Summary Background Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of ...nivolumab in patients with treatment-refractory oesophageal cancer. Methods We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. Findings Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9–14·3). 11 (17%, 95% CI 10–28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one 2%) patient each), grade 3 lung infection (five 8% patients), grade 3 decreased appetite (two 3% patients), grade 3 increased blood creatinine phosphokinase (two 3% patients), and grade 3 dehydration (two 3% patients). Serious adverse events that occurred during the study were lung infection (four 6% patients), dehydration (two 3%), interstitial lung disease (two 3%), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one 2% patient each). There were no treatment-related deaths. Interpretation Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. Funding Ono Pharmaceutical, Bristol-Myers Squibb.
Hemangioma in the submandibular gland or submandibular space is rare. A 31-year-old woman was referred to our department. She became aware of painless swelling in the right submandibular gland at 9 ...months ago. The right submandibular gland showed swelling with no tenderness, and the palpation was softer than the normal submandibular gland. Magnetic resonance imaging short T1 inversion recovery (STIR) sequence showed a 38 × 29 mm well-circumscribed, lobulated mass with high signal intensity attached with the submandibular gland. Computed tomography showed phlebolith formation. A clinical diagnosis of suspected hemangioma in submandibular gland was made, and submandibular gland excision including mass was performed with submandibular approach without complications. No unusual bleeding during the surgery was observed. Pathological finding indicated that thick walled vessels containing smooth muscle were proliferated with dilatation. Some vascular lumen included phlebolith calcification. Although the boundary with the submandibular gland was mainly clear, some parts were irregularly occupied with a component of hemangioma. The final diagnosis was venous hemangioma in submandibular gland. No postoperative recurrence was recognized in 1-year follow-up. A search of PubMed revealed that only 18 cases associated with hemangioma in the submandibular gland in 12 English articles. Literature review indicated that (1) approximately 70% patients showed painful swelling and (2) x-ray or computed tomography may indicate the phlebolith calcification. It may make an erroneous diagnosis of sialolithiasis. Magnetic resonance imaging finding would be needed for the diagnosis.