adjacent tumor in the majority of PDAC cases regardless of NAT. By Kaplan-Meier analysis, neither grading scheme correlated with overall survival in our cohort. However, the MDA score was significantly correlated with both time to primary tumor recurrence (p = 0.002) and time to distant recurrence (p = 0.04), whereas the modified Ryan score was not.

Altered Gemcitabine and Nab-paclitaxel Scheduling Improves Therapeutic Efficacy Compared with Standard Concurrent Treatment in Preclinical Models of Pancreatic Cancer.

PURPOSE: Concurrent gemcitabine and nab-paclitaxel treatment is one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). Previous studies demonstrate that caveolin-1 (Cav-1) expression is critical for nab-paclitaxel uptake into tumors and correlates with response. Gemcitabine increases nab-paclitaxel uptake by increasing Cav-1 expression. Thus, we hypothesized that pretreatment with gemcitabine would further enhance the sensitivity of PDAC to nab-paclitaxel by increasing Cav-1 expression and nab-paclitaxel uptake. EXPERIMENTAL DESIGN: We investigated the sensitivity of different gemcitabine and nab-paclitaxel treatment regimens in a panel of PDAC cell lines and orthotopic xenograft models. The sensitivity of different treatment regimens was compared with the standard concurrent treatment. RESULTS: Pretreatment with gemcitabine before nab-paclitaxel increased Cav-1 and albumin uptake and significantly decreased proliferation and clonogenicity compared with concurrent treatment, which correlated with increased levels of apoptosis. Cav-1 silencing reduced the uptake of albumin, and therapeutic advantage was observed when cells were pretreated with gemcitabine prior to nab-paclitaxel. In addition, we observed that pretreatment with gemcitabine resulted in partial synchronization of cells in the G2-M-phase at the time of nab-paclitaxel treatment, providing another mechanism for the benefit of altered scheduling. In heterotopic and orthotopic xenograft models, the altered schedule of gemcitabine prior to nab-paclitaxel significantly delayed tumor growth compared with concurrent delivery without added toxicity. CONCLUSIONS: Pretreatment with gemcitabine significantly increased nab-paclitaxel uptake and correlated with an increased treatment efficacy and survival benefit in preclinical models, compared with standard concurrent treatment. These results justify preclinical and clinical testing of this altered scheduling combination.

Clinical Outcomes and Multidisciplinary Patterns of Failure for Olfactory Neuroblastoma: The Ohio State Experience.

Purpose Olfactory neuroblastoma (ONB) is a rare head and neck cancer believed to be originated from neural crest cells of the olfactory membrane located in the roof of the nasal fossa. This study evaluates clinical outcomes and failure patterns in ONB patients of those patients treated with surgical resection at a high-volume tertiary cancer center. Methods and Materials Thirty-nine ONB patients who underwent surgical resection at our institution from 1996 to 2017 were retrospectively identified. Univariate, multivariate, and survival analysis were calculated using Cox regression analysis and Kaplan-Meier log-rank. Results Median follow-up time was 59 months (range: 5.2-236 months). The median overall survival (OS) and disease-free survival (DFS) for the entire cohort were 15 and 7.6 years, respectively. The 5-year cumulative OS and DFS were 83 and 72%, respectively. The 5-year OS for low Hyams grade (LHG) versus high Hyams grade (HHG) was 95 versus 61% ( p = 0.041). LHG was found in 66% of the early Kadish stage patients compared with 28% in the advanced Kadish stage patients ( p = 0.057). On multivariate analysis, HHG and positive node status predicted for worse OS and only HHG predicted for worse DFS. Of note, five patients (all Kadish stage A) who received surgical resection alone had no observed deaths or recurrences with a median follow-up of 44 months (range: 5-235 months). Conclusion In this retrospective cohort, patients with positive nodes or HHG have significantly worse clinical outcomes. Future studies should explore treatment intensification for HHG or positive nodes.