Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)

PURPOSE Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for <= 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup. RESULTS At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment

NRP1 haploinsufficiency predisposes to the development of Tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. It involves anatomical abnormalities that change the normal flow of blood through the heart resulting in low oxygenation. Although not all of the underlying causes of TOF are completely understood, the disease has been associated with varying genetic etiologies including chromosomal abnormalities and Mendelian disorders, but can also occur as an isolated defect. In this report, we describe a familial case of TOF associated with a 1.8 Mb deletion of chromosome 10p11. Among the three genes in the region one is Neuropilin1 (NRP1), a membrane co-receptor of VEGF that modulates vasculogenesis. Hemizygous levels of NRP1 resulted in a reduced expression at the transcriptional and protein levels in patient-derived cells. Reduction of NRP1 also lead to decreased function of its activity as a co-receptor in intermolecular VEGF signaling. These findings support that diminished levels of NRP1 contribute to the development of TOF, likely through its function in mediating VEGF signal and vasculogenesis

NRP1 haploinsufficiency predisposes to the development of Tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. It involves anatomical abnormalities that change the normal flow of blood through the heart resulting in low oxygenation. Although not all of the underlying causes of TOF are completely understood, the disease has been associated with varying genetic etiologies including chromosomal abnormalities and Mendelian disorders, but can also occur as an isolated defect. In this report, we describe a familial case of TOF associated with a 1.8 Mb deletion of chromosome 10p11. Among the three genes in the region one is Neuropilin1 (NRP1), a membrane co-receptor of VEGF that modulates vasculogenesis. Hemizygous levels of NRP1 resulted in a reduced expression at the transcriptional and protein levels in patient-derived cells. Reduction of NRP1 also lead to decreased function of its activity as a co-receptor in intermolecular VEGF signaling. These findings support that diminished levels of NRP1 contribute to the development of TOF, likely through its function in mediating VEGF signal and vasculogenesis

Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to <i>SF3B4</i> Mutations in Rodriguez Acrofacial Dysostosis

<div><p>The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in <i>SF3B4</i>, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an <i>SF3B4</i> mutation. We identified heterozygosity for <i>SF3B4</i> mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the <i>DLX5</i>, <i>DLX6</i>, <i>SOX9</i>, and <i>SOX6</i> transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how <i>SF3B4</i> mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.</p></div

SF3B4 and DLX5 are co-expressed in the human growth plate.

<p>Immunohistochemical staining of the distal femur growth plate from a control fetus with (A) anti-SF3B4 and (B) anti-DLX5 antibodies. The hypertrophic zone is marked with double arrows. The periosteum is identified by white arrows. Images were obtained at 20X (SF3B4) and 10X (DLX5) magnification. Scale bars are 100 μM.</p

Mutations in <i>SF3B4</i>.

<p>(A,B) Electropherogram representation of genomic DNA fragments from controls (top), (A) case R14-123A (bottom), (B) case R08-269B (bottom). (C) The insertion in the <i>SF3B4</i> cDNA of R14-123A (bottom) as compared with control (top). The positions of the insertion mutations are indicated by arrows. (D) Schematic diagram of predicted protein alterations caused by <i>SF3B4</i> frameshift mutations. The blue bars correspond to the reference amino acid sequence and the red bars indicate altered amino acid sequences that begin at the mutation site. RNA recognition motifs (RRM) are shown as purple ovals.</p

Pronounced disorganization of hypertrophic chondrocytes caused by <i>SF3B4</i> mutations.

<p>Toluidine blue staining of the distal femur growth plate from (A) a control fetus, (B) R14-123A, (C) R08-269A and (D) R08-269B. The hypertrophic zone is marked with double arrows. Images were obtained at 20X magnification. Scale bars are 100 μM.</p

Skeletal developmental genes with reduced expression in R08-269A.

<p>Skeletal developmental genes with reduced expression in R08-269A.</p

Radiographic phenotypes of cases R14-123A and R08-269A & B.

<p>(A) A/P radiograph of the chest of R14-123^a showing small scapulae, 11 ribs, and abnormally formed hypoplastic humeri with radioulnar synostosis. (B) Hand radiograph showing oligodactyly, hypoplastic carpal bones and preaxial polydactyly. (C) Bilateral lower extremities showing hypoplastic or absent fibulae with small stippled calcanei. (D) A/P radiograph of R08-269A showing hypoplastic radii, oligodactyly, absent thumbs, thin fibulae, and club foot. (E) A/P radiograph of R08-269B showing 11 ribs, absent radii and ulnae.</p

SF3B4 mutation leads to altered splicing.

<p>(A) Bar graph representation of altered splicing events in case R08-269A. The number of events in each category is indicated, with exon exclusion to the left (blue bars) and exon inclusion to the right (red bars). (B) GO enrichment analysis of alternative splicing events. The number of genes in each GO term is shown. SE, skipped exon; MXE, mutually exclusive exon; A5SS, alternative 5’ splice site; A3SS, alternative 3’ splice site; RI, retained intron.</p