Henry C. Pitot

BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.

In a pedigree derived from a mouse treated with the mutagen ethylnitrosourea, a mutation has been identified that predisposes to spontaneous intestinal cancer. The mutant gene was found to be dominantly expressed and fully penetrant. Affected mice developed multiple adenomas throughout the entire intestinal tract at an early age.

BACKGROUND: The carcinoid syndrome is a rare cause of acquired valvular heart disease. Although the typical echocardiographic features of carcinoid heart disease are well recognized, this large series provides new information about unusual manifestations of the disease as well as the role of Doppler echocardiography. METHODS AND RESULTS: Between 1980 and 1989, 132 patients with carcinoid syndrome underwent echocardiographic study. The echocardiographic, Doppler, and clinical features of the 74 patients (56%) with echocardiographic evidence of carcinoid heart disease are described. Among these patients, 97% had shortened, thickened tricuspid leaflets. Tricuspid regurgitation was present in all 69 patients with carcinoid heart disease who underwent Doppler examination, and it was of moderate or severe degree in 62 patients (90%). Severe tricuspid regurgitation was characterized by a dagger-shaped Doppler spectral profile with an early peak pressure and rapid decline. The pressure half-time was prolonged (mean, 116 msec), which is consistent with associated tricuspid stenosis. The pulmonary valve appeared thickened, retracted, and immobile in 36 patients (49%) and was diminutive to the extent of not being visualized in an additional 29 patients (39%). Among the 47 patients who underwent Doppler evaluation of the pulmonary valve, regurgitation was present in 81%, and stenosis was present in 53%. Left-sided valvular involvement was present in five patients (7%), four of whom had patent foramen ovale or carcinoid tumor involving the lung. Previously undescribed myocardial metastases were present in three patients (4%) and were confirmed by biopsy in each case. Small pericardial effusions were present in 10 patients (14%). Patients with and without echocardiographic evidence of carcinoid heart disease did not differ with regard to sex, age, location of the primary tumor, duration of diagnosis, or duration of symptoms of carcinoid syndrome. However, the mean pretreatment level of urinary 5-hydroxyindoleacetic acid was higher in patients with carcinoid heart disease than in patients without carcinoid heart disease (270 versus 131 mg/24 hrs, p < 0.001). The symptom of dyspnea was more prevalent among patients with carcinoid heart disease than in patients without the disease (54% versus 27%, p = 0.003); as expected, heart murmurs were also noted more frequently in patients with disease (92% versus 43%, p < 0.0001). Treatment regimens and response to therapy were similar in the two groups. Survival of patients with echocardiographic evidence of carcinoid heart disease was reduced compared with those without cardiac involvement (p = 0.0003). ECG and chest roentgenographic findings in patients with carcinoid heart disease were nonspecific. CONCLUSIONS: The broad spectrum of carcinoid heart disease is detailed in this large series. This includes not only right-sided valvular lesions but also left-sided involvement, pericardial effusion, and myocardial metastases.