Corrigendum: Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

[This corrects the article DOI: 10.3389/fimmu.2023.1230049.].

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition.

A phase II study of bevacizumab and temsirolimus in advanced extra-pancreatic neuroendocrine tumors.

We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored multicenter, open-label, phase II study (NCT01010126) enrolled patients with advanced, recurrent, or metastatic extra-pancreatic neuroendocrine tumors. All patients were treated with temsirolimus and bevacizumab until disease progression or unacceptable toxicity. Temsirolimus 25 mg was administered i.v. on days 1, 8, 15, and 22 and bevacizumab 10 mg/kg i.v. on days 1 and 15 of a 4-week cycle. Discontinuation of temsirolimus or bevacizumab did not require discontinuation of the other agent. The primary endpoints were objective response rate and 6-month progression-free survival rate. Fifty-nine patients were enrolled in this study, and 54 were evaluated for efficacy and adverse events. While median progression-free survival was 7.1 months, the median duration of treatment with temsirolimus was 3.9 months and that with bevacizumab was 3.5 months. The objective response rate of combination therapy was 2%, and 6-month progression-free survival was 48%. The most frequently reported grade 3-4 adverse events included fatigue (13%), hypertension (13%), and bleeding (13%). Close to 54% of the patients discontinued treatment due to adverse events, refusal of further treatment, or treatment delays. Three deaths occurred in the study, of which two were due to treatment-related bowel perforations. Given the minimal efficacy and increased toxicity seen with the combination of bevacizumab and temsirolimus, we do not recommend the use of this regimen in patients with advanced extra-pancreatic neuroendocrine tumors.

The role of solid solutions in iron phosphate-based electrodes for selective electrochemical lithium extraction.

Electrochemical intercalation can enable lithium extraction from dilute water sources. However, during extraction, co-intercalation of lithium and sodium ions occurs, and the response of host materials to this process is not fully understood. This aspect limits the rational materials designs for improving lithium extraction. Here, to address this knowledge gap, we report one-dimensional (1D) olivine iron phosphate (FePO4) as a model host to investigate the co-intercalation behavior and demonstrate the control of lithium selectivity through intercalation kinetic manipulations. Via computational and experimental investigations, we show that lithium and sodium tend to phase separate in the host. Exploiting this mechanism, we increase the sodium-ion intercalation energy barrier by using partially filled 1D lithium channels via non-equilibrium solid-solution lithium seeding or remnant lithium in the solid-solution phases. The lithium selectivity enhancement after seeding shows a strong correlation with the fractions of solid-solution phases with high lithium content (i.e., LixFePO4 with 0.5 ≤ x < 1). Finally, we also demonstrate that the solid-solution formation pathway depends on the host material's particle morphology, size and defect content.

N064A (Alliance): Phase II Study of Panitumumab, Chemotherapy, and External Beam Radiation in Patients with Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer. METHODS: The treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events. Enrollment of 50 patients was planned and the study fully accrued. RESULTS: Fifty-two patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9% were women. Twenty-two patients received at least 1 cycle of systemic therapy following radiotherapy, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The overall RR was 5.9% (95% CI: 1.2%-16.2%). The 12-month OS rate was 50% (95% CI: 38%-67%) which fell short of the per-protocol goal for success (51.1%). The median PFS was 7.4 months (95% CI: 4.5-8.6) and the median OS was 12.1 months (95% CI 7.9-15.9). Grade 3 or higher adverse events were reported by 88%. CONCLUSION: The combination of panitumumab, chemotherapy, and external beam radiation therapy was associated with very high rates of grades 3-4 toxicities and survival results did not meet the trial's goal for success. This regimen is not recommended for further study (ClinicalTrials.gov Identifier NCT00601627).

Real-world safety and supportive care use of second-line 5-fluorouracil-based regimens among patients with metastatic pancreatic ductal adenocarcinoma.

OBJECTIVE: Chemotherapy-related adverse events (AEs) can negatively impact the care of patients. The prevention and management of AEs often require additional medications. This study evaluated the percentages of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) undergoing second-line therapy with 5-fluorouracil (5-FU)-based regimens that experienced AEs during treatment and received medication to manage those AEs. METHODS: We conducted a retrospective observational analysis utilizing the Flatiron Health database of adult patients with mPDAC who started second-line therapy between January 2016 and August 2020. The occurrence of diarrhea, fatigue, nausea and vomiting, neuropathy, and hematologic AEs including G3/G4 anemia, neutropenia, and thrombocytopenia was assessed. The use of concomitant medications including atropine and granulocyte colony stimulating factor (G-CSF) was assessed. RESULTS: Of the 825 eligible patients, 29.0% (n = 239) received FOLFIRINOX, 24.0% (n = 198) received FOLFOX, 6.8% (n = 56) received FOLFIRI, and 40.2% (n = 332) received liposomal irinotecan-based regimens. FOLFIRI and FOLFIRINOX regimens were associated with the highest rates of anemia (16.1% and 15.5%), neutropenia (19.6% and 22.6%), and thrombocytopenia (14.3% and 9.6%). The liposomal irinotecan and FOLFOX regimens were associated with lower rates of anemia (11.8% and 12.1%), neutropenia (12.4% and 14.7%), and thrombocytopenia (2.4% and 8.1%). G-CSF use was observed among 63.6%, 34.9%, 33.9%, and 44.9% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Diarrhea was observed among 12.5%, 4.5%, 12.5%, and 10.2% of patients who were treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Nausea and vomiting occurred in 14.9%, 12.6%, 10.5%, and 13.1% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Atropine use was higher in patients treated with FOLFIRINOX and FOLFIRI (90.8% and 94.6%, respectively) than in patients treated with liposomal irinotecan-based regimens (75.6%). CONCLUSIONS: In patients with mPDAC who received second-line therapy, those who received liposomal irinotecan-based regimens had the lowest rates of anemia, neutropenia, and thrombocytopenia compared to FOLFIRI, FOLFIRINOX, and FOLFOX, while requiring a similar or lower level of medication to treat and manage those adverse events. Patients treated with FOLFIRI received the highest dose of pegfilgrastim to manage neutropenia. The results of this real-world analysis are consistent with prior evaluations of patients with mPDAC and highlight the importance of managing adverse events and associated cost implications.

Real-World Cost of Care for Commercially Insured versus Medicare Patients with Metastatic Pancreatic Cancer Who Received Guideline-Recommended Therapies.

BACKGROUND: Much of the literature about the costs of metastatic pancreatic cancer is focused on the Medicare population, but the cost in the commercially insured population is not well-documented. Differences in treatment patterns between commercially insured and Medicare patients with metastatic pancreatic cancer can provide insights into healthcare utilization and the total cost of care. OBJECTIVE: To compare the total cost of care for commercially insured versus Medicare patients with metastatic pancreatic cancer who are receiving National Comprehensive Cancer Network (NCCN)-recommended treatment regimens. METHODS: We identified 3904 patients (mean age at diagnosis, 56 years) with metastatic pancreatic cancer using International Classification of Diseases, Ninth/Tenth Revision diagnosis codes in claims data in the 2014-2018 MarketScan commercial database and 28,063 patients (mean age at diagnosis, 73 years) with metastatic pancreatic cancer in the 2014-2017 Medicare Parts A, B, and D 100% research identifiable data files. We calculated the total cost of care and resource utilization by NCCN-recommended (category 1) treatment regimen, including 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX); gemcitabine plus nab-paclitaxel; gemcitabine monotherapy; and liposomal irinotecan. All patients had ≥2 claims with a pancreatic cancer diagnosis more than 30 days apart and ≥1 subsequent claims with a secondary malignancy diagnosis for metastatic disease. RESULTS: The mean total cost of care was 186% higher in the commercially insured cohort than in the Medicare cohort. Excluding gemcitabine monotherapy, the total cost of care for patients with metastatic pancreatic cancer was similar between the regimens used in each cohort, ranging from $95,426 to $116,325 in the commercial insurance group and from $39,777 to $40,390 in the Medicare group. The components of hospital-based inpatient and outpatient costs varied between similar regimens in both cohorts. The inpatient admission patterns of patients' regimens were consistent across the 2 cohorts, with patients receiving gemcitabine monotherapy or liposomal irinotecan having the lowest overall number of admissions in each cohort. CONCLUSIONS: The treatment patterns varied across the regimens but were largely consistent between the commercially insured and the Medicare patients who received the same regimen for metastatic pancreatic cancer; the ratio of total cost of care was 3:1 (commercially insured to Medicare). The total costs of care were similar across the regimens in each cohort, but the components of the total cost varied. These results can inform clinical guidelines and pathways for pancreatic cancer therapy as new evidence and treatment options emerge, and in the context of increasing value-based care models.

Comparing outcomes for non-metastatic rectal cancer in academic vs. community centers: A propensity-matched analysis of the National Cancer Database.

BACKGROUND: Little is known regarding the impact of hospital academic status on outcomes following rectal cancer surgery. We compare these outcomes for nonmetastatic rectal adenocarcinoma at academic versus community institutions. METHODS: The National Cancer Database (2010-2016) was queried for patients with nonmetastatic rectal adenocarcinoma who underwent resection. Propensity score matching was performed across facility cohorts to balance confounding covariates. Kaplan-Meier estimation and Cox-proportional hazards regression were used to analyze survival, other short and long-term outcomes were analyzed by way of logistic regression. RESULTS: After matching, 15,096 patients were included per cohort. Academic centers were associated with significantly decreased odds of conversion and positive margins with significantly increased odds of ≥12 regional nodes examined. Academic programs also had decreased odds of 30 and 90-day mortality and decreased 5-year mortality hazard. After matching for facility volume, no significant differences in outcomes between centers was seen. CONCLUSIONS: No difference between academic and community centers in outcomes following surgery for non-metastatic rectal cancer was seen after matching for facility procedural volume.

Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]).

AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

Real-world outcomes associated with liposomal irinotecan dose reductions in metastatic pancreatic ductal adenocarcinoma.

Aim: This study sought to understand the association between liposomal irinotecan dose reductions (DRs) and clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma. Materials & methods: A retrospective study of adult patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan in the Flatiron Health database was conducted to assess treatment and clinical outcomes. Results: DRs occurred in 28.4% of the 320 patients in the study. Patients with DRs had longer overall survival (7.7 [95% CI: 6.2-10.2]) vs 3.6 [3.2-4.1] months) and time to discontinuation (4.2 [3.0-4.9] vs 1.4 [1.0-1.5] months) than patients without DRs. Results were consistent in a validation analysis requiring three cycles of treatment. Conclusion: Liposomal irinotecan DRs were associated with improved clinical outcomes compared with patients without DRs.

Trends in utilization, conversion rates, and outcomes for minimally invasive approaches to non-metastatic rectal cancer: a national cancer database analysis.

BACKGROUND: This study examined utilization and conversion rates for robotic and laparoscopic approaches to non-metastatic rectal cancer. Secondary aims were to examine short- and long-term outcomes of patients who underwent conversion to laparotomy from each approach. METHODS: The National Cancer Database (NCDB) was reviewed for all cases of non-metastatic adenocarcinoma of the rectum or rectosigmoid junction who underwent surgical resection from 2010 to 2016. Utilization rates of robotic, laparoscopic, and open approaches were examined. Patients were split into cohorts by approach. Subgroup analyses were performed by primary tumor site and surgical procedure. Multivariable analysis was performed by multivariable logistic regression for binary outcomes and multivariable general linear models for continuous outcomes. Survival analysis was performed by Kaplan-Meier and multivariable cox-proportional hazards regression. RESULTS: From 2010 to 2016, there was a statistically significant increase in utilization of the robotic and laparoscopic approaches over the study period and a statistically significant decrease in utilization of the open approach. The conversion rates for robotic and laparoscopic cohorts were 7.0% and 15.7%, p < 0.0001. Subgroup analysis revealed statistically lower conversion rates between robotic and laparoscopic approaches for rectosigmoid and rectal tumors and for LAR and APR. Converted cohorts had statistically significant higher odds of short term mortality than the non-converted cohorts (p < 0.05).Laparoscopic conversion had statistically higher odds of positive margins (p < 0.0001) and 30-day unplanned readmission (p < 0.0001) than the laparoscopic non-conversion. Increased adjusted mortality hazard was seen for converted laparoscopy relative to non-converted laparoscopy (p = 0.0019). CONCLUSION: From 2010 to 2016, there was a significant increase in utilization of minimally invasive approaches to surgical management of non-metastatic rectal cancer. A robotic approach demonstrated decreased conversion rates than a laparoscopic approach at the rectosigmoid junction and rectum and for LAR and APR. Improved outcomes were seen in the minimally invasive cohorts compared to those that converted to laparotomy.

Surgical resection of T4 colon cancers: an NCDB propensity score-matched analysis of open, laparoscopic, and robotic approaches.

Historically, T4 tumors of the colon have been a contraindication to minimally invasive resection. The purpose of this study was to conduct a National Cancer Database analysis to compare the outcomes after curative treatment for T4 colon cancer between robotic, laparoscopic, and open approaches. The US National Cancer Database was queried for patients with T4 adenocarcinoma of the colon who underwent curative resection. Groups were separated based on approach (open, laparoscopic, robotic). One to one nearest neighbor propensity score matching (PSM) ± 1% caliper was performed across surgical approach cohorts to balance potential confounding covariates. Kaplan-Meier estimation and Cox-proportional hazards regression were used to analyze primary outcome of survival. Secondary outcomes were analyzed by way of logistic regression. Inclusion criteria and PSM identified 876 cases per treatment approach (n = 2628). PSM provided adequate discrimination between treatment cohorts (0.6 < AUC < 0.8) and potential confounding covariates did not significantly differ between cohorts (all respective P > 0.05). Patients who underwent a robotic approach had lower odds of conversion to laparotomy compared to the laparoscopic cohort (P < 0.0001). Laparoscopic and robotic approaches were associated with increased odds of > 12 lymph nodes examined, decreased odds of positive margins, and decreased odds of 30-day readmission, 30-day mortality, and 90-day mortality compared to the open approach. Cox-proportional hazards regression showed that both robotic and laparoscopic approaches were significantly associated with decreased mortality hazards relative to open. Both laparoscopic and robotic-assisted surgeries achieved improved oncologic outcomes and survival compared to open resection of T4 cancers. A robotic-assisted approach was significantly associated with a lower conversion rate compared to the laparoscopic approach. This case-matched study demonstrates safety of using minimally invasive techniques in T4 cancers.

Lattice-Distortion-Enhanced Yield Strength in a Refractory High-Entropy Alloy.

Severe distortion is one of the four core effects in single-phase high-entropy alloys (HEAs) and contributes significantly to the yield strength. However, the connection between the atomic-scale lattice distortion and macro-scale mechanical properties through experimental verification has yet to be fully achieved, owing to two critical challenges: 1) the difficulty in the development of homogeneous single-phase solid-solution HEAs and 2) the ambiguity in describing the lattice distortion and related measurements and calculations. A single-phase body-centered-cubic (BCC) refractory HEA, NbTaTiVZr, using thermodynamic modeling coupled with experimental verifications, is developed. Compared to the previously developed single-phase NbTaTiV HEA, the NbTaTiVZr HEA shows a higher yield strength and comparable plasticity. The increase in yield strength is systematically and quantitatively studied in terms of lattice distortion using a theoretical model, first-principles calculations, synchrotron X-ray/neutron diffraction, atom-probe tomography, and scanning transmission electron microscopy techniques. These results demonstrate that severe lattice distortion is a core factor for developing high strengths in refractory HEAs.

Comparing real-world evidence among patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan.

There are questions surrounding the real-world effectiveness of chemotherapeutic treatments for pancreatic ductal adenocarcinoma. This literature review compared the clinical characteristics and outcomes of available real-world evidence (RWE) for liposomal irinotecan in combination with 5-fluorouracil (5-FU) and leucovorin (LV), a treatment regimen indicated for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously progressed on gemcitabine-based therapy. A targeted literature search was conducted in the PubMed Central® and Embase® databases to identify available RWE regarding patients with mPDAC receiving liposomal irinotecan published within the last 5 years (January 2014-September 2019). Data were extracted for prior lines of therapy, performance status, overall survival (OS), progression-free survival (PFS), duration of exposure, and adverse events. Six studies met inclusion criteria. A comparison of baseline patient characteristics and results with the included evidence reveals a clinically fragile, real-world patient population in terms of age (range: 61-68), prior lines of therapy with 34-61% of patients receiving ⩾2 lines of lines of prior therapy and performance status [49.8-100% of patients with Eastern Cooperative Oncology Group (ECOG) 0-1]. Studies observed wide OS (range: 5.3-9.4 months) and similar PFS (range: 2.3-4.1 months), with two studies measuring duration of exposure (7.3 weeks, 3.1 months). Patients analyzed by RWE studies tended to be older with significant disease progression, poor performance status, and more heavily pretreated compared with the phase III registrational trial (NAPOLI-1). Despite this, patients treated with liposomal irinotecan + 5-FU/LV therapy had similar outcomes as those in NAPOLI-1.

Temperature dependence of elastic and plastic deformation behavior of a refractory high-entropy alloy.

Single-phase solid-solution refractory high-entropy alloys (HEAs) show remarkable mechanical properties, such as their high yield strength and substantial softening resistance at elevated temperatures. Hence, the in-depth study of the deformation behavior for body-centered cubic (BCC) refractory HEAs is a critical issue to explore the uncovered/unique deformation mechanisms. We have investigated the elastic and plastic deformation behaviors of a single BCC NbTaTiV refractory HEA at elevated temperatures using integrated experimental efforts and theoretical calculations. The in situ neutron diffraction results reveal a temperature-dependent elastic anisotropic deformation behavior. The single-crystal elastic moduli and macroscopic Young's, shear, and bulk moduli were determined from the in situ neutron diffraction, showing great agreement with first-principles calculations, machine learning, and resonant ultrasound spectroscopy results. Furthermore, the edge dislocation-dominant plastic deformation behaviors, which are different from conventional BCC alloys, were quantitatively described by the Williamson-Hall plot profile modeling and high-angle annular dark-field scanning transmission electron microscopy.

Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer, a phase 1 trial of Vismodegib and Sirolimus combination.

BACKGROUND/OBJECTIVES: Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy. METHODS: Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle. RESULTS: Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected. CONCLUSIONS: The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.

A comparison of teaching opportunities for rural and urban family medicine residents.

CONTEXT: Medical schools of geographically large nations have expanded into rural areas to facilitate the development of a sustainable rural pipeline of physicians. Preceptor, or clinical teacher, recruitment at these sites has been an ongoing challenge. However, residents-as-teachers (RaT) curricula have not been modified to support the development of rural teachers. This study aimed to compare teaching opportunities between rural and urban family medicine residents and to identify mechanisms underlying potential differences. METHODS: Year-1 and Year-2 family medicine residents at seven Canadian institutions participated in a mixed-methods study utilising a quantitative survey and a qualitative interview. Rural and urban residents rated the quantity and types of teaching opportunities available during their training, from which a chi-squared analysis was completed. Volunteer respondents participated in a structured interview, from which a thematic analysis was performed. RESULTS: Rural family medicine residents had fewer opportunities to teach compared to their urban colleagues. This discrepancy was seen across multiple domains, including informal opportunities when on family medicine rotations, χ2 (4, n = 242) = 45.26, P < .000, Bonferroni's adjusted P < .000. Thematic analysis centred around determining factors influencing teaching opportunities and identified that the academic context, personal factors and programme factors were key dimensions. Within these dimensions, the number of medical students, a desire to be an educator and administrative support were cited as influences on teaching opportunities. CONCLUSIONS: The lack of teaching opportunities for rural trainees is attributable to a combination of practical and organisational factors revealed through thematic analysis. If rural graduates are not comfortable balancing the demands of service and teaching, this could compound the already prevalent issue of rural preceptor recruitment. It is essential to develop a rural-focused RaT curriculum to close this gap and produce competent educators who are ready to inspire generations of rural physicians.

Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. METHODS: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. RESULTS: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. CONCLUSIONS: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.