Citations

Abstract BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.

Abstract Background nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), using intraliposomal stabilisation technology to enable high drug load and in-vivo stability. The expansion of Phase I NCT01770353 evaluated nal-IRI in patients (pts) with mBC. Methods This Phase I expansion study enrolled mBC pts (Cohort 1: ER+ and/or PR+ HER2 BC (C-1); Cohort 2: Triple Negative BC (TNBC, C-2); Cohort 3: BC with active Brain Metastasis (C-3)). Key inclusion criteria: ECOG ≤1; adequate organ function; received >1 to ≤5 prior lines of cytotoxic therapy in metastatic setting, except TNBC pts who could have progressed within 12 months of adjuvant therapy. Pts received nal-IRI 50 mg/m2 (Free-base equivalent, FBE) q2w iv infusion, escalating to 70 mg/m2 FBE q2w, if tolerated. Results 30 pts (10 per cohort) were enrolled: 29 received >1 dose nal-IRI 50 mg/m2 FBE (median age 53 yrs, range 29-70 yrs). Median number of cytotoxic therapies prior to study entry was 3. The most frequent treatment emergent adverse events (TEAEs) were gastrointestinal disorders (all cohorts, 100%), primarily diarrhea (C-1, 100% / C-2, 100% / C-3, 70%), nausea (C-1, 80% / C-2, 56% / C-3, 30%), and vomiting (C-1, 60% / C-2, 33% / C-3, 30%). The incidence of neutropenia was low (C-1, 10% / C-2, 0% / C-3, 10%), all grade 1 / 2. Most common grade 3 TEAEs were diarrhea (28%), nausea (17%), fatigue (14%), hypokalemia (10%) and asthenia (10%), with none reported as grade 4. No grade 5 TEAEs were reported. Partial response (per RECIST) was observed in 10 pts for an objective response rate (ORR) of 35% (C-1, 40% / C-2, 33%) / C-3, 30%). Stable disease was observed in 5 pts (17%). Duration of Response (median, months) was C-1, 7.5 (6.4-13.0) / C-2, 5.6 (3.7-7.4) / C-3, 4.1 (0.0-22.2, extracranial: RECIST) / C-3, 1.8 (0.0-1.9, intracranial: mRECIST). Table 1.Study Demographics, Adverse Events, and Best Overall ResponseDemographicsCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=10Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=30Gender, Female, n (%)10 (100%)10 (100%)10 (100%)30 (100%)Age, Years Median (range)56 (49-68)52.5 (37-70)45.5 (29-63)53 (29-70)Race, n (%)WhiteBlack/AfricanOther8 (80%)02 (20%)8 (80%)1 (10%)1 (10%)7 (70%)1 (10%)2 (20%)23(77%)2 (7%)5(16%)Months Since Metastatic diagnosis, Months Median (Range)63.7 (16-87)20.7 (0-34)32.4 (8-55)24.0 (0-87)Number of Prior Cytotoxic Anti-cancer Regimens Median (Range)3.0 (1-6)3.0 (0-5)32.4 (1-6)3.0 (0-6)Safety PopulationCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=9Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=29ExposureTreatment Duration, Weeks Median (range)6.1 (0-78)12.3 (0-49)13.9 (1-105)12.3 (0-105)Adverse EventsAny TEAE10 (100%)9 (100%)10 (100%)29 (100%)Grade 38 (80%)6 (67%)10 (100%)20 (69%)Grade 41 (10%)06 (60%)3 (10%)TEAE Related to nal-IRI10 (100%)8 (89%)10 (100%)28 (97%)Grade > 36 (60%)3 (33%)3 (30%)12 (41%)TEAE Related to nal-IRILeading to Dose Adjustment*7 (70%)3 (33%)4 (40%)14 (48%)SAEs6 (60%)4 (44%)7 (70%)17 (59%)SAE Related to nal-IRI4 (40%)1 (11%)1 (10%)6 (21%)Duration of Objective ResponseRECIST 1.1RECIST 1.1RECIST 1.1mRECISTMonths Median (Range)7.5 (6.4-13.0)5.6 (3.7-7.4)4.1 (0.0-22.2)1.84 (0.0-1.9)Best Overall ResponseRECISTRECISTRECISTmRECISTComplete Response (CR)0000Partial Response (PR)4 (40%)3 (33%)3 (30%)3 (30%)Stable Disease (SD)03 (33%)2 (20%)3 (30%)Progressive Disease (PD)5 (50%)2 (22%)3 (30%)2 (20%)Not Evaluable (NE)1 (10%)1 (11%)2 (20%)2 (20%)Objective Response RateCR+PR(95% CI)4 (40%)12.2 -73.83 (33%)7.5-70.73 (30%)6.7-65.33 (30%)(6.7-65.3)*n=1 patient in Cohort 1 discontinued treatment due to TEAE related to treatment with nal-IRI CI, Confidence Interval; nal-IRI, Irinotecan Liposome Injection; SAE, Serious Adverse Event; TEAE, Treatment Emergent Adverse EventSystemic tumor response was evaluated according to RECIST version 1.1CNS tumor response was evaluated according to mRECIST (Anders C. et al., Breast Cancer Res Treat, 2014: 146(3):557-66) Conclusion nal-IRI monotherapy 50g/m2 FBE Q2W appears well tolerated, and achieved >30% ORR for systemic and CNS disease among heavily pre-treated mBC pts regardless of receptor status. Citation Format: Jasgit Sachdev, Pamela Munster, Donald Northfelt, Hyo S. Han, Cynthia MA, Fiona Maxwell, Tiffany Wang, Bruce Belanger, Bin Zhang, Yan Moore, Carey Anders. Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT048.

Favorable long-term functional outcomes after severe traumatic brain injury (TBI) may be underestimated. We analyzed 24-month functional outcomes from a consecutive series of severe TBI survivors. A prospective, observational database of severe TBI survivors from a single institution was analyzed. Glasgow Outcome Scale-Extended (GOS-E) scores were obtained at 3, 6, 12, and 24 months post-injury. GOS-E scores were dichotomized into unfavorable and favorable outcomes, and the proportion of survivors changing from unfavorable to favorable outcomes was calculated using Wilcoxon signed-rank tests. Surviving adults ( N = 304; mean age ± standard deviation = 35.06 ± 15.11; 80.92% male; mode of initial GCS = 7) were analyzed. A statistically significant mean increase in GOS-E was noted from 3 to 6, 6 to 12, 12 to 24, and 6 to 24 months after injury (0.65 [ p < 0.0001], 0.42 [ p < 0.0001], 0.23 [ p = 0.020], and 0.61 [ p < 0.0001], respectively). Moreover, 43% of survivors from 3 to 6 months, 36% from 6 to 12 months, 38% from 12 to 24 months, and 54% from 6 to 24 months progressed from an unfavorable to a favorable outcome. Two thirds of survivors in the unfavorable category at 3 months had favorable outcomes at 2 years. Overall, 74% of surviving adults with a documented GOS-E at 2 years after injury had a favorable outcome. Severe TBI survivors demonstrated significant improvement in functional outcomes from 3 to 24 months after injury. At 2 years, three fourths of survivors had a favorable outcome. Long-term prognosis in severe TBI is better than broadly appreciated.

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar‐arterial oxygen gradient (AaPO2) at 3 months in patients with HPS. We performed a randomized, double‐blind, placebo‐controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, –3.8 to 7.0 mm Hg) and those allocated to placebo (–2.4 mm Hg; IQR, –4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2‐expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.

Objective: Athletes who return to sport after anterior cruciate ligament reconstruction (ACLR) demonstrate persistent biomechanical and neuromuscular deficits of the knee. There is limited evidence on what effect a neuromuscular training (NMT) program has on knee biomechanics in a cohort of athletes with ACLR. Therefore, the primary aim of this study was to quantify the effect of an NMT program on knee biomechanics in a cohort of ACLR athletes. Second, the post-training knee biomechanics were compared between the cohort of ACLR and control athletes. Design: Cohort study. Setting: Controlled laboratory setting. Participants: Eighteen athletes with ACLR and 10 control athletes. Interventions: Neuromuscular training. Main Outcome Measures: Knee kinematics and kinetics during a double-limb jump-landing task. Results: There were no significant interactions (P > 0.05) observed for the athletes with ACLR. However, there was a significant main effect of biomechanics testing session (P < 0.05) for knee flexion angle and moments; athletes with ACLR demonstrated greater knee flexion angle and lower knee flexion moment during the post-training biomechanics testing session. Post-training comparison between the ACLR and control athletes demonstrated no significant interactions (P > 0.05) between the groups. There was a significant main effect of group (P < 0.05) for knee frontal angle, as athletes with ACLR landed with greater knee adduction than the control athletes. Conclusions: Significant improvements in knee sagittal plane biomechanical measures were observed after the NMT program by the athletes with ACLR. In addition, post-training comparison of the ACLR and control groups demonstrates comparable knee biomechanics.

Abstract Phosphomannomutase 2 (PMM2‐CDG) is the most common congenital disorder of N‐glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2‐CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2‐CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence‐based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2‐CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2‐CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2‐CDG patients.

Background and Objectives: The Family Medicine for America’s Health Workforce and Education Team aims to increase the number of medical students choosing family medicine to address the projected primary care physician shortage. This aim can be achieved by developing a well-trained primary care workforce. Our student- and resident-led FMAHealth work group aimed to identify factors that influenced fourth-year medical students’ choice to become family physicians. The secondary objective compared such factors between the 10 medical schools with the highest percentage of students matching into family medicine and non-top 10 medical schools. Methods: Fourth-year medical students nationwide participated in 90-minute virtual focus groups. Reviewers coded deidentified transcriptions and identified key themes and subthemes that were found to influence student choice. Results: Fifty-five medical students participated in focus groups over a 2-year period. Three key themes were found to influence students: perspective, choice, and exposure. Subthemes included: (1) the importance of high-quality preceptors practicing full-scope family medicine, (2) the value of a rural experience, and (3) institutional support to pursue family medicine. Physician compensation and loan repayment concerns were not major factors influencing student choice. Conclusions: Many factors influence student choice of family medicine including preceptors, clinical exposures, and institutional support. These factors varied by institution and many were found to be different between top 10 and non-top 10 schools. Addressing these factors will help increase students’ choice of family medicine and reduce the primary care shortage.