Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. PATIENTS AND METHODS: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. RESULTS: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. CONCLUSIONS: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study.

BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.

A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results.

BACKGROUND: The equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment. PATIENTS AND METHODS: Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period. RESULTS: Of 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59-1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ. CONCLUSIONS: Final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).

[Choice of the method of pancreatodigestive anastomosis after pancreatoduodenal resection].

Immediate results of 129 pancreatoduodenal resections were analyzed. All the patients were divided into 3 groups depending of the diameter of the pancreatic duct and the degree of fibrosis in pancreatic parenchyma. Two original methods of pancreatojejunostomy were used: end-loop and invaginated one. There is a high risk of pancreatic stump-dependent postoperative complications in patients with a narrow duct and loose pancreatic parenchyma. Original invaginated anastomosis reduced the rate of these complications to the number in the group of patients with a wide duct and dense parenchyma. This method has decreased postoperative lethality from 11.3 to 3.0%.

A novel computerized system for analyzing motor and social behavior in groups of animals.

We present here the VMB Tracking System, a novel method for tracking locomotor activity, posture, thigmotactic scanning behavior and social interactions of up to eight animals at a time, at a high resolution (up to+/-0.1 mm). We used a commercially available computerized system that is considerably cheaper than other available methods. This system utilizes a basic personal computer controlling three transponders ('towers') fixed in space above the tested area, where animals as small as rats stroll freely in their normal habitat or in an experimental arena. Each tower emits infra-red (IR) pulses to a transponder ('button') adhered to a plastic mount glued to a shaved area of skin on the animal's back. When the button detects the IR pulses it responds with a button-specific ultrasonic signal that is fed back to the towers. The 3D location of the buttons is calculated by triangulation. Movement parameters of each button, such as displacement trajectory, time, speed and acceleration, can be displayed on-line and stored for off-line analysis. This system can be used to track animals in any lighting conditions, and to assess drug effects on the CNS, neuromuscular junction or muscle. As an example we demonstrate the ataxic effects of pentobarbital in rats.

The use of a foam anesthesia donut for the positioning of a patient in the barber chair position.

The foam anesthesia donut proves quite useful in the positioning of the patient in the barber chair position. By placing the donut on top of the patient's face, it protects the patient's eyes from trauma by the assistants holding retractors. The endotracheal tube also can be secured to the ring, protecting it from disconnection during surgery. The inner foam of the donut, which is removed when applying to the face, also can be used to pad the ulnar nerve at the elbow.

Tips of the trade #31. The use of a Charnley retractor for intertrochanteric hip fractures.

The use of a Charnley retractor enables a surgeon in a community hospital to perform an intertrochanteric hip fracture procedure with only the aid of a scrub technician. The Charnley retractor will hold Bennett retractors placed superiorly and inferiorly to the femoral neck--thus making it easy to obtain exposure.

[The thrombocytolysis phenomenon in patients with myocardial infarct]. / Fenomen trombotsitoliza u bol'nykh infarktom miokarda.

The studies have revealed that the platelets of myocardial infarction patients are lysed when in vitro exposed to the necrotic myocardial antigen or to actomyosin proteins within this antigen, this lysis correlating with the disease clinical course. The reaction is specific. High antigen platelet lysis (greater than 14%) in the first day of myocardial infarction frequently aggravates the course of the disease. The prognosis based on this test helps single out the patients with an aggravated condition among those with myocardial infarction.

[Cytotoxic effect of the lymphocytes in ischemic heart disease]. / Tsitotoksicheskii éffekt limfotsitov pri ishemicheskoi bolezni serdtsa.

Coronary patients were shown to have a pool of sensitized killer T cells that produce a cytotoxic effect on target cells loaded with infarcted and intact myocardial antigens and on actomyosin proteins, and evidence of delayed hypersensitivity developing in association with coronary disease. Two kinds of immune shifts were identified with respect to the time of onset of this effect in acute myocardial infarction: in the first case, the appropriate level was exceeded within 2-3 weeks of the disease, and in the second case, within the first days in hospital. The disease tended to take a more severe course in patients with the second type of immune response.

Salivary secretion induced by L-DOPA in haloperidol-treated rats.

The effect of chronic haloperidol treatment on salivary secretion induced by L-dopa, was studied in male Sprague-Dawley rats. Dose-response relationships for L-dopa, obtained 24 h after haloperidol treatment, showed that salivary secretion was greater in rats that had been injected with haloperidol (2 mg/kg/day, i.p.) for 7 days than in controls. The threshold doses requirements were significantly reduced in that group. Pretreatment with carbidopa suppressed the salivary secretion produced by L-dopa in haloperidol-treated and control rats whose glands had been denervated. The secretory response in innervated glands was higher in haloperidol-treated animals than in controls. Haloperidol treatment also increased salivation induced by L-noradrenaline as determined by dose-response relationships. This was associated with a decrease in the threshold doses requirement. In controls and in rats chronically treated with haloperidol, the salivary responses to L-noradrenaline were temporarily depressed by 80-90% by a prior acute injection of haloperidol (2 mg/kg, i.v.) presumably acting as an alpha blocker. A similar reduction was observed after acute treatment with phentolamine (3 mg/kg, i.v.). The data obtained in this study, i.e. that chronic administration of haloperidol increases the salivary response to L-dopa and L-noradrenaline, suggests that such an affect could be due to the development of supersensitivity of striatal dopamine receptors as well as of peripheral alpha-adrenergic receptors.

[Immunologic shifts at different stages of coronary disease]. / Immunnye sdvigi na raznykh étapakh koronarnoi nedostatochnosti.

Immunologic shifts and indices of nonspecific reactivity were examined in 261 coronary heart disease patients (40 patients with angina pectoris, 137 with acute myocardial infarction and 124 patients with postinfarctional cardiosclerosis). Cell-mediated and humoral immune responses to the infarctional antigen affecting the prognosis and the clinical course of the disease were determined in the acute, subacute and long-term periods of coronary pathology. Autoimmune reactions to the myocardial innate antigen can be detected at all stages of coronary heart disease. Myocardial infarction is also characterized by dysfunctions of individual links of nonspecific reactivity.

Immunological changes in the organism of patients with myocardial infarction.

The study included 261 patients with myocardial infarction in whom heart antibody titre, the index of leucocyte migration and the indicator of their agglomeration with antigen from the infarction and perinfarction region were investigated. Two variants of immunological changes occurring in acute coronary disease were identified--one characteristic of a favourable course of the disease, the second characteristic of a complicated course in the acute and late periods. In patients with prior myocardial infarction, residual sensibilization is present both after discharge from the hospital and 1 to 3 years later.

Study of the neural basis of circling behavior induced by L-dopa in lesioned entopeduncular cats.

Experiments were carried out in cats bearing unilateral electrolytic lesion of the entopeduncular nucleus. The animals were tested for circling 1-2 weeks after surgery. Postoperatively the cats displayed transient spontaneous ipsiversive turning. The administration i.p. of L-DOPA (80 mg/kg) plus CarbiDOPA (30 mg/kg), suspended in 10% Tween 80, induced rotational behavior toward the lesioned side. This effect began about 26 min after drug administration and reached its maximum 40-110 min after the injection. Electrolytic lesions placed in the superior colliculus, strionigral pathway or pedunculopontine nucleus, contralateral to the lesioned entopeduncular nucleus did not modify the circling behavior induced by L-DOPA. Similar results were observed following unilateral lesion of the sensorimotor cortex or the VL thalamic nucleus. These results suggest that the circus movements induced by L-DOPA, in animals with unilateral lesion of the entopeduncular nucleus, is not mediated by the classic outflow of the striopallidal system.