Neoantigen prediction and computational perspectives towards clinical benefit: recommendations from the ESMO Precision Medicine Working Group.

BACKGROUND: The use of next-generation sequencing technologies has enabled the rapid identification of non-synonymous somatic mutations in cancer cells. Neoantigens are mutated peptides derived from somatic mutations not present in normal tissues that may result in the presentation of tumour-specific peptides capable of eliciting antitumour T-cell responses. Personalised neoantigen-based cancer vaccines and adoptive T-cell therapies have been shown to prime host immunity against tumour cells and are under clinical trial development. However, the optimisation and standardisation of neoantigen identification, as well as its delivery as immunotherapy are needed to increase tumour-specific T-cell responses and, thus, the clinical efficacy of current cancer immunotherapies. METHODS: In this recommendation article, launched by the European Society for Medical Oncology (ESMO), we outline and discuss the available framework for neoantigen prediction and present a systematic review of the current scientific evidence. RESULTS: A number of computational pipelines for neoantigen prediction are available. Most of them provide peptide major histocompatibility complex (MHC) binding affinity predictions, but more recent approaches incorporate additional features like variant allele fraction, gene expression, and clonality of mutations. Neoantigens can be predicted in all cancer types with high and low tumour mutation burden, in part by exploiting tumour-specific aberrations derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other tumour-specific processes that could yield more potently immunogenic tumour neoantigens. Ongoing clinical trials will highlight those cancer types and combinations of immune therapies that would derive the most benefit from neoantigen-based immunotherapies. CONCLUSIONS: Improved identification, selection and prioritisation of tumour-specific neoantigens are needed to increase the scope of benefit from cancer vaccines and adoptive T-cell therapies. Novel pipelines are being developed to resolve the challenges posed by high-throughput sequencing and to predict immunogenic neoantigens.

Treatment of vasospastic angina pectoris at rest with nitroglycerin ointment: a short-term controlled study in the coronary care unit.

The effectiveness of nitroglycerin ointment in vasospastic angina pectoris at rest was evaluated in 10 patients selected for study. The study was performed after a 24 hour control period, and a randomized single-blind crossover experimental design was followed. Two percent nitroglycerin ointment (15 mg) or placebo ointment was administered every 6 hours for a period of 48 hours each; the first treatment period was followed by a second in which each preparation was used for a 24 hour period. All patients were hospitalized in the coronary care unit; an objective evaluation was carried out using a multichannel electrocardiographic recording to assure recognition of the painless ischemic episodes. Coronary angiography showed critical stenosis of one or two vessels in 9 of the 10 patients; spasm was demonstrated in 3. Results of the ergonovine test were positive in nine of nine patients. Nitroglycerin ointment produced a significant reduction in the mean daily number of episodes during the first (12.5 +/- 3.9 versus 0.5 +/- 0.4, p less than 0.02) as well as the second treatment period (10.6 +/- 3.8 versus 0.6 +/- 0.4, p less than 0.02). These results demonstrate that nitroglycerin ointment provides effective, long-lasting protection against angina due to coronary spasm.

Amount and duration of alcohol intake as risk factors of symptomatic liver cirrhosis: a case-control study.

We carried out a hospital based case-control study involving 320 patients with symptomatic liver cirrhosis (LC) and 320 pair-matched control individuals, in order to estimate the dose-response relationship between both the daily amount and the duration of alcohol intake and the risk of LC. Lifetime alcohol consumption was measured by a standardized and reproducible questionnaire, and expressed as lifetime daily alcohol intake (LDAI) and duration of alcohol consumption (DAC). The odds ratio (OR) for LC was estimated by the conditional logistic regression. It increased from 1.0 for lifetime abstainers to 4.2 for LDAI of 225 g or more. Comparing durations of alcohol consumption of < or = 10 and > or = 30 years in the model, the ORs consistently decreased for all the LDAI categories: from 4.1 to 0.6 in the 25-50 g category; from 15.1 to 0.9 in the 75-100 g category; from 67.2 to 1.5 in the 125 g or more category. Our results suggest that the dose-dependent relationship between alcohol and LC may be mediated by the degree of individual susceptibility to the detrimental effect of alcohol to the liver.

Changes induced by gemfibrozil on lipidic, coagulative and fibrinolytic pattern in patients with type IV hyperlipoproteinemia.

A short term open study (90 days) was carried out with Gemfibrozil in patients (n = 10) suffering from type IV hyperlipoproteinemia. For the whole observation period (120 days) the patients followed a standard diet. Every 30 days the following parameters were checked: total cholesterol, serum triglycerides, HDL-C and its fractions (HDL2-C and HDL3-C), apolipoprotein A1 and B, glucose, fibrinogen, plasminogen, euglobulin lysis time, antithrombin III, alpha-2-antiplasmin and PTT. The administration of the drug caused a reduction of serum triglycerides by 39.5%, an increase of HDL-C by 16.2% together with a significant increase of cholesterol bound to HDL2 (+27.6%). A significant increase was also noticed for the mean levels of apolipoprotein A1 (+19.8%), confirming thus the antidislipidemic effect of the drug. Significant reductions were also found in the mean levels of fibrinogen and alpha-2-antiplasmin together with a return to normality of mean values of antithrombin III and of the euglobulin lysis time. The effect on the lipid, haemocoagulative and fibrinolytic parameters shows that the administration of Gemfibrozil causes favourable changes both on the hyperlipoproteinemic pattern and on the thrombophilic state present in these patients.

Evaluation of a sustained-release buccal nitroglycerin preparation in stable angina pectoris.

The efficacy of a 2.5 mg sustained-release buccal nitroglycerin preparation given 8-hourly in effort-induced stable angina pectoris was investigated by means of graded exercise testing in 15 patients. An initial double-blind crossover study, compared with a placebo (duration six days) was followed by a further 15-day open treatment period on the active drug. Exercise testing was carried out 2 and 7 h after tablet administration at the conclusion of active treatment in the double-blind phase, and 2 h after tablet administration at the conclusion of the open treatment phase. Workload and exercise duration were significantly increased and mean electrocardiographic ST segment depression and ST segment recovery time significantly reduced by buccal nitroglycerin in the initial phase of the study, and these improvements were maintained over the subsequent 15-day assessment period. Systolic blood pressure at rest was significantly decreased by active treatment; other haemodynamic parameters remained unchanged. The study demonstrated the efficacy of sustained-release buccal nitroglycerin in effort-induced stable angina pectoris, and an absence of (+) tolerance to the therapeutic effects of this mode of nitrate administration.

Loss of color from Jiffy tubes.

Colored, disposable applicator tubes have been said to lose color to their contents during use. Since they are used to contol the placement of a variety of accessory materials important to clinical dentistry, a selection of restorative materials and solvents was evaluated to determine which had a color-leaching potential. Neither aqueous system nor alcohol, chloroform, eugenol, xylene, or ether caused a loss of color that was clinically significant. Acetone and amyl acetate caused a visibly apparent loss of color and softening of the tube matrix. Methyl methacrylate completely dissolved specimens of celluloid tubes. Unfilled resins containing methyl methacrylate in their liquid catalysts leached sufficient red color form the test specimens to stain the restorative noticeably pink; the composite resins and cements that were evaluated did not.

Gemfibrozil in CAPD patients.

Gemfibrozil was given at a daily oral dose of 600 mg to 28 CAPD patients with serum triglyceride levels higher than 200 mg/dl, after 2 months of low fat low calorie diet. Eleven patients dropped out from the study due to spontaneous withdrawal of the drug or to intercurrent hospitalization. The 17 patients who completed the study showed a significant decrease in serum total (434.6 +/- 207.9 to 237.5 +/- 81.6 mg/dl, p 0.003), VLDL (268.8 +/- 17.8 to 109.2 +/- 66.9 mg/dl, p less than 0.005) and LDL (152.9 +/- 34.6 to 119.2 +/- 30.7 mg/dl, p = 0.004) triglyceride. Serum VLDL cholesterol increased from 108.7 +/- 54.1 to 59.9 +/- 29.0 mg/dl, p = 0.003. Serum HDL cholesterol decreased from 25.4 +/- 4.8 to 35.3 +/- 6.3 mg/dl (p less than 0.001). Apo A1 increased from 117.8 +/- 16.7 to 130.8 +/- 16.7 mg/dl (p less than 0.001) and Apo B increased from 173 +/- 26.7 to 137.8 +/- 21.9 mg/dl (p less than 0.001). No clinical or laboratory side effect was observed in the patients who completed the study. Therefore dropouts were due to the poor patients' compliance rather than to the severity of side effects.

Mechanical anterior resection for carcinoma of the midrectum: long-term results.

Long term results are reported on 108 patients treated by curative mechanical anterior resection for midrectum carcinoma. The functional results were good but there was a large number of local recurrences for carcinoma at Dukes C stage (28% of the total cases). Oncological results suggest that greater importance should be given to early diagnosis and to pathogenesis and risk factors for recurrence.

[Classification of varices with Doppler ultrasonography mapping. Clinical and hemodynamic correlation]. / Classificazione delle varici con mappaggio eco Doppler. Correlazione clinica ed emodinamica.

The authors report their experience concerning the outpatient echo Doppler mapping of peripheral venous circulation in the lower limbs. Out of a total of 240 patients examined, 190 showed monolateral venous insufficiency and 50 bilateral. These results were correlated to the age of the patients and showed that saphenous pathology tended to affect the entire vein in elderly patients, whereas only partial damage was observed in young patients. Varices seemed to appear with the first signs of the insufficiency of collateral veins before signs of saphenous insufficiency became manifest.

[Action and tolerability of delayed-action buflomedil in obliterating arteriopathies of the lower limbs. A multicenter study]. / Attività e tollerabilità di buflomedil ritardo nelle arteriopatie obliteranti degli arti inferiori. Studio policentrico.

A new buflomedil retard preparation has been evaluated in 318 patients, suffering from obliterating arterial disease of the lower limbs, for 90 days at once daily 600 mg doses. After 30 days of treatment a significant (p less than 0.001) improvement of paresthesia, hypothermia and "claudicatio intermittens" has been found. The same trend has been found after 90 days with improvement of walking distance (+ 81.1%), walking time (+ 62.1%), walking speed (+ 15.0%) as well as a significant decrease of functional recovery time (-24.6%). The AA. stress the good tolerability and compliance of this new retard preparation.

[Ultrasound-guided trans-parietohepatic cholecystostomy in the critical patient: current indications]. / La colecistostomia trans-parietoepatica ecoguidata nel paziente critico: attuali indicazioni.

The appearance of acute cholecystitis can make to complicate a natural history of cholelitiasis or post-operating time of patients that have concomitant predisposition factors. The best therapy is the cholecystectomy but somewhere for the critical general conditions is too much dangerous to make a surgical procedure. However we need to stabilize patients conditions, also for a short time. Our experience suggest us that percutaneous transhepatic cholecystostomy is a simple method without any complications, efficacious to resolve the acute sepsis in patients with cholecystitis that not be able to tolerate a surgical procedure.

Identification and characterization of substance P receptors on LRM55 glial cells.

Substance P (SP) receptors were described by the specific binding of [3H]SP to several neuronal and glial cell lines. The neuronal cell lines N18 and NG108-15 were found to contain few if any SP receptors (less than 5 fmol/mg of protein). The glial cell line LRM55 contained large numbers (Bmax = 707 fmol/mg of protein) of a single class of SP binding sites (Kd = 276 pM). [3H]SP binding could be inhibited by a number of c-terminal SP fragments and the tachykinins physalaemin, eledoisin and kassinin. The binding kinetics and pharmacology of these receptors are similar to those the authors have previously described in the brain. Activation of SP receptors was shown to inhibit cyclic AMP-dependent, beta adrenergic-stimulated taurine release from LRM55 glial cells. SP inhibition must occur by mechanisms affecting taurine release after adenylate cyclase activation, inasmuch as SP has no significant effect on beta adrenergic-stimulated increases or basal levels of intracellular cyclic AMP.

Protein kinase C activity and reactivity to phorbol ester in vascular smooth muscle from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY).

Protein kinase C (PKC) activity in aortic and renal arterial smooth muscle from SHR (20-23 wk male; mean arterial pressure = 178 mm Hg) and WKY (age/sex matched; mean arterial pressure = 126 mm Hg) was quantitated. Activity was greatest in the particulate fractions relative to the soluble fractions in all sources. The only difference between SHR and WKY was in the soluble fraction from SHR renal arteries, which had 2 fold more activity (255 pmol/mg/min) when compared with WKY (136 pmol/mg/min). This difference was not apparently related to force modulation, since the magnitude of isometric force development in renal arteries in response to phorbol 12,13-dibutyrate was not different between SHR and WKY. The magnitude of force developed in response to phorbol 12,13-dibutyrate and PKC activity in the particulate fraction was greatest in aorta vs. renal arteries in both WKY and SHR. These results suggest that regional vascular differences in the amount of PKC activity may exist which are not apparently related to a disease state (i.e., hypertension). These differences may be related to differential sensitivity to phorbol ester-mediated contractions in isolated smooth muscle.

Effect of orange juice consumption on urinary pH.

The effect of orange juice consumption on urinary pH was studied in seven adult male subjects, each of whom served as his own control. The diet of the subjects was standardized during the work-day. The effects of two regimens of orange juice were studied: 1500 ml divided into five 300-ml portions during the day, and 300 ml once in the morning. Urine was collected, its pH recorded, and titrated with HCl to determine the mEq of base excreted per unit time. The consumption of 300 ml of orange juice did not significantly alter urinary pH. The consumption of 1500 of orange juice changed the urinary pH by an average of one pH unit. A change of this magnitude could cause clinically significant variation in the overall excretion pattern of acidic or basic drugs.