Case Report: Partial Response Following Nivolumab Plus Docetaxel in a Patient With EGFR Exon 20 Deletion/Insertion (p.N771delinsGF) Mutant Lung Adenocarcinoma Transdifferentiated From Squamous Cell Carcinoma

The histological transformation from lung squamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) and p. N771delinsGF mutations in EGFR exon 20 (ex20) are exceedingly rare in non–small cell lung carcinoma (NSCLC). EGFR ex20 mutations are insensitive to EGFR tyrosine kinase inhibitors in NSCLC. Here, we present a 76-year-old male smoker harboring LUAD with a novel p. N771delinsGF deletion/insertion mutation in EGFR ex20 transdifferentiating from advanced LUSC after chemoradiotherapy. The patient presented reduced hydrothorax and relieved tightness with the treatment of nivolumab plus docetaxel and carboplatin after the failure of second-line chemotherapy. The case highlights the importance of rebiopsy and molecular retesting after the progression of lung cancer and supports the idea that the combination of immune checkpoint blockade and chemotherapy may be an attractive option for patients with EGFR ex20 mutations associated with LUSC–LUAD transformation.

Cochlear implantation in a Chinese patient with a novel frameshift variant in POU3F4 gene and incomplete partition type III: a case report

Variations in the POU Class 3 Homeobox 4 ( POU3F4) gene are associated with X-linked mixed deafness. Here, the identification of a novel variant of POU3F4 in a male paediatric patient (the proband) with incomplete partition type III (IP-III) hearing impairment, is described. Clinical data were collected from the proband and his biological parents. Whole exome sequencing of the proband revealed a novel frameshift insertion mutation in POU3F4 (c.717_718ins GTGCCTTGCAG : p.Leu240Valfs*5) in a hemizygous state. This variant likely truncates the protein within the POU-specific domain, and the proband’s biological mother was found to be a carrier of this variant. After excluding all contraindications, the proband underwent cochlear implantation in the right ear in June 2020. Cerebrospinal fluid (CSF) gushing was observed during surgery, but there were no postoperative complications, such as CSF leak, meningitis, or facial nerve stimulation. A novel pathogenic frameshift variant of POU3F4 was identified, enriching the known mutation spectrum of POU3F4. Effective perioperative prevention and response measures should be taken to reduce the incidence of CSF gushing and meningitis in patients receiving IP-III cochlear implantation.

Molecular Mechanisms Driving the In Vivo Development of KPC-71-Mediated Resistance to Ceftazidime-Avibactam during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections

In this study, we report an ST11-type clinical CRKP isolate that produces KPC-71, a novel plasmid backbone KPC variant that confers the development of CZA resistance during treatment. Furthermore, we reveal that resistance to CZA is mediated by the 182S insertion mutation in the KPC enzyme, which increases ceftazidime affinity and decreases avibactam inhibition.

Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin

The emergence of a heavily mutated SARS-CoV-2 variant (B.1.1.529, Omicron) and it’s spread to 6 continents within a week of initial discovery has set off a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its shared or distinctive clinical phenotypes with other SARS-CoV-2 variants. We compared the mutations of Omicron with prior variants of concern (Alpha, Beta, Gamma, Delta), variants of interest (Lambda, Mu, Eta, Iota and Kappa), and all 1523 SARS-CoV-2 lineages constituting 5.4 million SARS-CoV-2 genomes. Omicron’s Spike protein has 26 amino acid mutations (23 substitutions, two deletions and one insertion) that are distinct compared to other variants of concern. Whereas the substitution and deletion mutations have appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) has not been previously observed in any SARS-CoV-2 lineage other than Omicron. The nucleotide sequence encoding for ins214EPE could have been acquired by template switching involving the genomes of other viruses that infect the same host cells as SARS-CoV-2 or the human transcriptome of host cells infected with SARS-CoV-2. For instance, given recent clinical reports of co-infections in COVID-19 patients with seasonal coronaviruses (e.g. HCoV-229E), single cell RNA-sequencing data showing co-expression of the SARS-CoV-2 and HCoV-229E entry receptors (ACE2 and ANPEP) in respiratory and gastrointestinal cells, and HCoV genomes harboring sequences homologous to the nucleotide sequence that encodes ins214EPE, it is plausible that the Omicron insertion could have evolved in a co-infected individual. There is a need to understand the function of the Omicron insertion and whether human host cells are being exploited by SARS-CoV-2 as an ‘evolutionary sandbox’ for host-virus and inter-viral genomic interplay.

Complete Response of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)-Associated Renal Cell Carcinoma to Pembrolizumab Immunotherapy: A Case Report

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase (FH) gene; it manifests as cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. Here, we describe aggressive HLRCC in a 26-year-old man who presented with RCC that exhibited a novel heterozygous germline insertion mutation in exon 2 of the FH gene (c.191dupA: p.N64fs). Systemic lymph node metastasis had already occurred. The patient underwent robot-assisted laparoscopic resection of the right kidney, but new metastases appeared within 5 months postoperatively. Histological staining of the resected tumor showed high expression levels of programmed cell death-ligand 1 (PD-L1) and programmed cell death-1 (PD-1). The patient was treated with anti-PD-1 antibody as first-line therapy. After 2 years of immune checkpoint inhibitor (ICI) treatment, all lesions had disappeared; this response was maintained at 51 months. To our knowledge, this is the first successful treatment of HLRCC-RCC with single-agent immunotherapy. Our approach might be effective for patients with advanced HLRCC-RCC.