Search

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3. Patients and Methods: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles. Results: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%). Conclusions: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification.

PURPOSE National Cancer Institute–Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2-activating mutations. METHODS Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute–Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction > 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates. RESULTS A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received > 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor–positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor–positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common (> 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events. CONCLUSION Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.

PURPOSE The National Cancer Institute–Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations. PATIENTS AND METHODS Tumors from patients age 1-21 years with refractory solid tumors, lymphomas, or histiocytic disorders were subjected to cancer gene panel sequencing and limited immunohistochemistry to identify actionable alterations for assignment to phase II treatment arms. The rates of treatment arm assignment and enrollment were compared between clinical and demographic groups. RESULTS Testing was completed for 94.7% of tumors submitted. Actionable alterations were detected in 31.5% of the first 1,000 tumors screened, with treatment arm assignment and enrollment occurring in 28.4% and 13.1% of patients, respectively. Assignment rates varied by tumor histology and were higher for patients with CNS tumors or enrolled at Pediatric Early Phase Clinical Trials Network sites. A reported history of prior clinical molecular testing was associated with higher assignment and enrollment rates. Actionable alterations in the mitogen-activated protein kinase signaling pathway were most frequent (11.2%). The most common reasons provided for not enrolling on treatment arms were patients receiving other treatment or poor clinical status. CONCLUSION The Pediatric MATCH trial has proven the feasibility of a nationwide screening Protocol for identification of actionable genetic alterations and assignment of pediatric and young adult patients with refractory cancers to trials of molecularly targeted therapies. These data support the early use of tumor molecular screening for childhood patients with cancer whose tumors have not responded to standard treatments.

Background NCI-COG Pediatric MATCH assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of pre-defined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. Methods Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and tolerability of tazemetostat. Results Twenty patients (median age, 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (ATRT; n = 8) and malignant rhabdoid tumor (MRT; n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), ATRT (n = 1), renal medullary carcinoma (n = 1). Six-month PFS was 35% (95% CI: 15.7%, 55.2%) and six-month OS, 45% (95% CI 23.1, 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. Conclusion Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (ORR: 5%, 90% CI 1%, 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of > 6 months (range: 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.

Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform–specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss). PATIENTS AND METHODS: Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2–positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival. RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ≥ 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10). CONCLUSION: The study met its primary end point with an ORR of 16% (P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

PURPOSE The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis of detection of predefined genetic alterations. Patients with tumors harboring mutations or fusions driving activation of the mitogen-activated protein kinase (MAPK) pathway were treated with the MEK inhibitor selumetinib. METHODS Patients received selumetinib twice daily for 28-day cycles until disease progression or intolerable toxicity. The primary end point was objective response rate; secondary end points included progression-free survival and tolerability of selumetinib. RESULTS Twenty patients (median age: 14 years) were treated. All were evaluable for response and toxicities. The most frequent diagnoses were high-grade glioma (HGG; n = 7) and rhabdomyosarcoma (n = 7). Twenty-one actionable mutations were detected: hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), inactivating mutations in NF1 (n = 7), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease including two patients with HGG ( NF1 mutation, six cycles; KRAS mutation, 12 cycles). Six-month progression-free survival was 15% (95% CI, 4 to 34). Five patients (25%) experienced a grade 3 or higher adverse event that was possibly or probably attributable to study drug. CONCLUSION A national histology-agnostic molecular screening strategy was effective at identifying children and young adults eligible for treatment with selumetinib in the first Pediatric MATCH treatment arm to be completed. MEK inhibitors have demonstrated promising responses in some pediatric tumors (eg, low-grade glioma and plexiform neurofibroma). However, selumetinib in this cohort with treatment-refractory tumors harboring MAPK alterations demonstrated limited efficacy, indicating that pathway mutation status alone is insufficient to predict response to selumetinib monotherapy for pediatric cancers.

Students perceive crossword puzzles as enjoyable. In addition to students’ perceptions, crossword puzzles actually improve knowledge retention. However, crossword puzzles increased exam scores for some students but not others. Recommendations have been made for students to create puzzles for their classmates to complete with the rationale that students are encouraged to research and understand the material in order to write meaningful clues for the puzzle. While students enjoy creating their own crossword puzzles, the association between students creating crossword puzzles and knowledge retention is unknown. The purpose of this project was to determine if creating crossword puzzles and completing peers’ crossword puzzles were associated with improved knowledge retention indicated by higher scores on quizzes. Students in a research course from two institutions across three semesters had the option each week to upload a blank puzzle they created prior to completing each other’s puzzles and taking a quiz. Quiz scores were compared between those who did versus did not create their own puzzles and complete their peers’ puzzles. Results varied by institution and programs as well as the same program within the same institution but different semesters. Results highlight the importance of moving beyond student perceptions and towards assessing knowledge retention while taking into consideration institution, program, and semester.

PURPOSE Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform–specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss). PATIENTS AND METHODS Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2–positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival. RESULTS Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ≥ 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10). CONCLUSION The study met its primary end point with an ORR of 16% ( P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

We have measured the Raman spectra of some oligothiophenes (bithiophene, terthiophene, quarterthiophene, sexithiophene and octithiophene) and polythiophene with wavelengths from 325–1064 nm (3.815–1.165 eV). All of the materials give good quality spectra with 1064 nm excitation, although there is weak background fluorescence for some of them. The UV lines of 405 and 324 nm generally provide good-quality spectra, albeit with significant fluorescence for bithiophene and quarterthiophene. Surprisingly, there is little difference between the relative intensities (i.e., the ratio of a band’s intensity as compared to the strongest band) of the spectra with the different excitation wavelengths. However, close inspection of the 2000–3200 cm−1 region of octithiophene and polythiophene with 325 and 405 nm excitation shows several modes in this region that can be assigned to combinations and overtones involving the ~1440 cm−1 C–C ring stretch that do not appear with 1064 nm excitation. The presence of overtones and combinations with anomalously large intensities is a hallmark of resonance Raman spectroscopy.

Representativeness of Study Participants

Purpose:Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3.Patients and Methods:Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles.Results:Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%).Conclusions:Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification.

PURPOSE NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 ( NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Supplemental Figure S2. PAR levels in patient PBMC samples. Data shown in dark red are from patients who reported deleterious BRCA mutations, data shown in dark blue are from patients reporting wildtype BRCA status, and data in grey are from patients with unknown BRCA status.

Investigator's Choice (IC) Dosing Regimens

1) Eligible mutations/fusions, 2) identified mutations/fusions, 3) Treatment-related toxicities, 4) Number of treatment cycles and reasons for discontinuation

Supplementary Legend

DLC-001 Study Design (CONSORT diagram)

Supplemental Figure S1. Kaplan-Meier analysis of the progression free survival (PFS) of patients on each treatment arm stratified by BRCA status showed no significant differences.

Grade 3/4 Treatment-Emergent Adverse Events Reported in {greater than or equal to}5% of Patients (Safety Population)

Supplemental Figure S3. Heat map of gene expression profiling results with clusters for treatment response of 55 patients and 203 DNA repair genes.

Supplemental Table

Purpose:Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers.Patients and Methods:Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with NRAS-mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post hoc analysis examined the association of NRAS mutation type with outcome.Results:In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 NRAS mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A patient with NRAS codon 61–mutated colorectal cancer had an unconfirmed PR, and two other patients with NRAS codon 61–mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer bearing a NRAS codon 61 mutation (n = 8) had a significantly longer OS (P = 0.03) and PFS (P = 0.007) than those with codon 12 or 13 mutations (n = 16).Conclusions:Single-agent binimetinib did not show promising efficacy in NRAS-mutated cancers. The observation of increased OS and PFS in patients with codon 61 NRAS-mutated colorectal cancer merits further investigation.

List of Primer Sequences

Supplementary Expression Data. Individual expression values for all 211 genes interrogated in the tumor tissue of 55 patients.

Purpose:Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with BRAF mutations outside the V600 locus, and in BRAF fusions. Thus, Subprotocol R of the NCI-MATCH study tested the MEK inhibitor trametinib in this population.Patients and Methods:The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in BRAF were assigned to Subprotocol R using the NCI-MATCHBOX algorithm. The primary endpoint was objective response rate (ORR).Results:Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a BRAF fusion and 31 had BRAF mutations (13 and 19 with class 2 and 3 mutations, respectively). There were no complete responses; 1 patient (3%) had a confirmed partial response (patient with breast ductal adenocarcinoma with BRAF G469E mutation) and 10 patients had stable disease as best response (clinical benefit rate 34%). Median progression-free survival (PFS) was 1.8 months, and median overall survival was 5.7 months. Exploratory subgroup analyses showed that patients with colorectal adenocarcinoma (n = 8) had particularly poor PFS. No new toxicity signals were identified.Conclusions:Trametinib did not show promising clinical activity in patients with tumors harboring non-V600 BRAF mutations, and the subprotocol did not meet its primary endpoint.

Supplementary Figure 2: "Swimmer's plot as in Figure 2B also demonstrating mutation locations in individual patients, showing treatment duration for all 32 evaluable patients and their occurrence of response (*), disease progression (+) and death (#)

Supplemental Figures

Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival. Clin Cancer Res; 21(7); 1574–82. ©2015 AACR.

Supplementary Figure Legend

Supplementary Methods, Tables S1 and S2, Figure Legend

Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127–37. ©2017 AACR.

Climate change is increasing global-mean tropospheric temperatures, but the localised trends are uneven, including cooling the lower stratosphere and lifting the tropopause. The wind speeds are also being modified, both at the surface and aloft. A further effect, additional to wind and temperature alone, is of increasing fluctuations and severity of extreme weather. These are impacting air transport, and this will continue. The effects are known to include increased take-off distances where excess runway lengths exist and reduced payloads where they do not, increased en-route flight times, increased frequency and severity of encounters with clear air turbulence in some regions, changed patterns of wildlife — particularly bird — activity in some regions (potentially also for other anthropogenic reasons) are shifting locations of flight safety hazards, and increased burdens upon airport and associated infrastructure. There is increasing understanding and acknowledgment by companies and authorities of these effects and the importance of mitigating them, although this is not universal and there are as yet no universally understood best practices for air transport climate change mitigation.

PURPOSEWe report the results from a Foundation for the National Institutes of Health Biomarkers Consortium project to address the absence of well-validated quality control materials (QCMs) for circulating tumor DNA (ctDNA) testing. This absence is considered a cause of variance and inconsistencies in translating ctDNA results into clinical actions.METHODSIn this phase I study, QCMs with 14 clinically relevant mutations representing single nucleotide variants, insertions or deletions (indels), translocations, and copy number variants were sourced from three commercial manufacturers with variant allele frequencies (VAFs) of 5%, 2.5%, 1%, 0.1%, and 0%. Four laboratories tested samples in quadruplicate using two allele-specific droplet digital polymerase chain reaction and three (amplicon and hybrid capture) next-generation sequencing (NGS) panels.RESULTSThe two droplet digital polymerase chain reaction assays reported VAF values very close to the manufacturers’ claimed concentrations for all QCMs. NGS assays reported most single nucleotide variants and indels, but not translocations, close to the expected VAF values. Notably, two NGS assays reported lower VAF than expected for all translocations in all QCM mixtures, possibly related to technical challenges detecting these variants. The ability to call ERBB2 copy number amplifications varied across assays. All three QCMs provided valuable insight into assay precision. Each assay across all variant types demonstrated dropouts at 0.1%, suggesting that the QCM can serve for testing of an assay’s limit of detection with confidence claims for specific variants.CONCLUSIONThese results support the utility of the QCM in testing ctDNA assay analytical performance. However, unique designs and manufacturing methods for the QCM, and variations in a laboratory’s testing configuration, may require testing of multiple QCMs to find the best reagents for accurate result interpretation.

The past 20 years has seen a growing focus on the integration of Science, Technology, Engineering and Mathematics (iSTEM) disciplines in schools to provide students with authentic experiences in solving real-world problems. A frequently stated aim for iSTEM projects has been increasing engagement and interest in pursuing STEM subjects in senior high school and tertiary studies. In order to better understand the iSTEM projects’ landscape in school classes, this systematic literature review analysed empirical studies of integrated STEM projects carried out in secondary schools to answer the following questions: What are the characteristics of the projects described and to what extent do these projects reflect characteristics of effective STEM projects; and to what extent does research into iSTEM projects in classrooms investigate specific methods of integration of STEM domains? Thirty-five peer-reviewed publications were identified from database searches that met the following inclusion criteria: (a) integrating two or more of the STEM areas, (b) middle/high school education and (c) explicitly describing the research intervention. The review revealed a diversity of iSTEM approaches in the literature, with Engineering and Science, particularly Physics, the most commonly integrated fields. Concerns are raised about the degree to which projects are relevant to students and their context and address the diversity found within student cohorts. A gap was found in the literature in detailing how teachers and students enact integration of STEM skills in these projects.

We describe a novel technique, based on image compression and machine learning, for transverse phase space tomography in two degrees of freedom in an accelerator beamline. The technique has been used in the CLARA accelerator test facility at Daresbury Laboratory: results from the machine learning method are compared with those from a conventional tomography algorithm (algebraic reconstruction), applied to the same data. The use of machine learning allows reconstruction of the 4D phase space distribution of the beam to be carried out much more rapidly than using conventional tomography algorithms, and also enables the use of image compression to reduce significantly the size of the data sets involved in the analysis. Results from the machine learning technique are at least as good as those from the algebraic reconstruction tomography in characterising the beam behaviour, in terms of the variation of the beam size in response to variation of the quadrupole strengths.

Background Most studies of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) measure antibody or cellular responses in blood; however, the virus infects mucosal surfaces in the nose and conjunctivae and infectious virus is rarely if ever present in the blood. Methods We used luciferase immunoprecipitation assays to measure SARS-CoV-2 antibody levels in the plasma, nose, and saliva of infected persons and vaccine recipients. These assays measure antibody that can precipitate the SAR-CoV-2 spike and nucleocapsid proteins. Results Levels of plasma anti-spike antibody declined less rapidly than levels of anti-nucleocapsid antibody in infected persons. SARS-CoV-2 anti-spike antibody levels in the nose declined more rapidly than antibody levels in the blood after vaccination of infected persons. Vaccination of previously infected persons boosted anti-spike antibody in plasma more than in the nose or saliva. Nasal and saliva anti-spike antibody levels were significantly correlated with plasma antibody in infected persons who had not been vaccinated and after vaccination of uninfected persons. Conclusions Persistently elevated SARS-CoV-2 antibody in plasma may not indicate persistence of antibody at mucosal sites such as the nose. The strong correlation of SARS-CoV-2 antibody in the nose and saliva with that in the blood suggests that mucosal antibodies are derived primarily from transudation from the blood rather than local production. While SARS-CoV-2 vaccine given peripherally boosted mucosal immune responses in infected persons, the increase in antibody titers was higher in plasma than at mucosal sites. Taken together, these observations indicate the need for development of mucosal vaccines to induce potent immune responses at sites where SARS-CoV-2 infection occurs. Clinical Trials Registration NCT01306084.

In light of the fact that technology teachers’ understandings of the nature of technology (NoT) determine students’ perceptions of NoT, this study turned attention to technology teachers, and developed a comprehensive theoretical instrument for assessing their understandings of NoT. The theoretical framework of NoT was proposed using a theory-based explanation informed by the philosophy of technology (PoT), historical, sociological and educational literature. The eight dimensions were as follows: ‘technology as object’, ‘technology as knowledge’, ‘technology as activity’, ‘technology as volition’, ‘history of technology’, ‘the role of technology in society’, ‘the relationship between science and technology’, and ‘technology as a double-edged sword’. Eight international experts were invited to review the content validity of the NoT scale, and 835 valid questionnaires answered by Chinese high school general technology teachers were used to test the reliability and convergent validity of the scale. The results showed that the NoT scale had a high reliability and good validity, which could be used to measure and assess technology teachers’ understandings of NoT. The development of the NoT scale provided a new perspective for interpreting NoT, and helped technology teachers consider how to more effectively transfer their understandings of NoT to students.

Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of PTPN2 expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.

Molecular profiling of childhood CNS tumors is critical for diagnosis and clinical management, yet tissue access is restricted due to the sensitive tumor location. We developed a targeted deep sequencing platform to detect tumor driver mutations, copy number variations, and heterogeneity in the liquid biome. Here, we present the sensitivity, specificity, and clinical relevance of our minimally invasive platform for tumor mutation profiling in children diagnosed with CNS cancer.

Owing to the influence of topography on soil properties, studies on the variability of soil properties become imperative. This study assessed spatial variability of some selected soil properties in three physiographic units: upper slope, lower slope and recent alluvial soils on channels of present active river in two locations in Bayelsa State. In each unit, one representative soil profile was dug, soil samples collected from generic horizons and analyzed. The results showed varying degree of spatial variability in physical and chemical characteristics, flooding, the source of parent materials and degree of hydromorphism; being the major determining factors. Among the soil separates, clay was highly variable in two physiographic units while sand and silt showed moderate variability. Organic C was moderately to highly variable (CV=20.13 – 112.77%), while total N (36.53 – 90.01%) and available P (41.49 – 58.71%) were highly variable in all the mapping units. Calcium was moderately variable (CV=26.85%) in the upper slope, and highly variable in the middle slope (CV=43.17%) and moderately variable (CV=28.93%) in recent alluvial soils in the channel of the present active river of Elemebiri and in Trofani soils; low (CV=10.01%) in the upper slope, highly variable (CV=41.33%) in the middle slope and moderately variable (CV=22.08%) recent alluvial soils in the channel of the present active river while Mg (CV=66.79 – 80.29%) and K (CV=39.27 – 101.53%) were highly variable in the different physiographic units of the two locations. Flooding, wetness and soil fertility are major constraints to agricultural intensification that requires attention.