bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quadriceps Tendon Graft Anatomy in the Skeletally Immature Patient
Authors: Shea Kevin G. , Burlile Jessica F. , Richmond Connor G. , Ellis Henry B. , Wilson Philip L. , Fabricant Peter D. , Mayer Stephanie , Stavinoha Tyler , Troyer Stockton , Dingel Aleksei B. , Ganley Theodore J. 
Published: July 2019

Background: The quadriceps tendon (QT) is increasingly considered for primary and revision anterior cruciate ligament reconstruction in skeletally immature patients, as it may be harvested as a purely soft tissue graft with considerable tissue volume. Because of distinct rectus tendon (RT) separation from the QT complex, the potential for RT retraction exists and could lead to QT weakness after QT graft harvest. Purpose: To describe the anatomy of the pediatric QT and clarify decussation of the RT and QT to avoid the risk of delayed RT retraction and QT weakness after QT graft harvest. Study Design: Descriptive epidemiology study. Methods: Nine cadaveric knee specimens (aged 4-11 years) underwent gross dissection. Coronal-plane width and depth of the QT were measured at intervals proximal to the superior pole of the patella at distances of 0.0, 0.5, 1.0, and 1.5 times the length of the patella. The distance was measured from the superior patellar pole to the point of RT separation from the remainder of the deeper/posterior QT. Results: The median patellar length was 28 mm (interquartile range, 26-37 mm). The coronal-plane width of the QT was larger superficially/anteriorly when closest to the patella but wider when measured deeper/posteriorly as the tendon extended proximally. The median distance between the superior pole of the patella and RT separation from the QT was 0.95 times the patellar length. The distance to widening of the deeper/posterior aspect of the QT was 1.14 times the patellar length proximal to the patella. Conclusion: The RT begins a distinct separation from the QT above the superior pole of the patella at a median of 0.95 times the patellar length in skeletally immature specimens. The deeper/posterior aspect of the QT begins to increase in coronal-plane width proximally after a distance of 1.14 times the patellar length above the knee, while the superficial/anterior aspect of the tendon continues to narrow. Awareness of the separation of the RT from the QT, and the coronal-plane width variation aspects of the QT proximally, is important for surgeons utilizing the QT as a graft to avoid inadvertent release of the RT from the rest of the QT complex.
Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study
Authors: Hillmen Peter , Rawstron Andy C. , Brock Kristian , Muñoz-Vicente Samuel , Yates Francesca J. , Bishop Rebecca , Boucher Rebecca , MacDonald Donald , Fegan Christopher , McCaig Alison , Schuh Anna , Pettitt Andrew , Gribben John G. , Patten Piers E.M. , Devereux Stephen , Bloor Adrian , Fox Christopher P. , Forconi Francesco , Munir Talha 
Published: July 2019

PURPOSE The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.
Final analysis of nelipepimut-S plus GM-CSF with trastuzumab versus trastuzumab alone to prevent recurrences in high-risk, HER2 low-expressing breast cancer: A prospective, randomized, blinded, multicenter phase IIb trial.
Authors: Hickerson Annelies , Clifton G. Travis , Hale Diane F. , Peace Kaitlin M. , Holmes Jarrod P. , Vreeland Timothy J. , Litton Jennifer Keating , Murthy Rashmi Krishna , Lukas Jason Jerome , Mittendorf Elizabeth A. , Peoples George Earl 
Published: July 2019

1 Background: Preclinical data shows synergism between trastuzumab (Tz) and HER2-targeted vaccines. We evaluated adjvuant nelipepimut-S (NPS) + GM-CSF with Tz compared to Tz with GM-CSF alone in HER2 low-expressing (LE) breast cancer (BC) patients (pts) to prevent recurrences. After a planned interim analysis showed benefit in triple negative BC (TNBC) pts, the decision was made to close the trial with guidance from the independent DSMB. Here, we report the final analysis of the trial with 7 months (mo) of added follow-up (f/u). Methods: The phase 2b trial enrolled clinically disease-free BC pts after standard therapy. Pts were HLA-A2, A3, A24, and/or A26+, had HER2-LE (IHC 1-2+, FISH non-amplified) BC and were node positive and/or TNBC. Pts were randomized to placebo with GM-CSF(control group, CG) or NPS with GM-CSF (vaccine group, VG), while all received Tz Q3wk for 1 year. GM-CSF or NPS + GM-CSF were given q3wks x 6 starting with the 3rd Tz dose, and boosters every 6 months x 4. Safety was assessed and pts were followed clinically for recurrences. The primary outcome was DFS at 24 mo. Results: 589 pts were screened at 26 sites. 275 pts were enrolled and randomized (VG:136, CG:139). There were no clinicopathologic differences between groups. Concurrent Tz and NPS was safe with no added overall or cardiac toxicity compared to CG and no grade 4/5 toxicities. In the ITT analysis (median f/u 25.7 mo), the estimated DFS was favorable but did not reach significance in the VG compared with the CG (HR 0.62, 95% CI: 0.31-1.25, p = 0.18). In the TNBC pts, the VG had statistically improved DFS compared to the CG (HR 0.26, 95% CI: 0.08-0.81, p = 0.013). Conclusions: The combination of NPS with Tz is safe with no added toxicity compared to Tz alone, even after prolonged exposure (25.7 mo). In this final analysis, there was a trend towards benefit in the ITT population that improved since the interim analysis with added f/u. The significant benefit seen at interim in the TNBC pts continued to strengthen in the VG group. These findings could position the NPS + Tz combination as an adjuvant therapy for early-stage TNBC and warrant further study. Clinical trial information: NCT01570036.
Evaluation of PQ500, a 500-plasma protein blood panel in NSCLC subjects using high-throughput MRM mass spectrometry.
Authors: Dupuis Nicholas , Muller Sebastian , Treiber Tobias , Escher Claudia 
Published: July 2019

110 Background: Monitoring of circulating proteins in cancer subjects can provide insight into the host response to the tumor. Recent studies have demonstrated the utility of circulating proteins for early detection, differential diagnosis, and predicting response to therapy. Although the utility is clear, standardization of measurement methods across a large number of proteins from plasma has remained challenging. Here, we evaluate the detection of proteins from a > 500-protein plasma panel assembled from stable-isotope standard (SIS) peptides and measured in a high-throughput MRM workflow. Methods: Plasma samples from subjects with Stage III-IV non-small cell lung cancer (n = 15), Stage IV pancreatic cancer (n = 6) and healthy donors (n = 15) were prepared for analysis. Prior to analysis, a panel of SIS peptides covering 582 plasma proteins (804 peptides), was spiked into each sample enabling absolute quantification of detectable peptide species. All samples were analyzed using a capillary flow liquid chromatography (5 µl/min) with a one-hour gradient coupled to a Thermo Scientific TSQ Altis triple quadrupole mass spectrometer. Protein data was extracted and quantified for statistical analysis using SpectroDive (Biognosys). Results: Across all samples, 607 peptides representing 411 proteins were quantified at least once, with an average of 300 proteins quantified per sample. From triplicate analyses, the median CV across all proteins was 5.3%. Statistical testing identified 42 significantly regulated proteins (36 up- and 6 down-regulated; q-value > 0.05 and log2 fold change > 0.58). Key species that were strongly dysregulated in cancer samples included: c-reactive protein (CRP), serum amyloid a (SAA1/SAA2), complement C9, S100A8/S100A9, and leucine rich glycoprotein 1 (LRG1). Conclusions: PQ500 is a comprehensive blood-focused multiplexed biomarker panel that enables absolute quantification of plasma proteins. The dysregulated proteins identified in this study highlight that the PQ500 can monitor the host immune response through multiple pathways. Accurate monitoring these proteins offers the possibility to define molecular based markers with clinical and diagnostic utility.
Galectins role as predictive markers for anti-PD-1-based immunotherapy in non-small cell lung cancer.
Authors: Capalbo Carlo , Filetti Marco , Scafetta Giorgia , Marchetti Paolo , Bartolazzi Armando 
Published: July 2019

111 Background: Checkpoint inhibitor-based immunotherapy is opening a promising scenario in oncology with objective responses registered in several tumors. However reliable predictive markers of tumor responsiveness are still lacking. These markers need to be urgently identified for a better selection of patients candidate to immunotherapy. In NSCLC setting, the pleiotropic molecules Galectin 1 and 3 regulate apoptosis and tumor immune-escape and are in the right position to play as predictive marker in anti-PD1 based immunotherapy. Methods: 27 consecutive patients with non small cell lung cancer (NSCLC) stage IV, treatment-naive, selected on the basis of PD-L1 tumor proportion score (TPS) ≥ 50 % were considered for immunotherapy with anti PD-1 antibodies as a first-line treatment. Patients assessments were conducted at baseline and after 3 cycles of therapy (week 12) and classified according to immune-related response criteria (iRECIST). Immunohistochemical analysis was performed on primary tumor biopsies before treatment in order to evaluate Gal-1 and Gal-3 expression both in cancer cells and tumor interstitium. Tumors were grouped in 2 different classes depending on the expression level of these molecules. Results: In our preliminary data there seems to be a strong correlation between the responses to anti-PD-1 treatment and a low-intermediate expression of intratumoral Gal-3 and interstitial Gal-1. In fact, all patients in the intratumoral Gal-3 low-intermediate expression group had an excellent response to immunotherapic treatment (10/10 patients), while 15/17 patients with high intracellular Gal-3 expression had clinical and radiographic progression of the disease after only three cycles of treatment, despite the high expression of PD-L1. In contrast, 8/11 patients with a low-intermediate interstitial expression of Gal-1 had an excellent response to treatment, whereas in the group with high interstitial expression of Gal-1, the response rate was drastically lower (5/15 patients). Conclusions: The expression of interstitial Gal-1 protein and intratumoral Gal-3 protein appear to be a good candidates as predictive markers of response to immunotherapy.
Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC.
Authors: Shah Arpeet , Padda Sukhmani K. , Neal Joel W. 
Published: July 2019

114 Background: Evidence from randomized clinical trials and retrospective studies has shown that tumors with specific driver mutations may be less likely to respond to ICI; the optimal timing of ICI is unknown in this population. In this analysis, we evaluated the characteristics of responders to ICI compared to non-responders, with emphasis on the role of driver mutations. Methods: We retrospectively collected clinical characteristics and outcomes for patients who received ICI for NSCLC at Stanford University between April 2015 and August 2016. Patients were classified as responders if time on ICI was 180 days or more, and as non-responders if less than 180 days. Outcomes included radiographic improvement while on ICI, survival from diagnosis, and survival from ICI initiation. Results: Data were available for 84 patients, with median follow-up of 31 months. 18 patients were deemed responders (21%); 66 were deemed non-responders (79%). Of the patients who underwent genomic testing, 13% (2/15) of responders had mutations in EGFR/ALK/ROS1, compared to 32% (17/49) of non-responders (p = 0.195). Within the responders, 89% (16/18) had an associated radiographic improvement, compared to 11% (7/66) of non-responders (p < 0.0001). Patients with mutations in EGFR/ALK/ROS1 had a median overall survival of 46 months from diagnosis, compared to 26 months in those without these mutations (p = 0.08). Patients with mutations in EGFR/ALK/ROS1 had a median survival of 4.9 months from ICI initiation, compared to 7.0 months in those without (p = 0.45). Conclusions: Patients receiving ICI for 180 days or more had a significantly higher rate of radiographic improvement, suggesting that time on therapy appears to be a surrogate endpoint of clinical benefit. While there was not a statistically significant smaller number of responders with EGFR/ALK/ROS1, there appeared to be clinically meaningful lower response rate in these patients. This was likely limited by sample size; expansion of the sample size is planned. There was a trend to overall survival benefit in patients with driver mutations, likely driven by targeted therapy as there were no statistical differences in survival from time of ICI initiation.
Tumor mutational burden (TMB): Assessment of inter- and intra-tumor heterogeneity.
Authors: Conroy Jeffrey M. , Pabla Sarabjot , Glenn Sean T. , Nesline Mary , Burgher Blake , Lenzo Felicia L. , Papanicolau-Sengos Antonios , Gardner Mark , Morrison Carl 
Published: July 2019

27 Background: As an emerging biomarker, a high TMB is associated with response to immune checkpoint inhibitors. The tissue selected for molecular analysis could be critical for accurate TMB assessment and therapeutic selection. We evaluated TMB and the tumor specimen tested to determine the extent tissue selection has on TMB analysis. Methods: TMB profiling was performed on 73 cases representing 8 tumor types. 8 patients with multiple specimens from the same surgical event were evaluated for intra-tumor heterogeneity, and 20 patients with specimens from multiple surgical events spanning up to seven years were tested for inter-tumor heterogeneity. Two to six specimens, including primary, recurrent and metastatic cases, were evaluated per patient. For each patient, TMB values within and between tumors were assessed for concordance using a clinically relevant TMB-high cutoff of ≥ 10 mutations/Mb. Results: TMB values ranged from 0 – 58, with 7 cases scored as TMB-high. One patient with a primary skin melanoma and a lung metastasis biopsied after 34 months was concordant for TMB-high. For 19 patients (76%), all samples were concordant for TMB-low. For intratumor testing, 2 of 8 (25%) patients had discordant specimens (crossed the TMB-cutoff). The first patient had 4 intra-tumor CRC samples with TMB values of 10.6, 10.7, 9.7 and 9.7. The second patient had 5 intra-tumor pancreatic samples with TMB values of 10.7, 4.4, 6.2, 8.8, 7.9. Of the patients with 20 inter-tumor samples, 2 patients (each with melanoma) had discordant TMB-high calls. One had a lymph node metastasis TMB of 12.3 and a liver metastasis collected five months later with a reduced TMB of 0.9. In contrast, the second discordant melanoma patient had a peritoneum metastasis with an elevated TMB of 11.4 collected 14 months after a mesentery metastasis with a TMB of 8.7. Conclusions: TMB variation within tumors and between tumors from different surgical events occurs equally and in 17% of patients. This clinical tumor heterogeneity on the inter- or intra-tumor level may limit the utility and the application of TMB at a cutoff of 10. A careful analysis of tissues to enrich for neoplastic cells may improve assay sensitivity and increase analytical accuracy at this precise cut point.
Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Carmagnani Pestana Roberto , Vence Luis M. , Blando Jorge M. , Singh Shalini , Ikoma Naruhiko , Vauthey Jean-Nicolas , Allison James Patrick , Sharma Padmanee 
Published: July 2019

52 Background: In HCC, surgical resection is associated with high recurrence rate, and no effective neoadjuvant or adjuvant therapies currently exist. On the basis of previous reports on the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC, we initiated a randomized pilot trial of perioperative immunotherapy for resectable HCC. Methods: This is a randomized, phase II pilot trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as peri-operative treatment for patients (pt) with HCC who are eligible for surgical resection. Pt are given nivolumab 240 mg every 2 weeks (wk) for a total of 6 wk. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wk. Surgical resection occurs within 4 weeks after last cycle of therapy. Pt continue adjuvant immunotherapy for up to 2 years after resection. Primary objective is the safety and tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 9 pt were enrolled at the time of first interim analysis, and 8 pt were evaluable (5 in Arm A, 3 in Arm B). Most pt (78%) were 60-69 yo, and males (78%). 5 pt were HCV-positive and 1 had chronic hepatitis B infection. 7 pt proceeded with resection as planned; surgery was aborted for 1 pt due to frozen abdomen from previous surgery. Pathologic complete response (pCR) was observed in 3/8 pt – 2 in Arm A and 1 Arm B (37.5% pCR). 2 pt in Arm B and 1 in Arm A experienced grade 3 or higher toxicity. No grade 4 or higher toxicity were observed. Immune analysis of the first case with a pCR in Arm B demonstrated that clinical response correlated with an increase in CD8+ T cell infiltration, notably an increase in two effector T cell clusters. Conclusions: We report a pCR rate of 37.5% in the first interim analysis of a phase II pilot trial of perioperative immunotherapy for resectable HCC. Treatment was safe and surgical resection was not delayed. The study is ongoing and results may contribute to a paradigm shift in the perioperative treatment of HCC. Clinical trial information: NCT03222076.
Planning for survivorship after checkpoint inhibitors: A multidisicplinary education initiative.
Authors: Perloff Tara , Dawkins Monique , Hurd Mary , Wang Jennifer , Hallmeyer Sigrun 
Published: July 2019

98 Background: Survivorship care plans are a key piece of coordinated, patient-centered care delivery. As with other cancer treatment modalities, patients with metastatic disease who achieve durable benefit with immunotherapy (IO) treatment may experience late physical and psychosocial effects which can negatively impact quality of life. An online education program was created to educate the multidisciplinary cancer care team on the nuances related to survivorship for patients who are treated with checkpoint inhibitors. Methods: A medical oncologist, oncology nurse, oncology social worker and patient developed a curriculum to identify challenges and solutions for survivorship care planning, prepare care teams for nuances related to survivorship for IO patients, and optimize coordination and communication between the care team and the patient. In June 2018, a live-online 1-hour webcast that included a panel discussion with presentation slides, participant polling, and live ‘ask the panel’ questions was produced and made available on-demand. Results: A total of 149 learners viewed the webcast; 86 of these learners participated in the live webinar and 63 watched on-demand. To date, an estimated 590 patients per month are impacted by this education. Learners were actively engaged for an average of 35 minutes (out of 52 minutes). Most learners indicated specializing in oncology (49%), were practicing physicians (39%), and saw 1-10 new patients on an IO therapy each week (59%) in a hospital-based setting (42%). Due to the education provided, learners reported improvements in their ability to identify challenges and solutions for IO survivorship care planning (97%) and handle nuances related to survivorship for patients on cancer immunotherapies (88%). Learners also demonstrated improved comprehension via case study by identifying the most common, concerning side-effect for a high-risk melanoma patient treated with ipilimumab and nivolumab. Conclusions: Continued refinement of care coordination practices related to survivorship is recommended to improve the long-term management of patients who are treated with checkpoint inhibitors.