An Unusual Case of Gastrointestinal Bleeding

A 10-year-old boy presented with a 3-day history of worsening abdominal pain, fever, emesis and melena. Abdominal ultrasound revealed a right upper quadrant mass that was confirmed by computed tomography angiogram (CTA), which showed an 8 cm well-defined retroperitoneal vascular mass. 123Iodine metaiodobenzylguanidine (123MIBG) scan indicated uptake only in the abdominal mass. Subsequent biopsy revealed a paraganglioma that was treated with chemotherapy. This case represents an unusual presentation of a paraganglioma associated with gastrointestinal (GI) bleeding and highlights the utility of CTA and 123MIBG in evaluation and treatment

Additional file 2: Table S1. of Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy

Baseline patient characteristics from CA209-003 in all treated patients. (DOCX 17 kb

Additional file 1: Figure S1. of Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy

Study design. AE = adverse event; cCR = confirmed complete response; cPD = confirmed progressive disease; CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; uCR = unconfirmed complete response; Q2W = every 2 weeks; Q8W = every 8 weeks. (PDF 860 kb

Additional file 6: Figure S4. of Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy

Exposure-response for efficacy of nivolumab by dose level in NSCLC. (A) Probability of OR vs Cminss, overall and by dose. (B) Probability of OR vs CL, overall and by dose. CL = clearance; Cminss = steady-state trough concentration; NSCLC = non-small cell lung cancer; OR = objective response. (PDF 784 kb

First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568) : Outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.</p

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial

Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials. gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14.5%, 95% CI 8.7-22.2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3 . 3 months (IQR 2.2-4.8), and median duration of response was not reached (95% CI 8 . 31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6 . 0 months, 95% CI 4.7-10.9). 20 (17%) of 117 patients reported grade 3-4 treatmentrelated adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment

RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.

BACKGROUND: Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS: We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS: Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS: Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann–La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.