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Introduction: MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial., Methods: Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay., Results: Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression., Conclusion: The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data., (Copyright © 2021. Published by Elsevier Inc.)

Background: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer., Methods: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m 2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual., Findings: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group)., Interpretation: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required., Funding: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A common rationale in molecular diagnostic laboratories is that implementation of next-generation sequencing (NGS) enables simultaneous multigene testing, allowing increased information benefit compared with non-NGS assays. However, minimal published data exist to support this justification. The current study compared clinical diagnostic yield of TruSight Tumor 26 Sequencing Panel (TST26) in melanoma, colorectal (CRC), and gastrointestinal stromal (GIST) tumors with non-NGS assays. A total of 1041 formalin-fixed, paraffin-embedded tumors, of melanoma, CRC, and GIST, were profiled. NGS results were compared with non-NGS single-gene or single-variant assays with respect to variant output and diagnostic yield. A total of 79% melanoma and 94% CRC tumors were variant positive by panel testing. TST26 panel improved serine/threonine-protein kinase B-raf (BRAF) variant detection in melanoma compared with single-variant BRAF Val600Glu/Lys (V600E/K) routine tests by 24% and detected variants in genes other than BRAF, NRAS, and KIT, which could impact patient management in 20% additional cases. NGS enhanced diagnostic yield in CRC by 36% when compared with routine single-gene assays. In contrast, no added benefit of NGS-based testing for GIST tumors was observed. TST26 panel either missed or inaccurately called complex insertion/deletion variants in KIT exon 11, which were accurately identified by non-NGS methods. Findings of this study demonstrate the differential impact of cancer site and variant type on diagnostic test information yield from NGS assays., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: KRAS and TP53 are common mutations in non-small-cell lung cancer (NSCLC). The Lung Adjuvant Cisplatin Evaluation Biological Program group found adjuvant chemotherapy to be deleterious in patients with coexisting KRAS/TP53 mutations., Patients and Methods: To validate these results, patients with NSCLC tested for KRAS and TP53 mutations and receiving chemotherapy for any stage NSCLC were selected. Mutation status was analyzed using next generation sequencing (Illumina) or multiplex recurrent mutation detection (MassARRAY, Agena Biosciences) assays, and was correlated with clinical and demographic data. Disease-free (DFS) or progression-free survival (PFS) was the main endpoint, and overall survival (OS) was the secondary endpoint., Results: Among 218 patients, 28 had coexisting KRAS/TP53 mutations, 77 TP53, 37 KRAS, 76 had neither KRAS nor TP53 mutation (WT/WT). There was no DFS/PFS difference for the KRAS/TP53 group versus all others among 99 patients who received adjuvant chemotherapy (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.61-2.44; P = .57), 27 stage III patients who received chemo-radiation (HR, 0.87; 95% CI, 0.32-2.38; P = .8), and 63 patients who received palliative chemotherapy (HR, 0.68; 95% CI, 0.31-1.48; P = .33). OS was longer in the WT/WT group compared with any other group (KRAS: HR, 1.87; 95% CI, 1.02-3.43; P = .043; TP53: HR, 2.17; 95% CI, 1.3-3.61; P = .0028; KRAS/TP53: HR, 2.06; 95% CI, 1.09-3.88; P = .026). No OS difference was seen for KRAS/TP53 compared with the other groups (HR, 1.26; 95% CI, 0.75-2.13; P = .38)., Conclusions: There was no significant difference in DFS/PFS between the 4 groups. However, OS was longer for patients with TP53 and KRAS wild-type NSCLC who received chemotherapy for any stage compared with patients with KRAS, TP53 mutation, or double mutant tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Following initial characterization of the reference human genome, initiatives have evolved worldwide to identify genomic aberrations in cancer with the aim of deriving diagnostic, prognostic and predictive information. However, the functional and clinical relevance of many somatic variants in cancer are presently unknown and there is no consensus definition of 'actionability' for genomic aberrancies. Therefore, while robust detection of a variety of genetic aberrations in clinical specimens remains a technical hurdle, the greater challenge lies in the interpretation of these alterations. Critical evaluation of genomic variation in cancer requires the integration of available clinical and preclinical evidence related to their frequencies, functions and roles as therapeutic targets. Many publicly accessible data resources have compiled such evidence to facilitate the understanding of genomic results and ultimately translating results to clinical action. Information for these data resources is derived from various sources including large population genomic datasets, curation of published literature, and data sharing by the scientific community. Currently, there is no widely accepted guidance to definitively assess and integrate the diagnostic, prognostic and predictive information of somatic variants using these knowledge databases. This review will describe data resources pertinent to the identification and interpretation of actionable genomic aberrations by clinicians, and highlight relevant issues in the clinical application of tumor molecular profiling results., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Auditory development is disrupted without normal hearing but might proceed to some extent depending on the type and onset of deafness. We therefore hypothesized that activity in the auditory cortex would be highly variable in children who are deaf., Methods: To answer this, activity in the deaf brain was evoked by electrical pulses from newly provided bilateral cochlear implants (CIs) in 72 children (n=144 responses)., Results: Responses were categorized by visual inspection into 3 main types which were validated by principal component cluster analyses; 49% had a negative amplitude wave similar to that previously reported in pre-term infants, 26% were dominated by a positive peak typical of responses in young normal hearing children and experienced paediatric CI users, 25% were novel multi-peaked responses. No significant demographic differences, including duration and onset of deafness, were found between response types. However, children with severe biallelic mutations of GJB-2 showed predominately negative peak type responses (79%) as compared with their peers without these mutations who had a more equal distribution between cortical response types., Conclusion: Cortical development in children who are deaf is heterogeneous but can be better predicted when the genotype is known to be a GJB-2 mutation., Significance: Remediation of childhood deafness seeks to restore normal development and function of central auditory functions and thus may need to be tailored to account for effects specific to the aetiology of deafness., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Delivering recombinant therapeutic proteins from a universal microencapsulated cell line is an alternate method for gene therapy. It has proved effective in the treatment of several murine models of human genetic diseases. However, in scaling up to large animal models, intraperitoneal Implantations of these microcapsules in canines were associated with excessive Inflammatory response and rapid degradation. We now show that subcutaneous implantation of microencapsulated cells in canines is effective in delivering recombinant product systemically for extended periods, provides a surgically benign site, leads to less inflammatory response, and permits longer-term survival of microcapsules. Allogeneic MDCK cells engineered to secrete human growth hormone (hGH) were microencapsulated in alginate-poly-L-lysine-alginate and implanted subcutaneously. Systemic delivery of hGH was evident within 4 hours and peaked by day 1 after implantation in all dogs. The gradual decline of hGH in the circulation in the first 2 weeks coincided with the development of anti-hGH antibodies by day 11. The high titer persisted for more than 1 month, demonstrating indirectly the persistent delivery of hGH. Microcapsules retrieved from the subcutaneous implant maintained their structure throughout the experiment and were free of host cellular adhesions. The mechanical integrity of the subcutaneously implanted microcapsules also appeared superior to that of the intraperitoneal implant. Hence the subcutaneously implanted microcapsules required minimal surgical intervention and led to a low level of inflammatory response, and the implant survived for at least 1 month, thus demonstrating the feasibility of systemic delivery of recombinant products via subcutaneous implantation in large animals.