TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade.

Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p < 0.0001) and overall survival (p < 0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.

Testing the effects of drying methods on willow flavonoids, tannins, and salicylates.

In this study, we compared the effects of several preservation methods on the secondary phenolics of the mature leaves of purple willow (Salix purpurea L., salicaceae) with results obtained with fresh leaf analyses. Conventional freeze-drying, in which the leaves were first frozen with liquid nitrogen and then placed in a freeze-dryer, produced substantial qualitative and quantitative changes in purple willow flavonoids and salicylates. Modified freeze-drying, in which leaves were put into a freeze-dryer without being prefrozen, gave concentrations that, for most secondary components, were comparable with those found in fresh leaves. Reducing the freeze-dryer chamber temperature hindered the decomposition of phenolics in prefrozen leaves and in leaves dried without prefreezing. Heat drying induced substantial changes in the composition of all phenolics, except for apigenin-7-glucoside. Vacuum drying at room temperature gave the highest concentrations for nearly all phenolics, while room-drying with desiccation gave results that were comparable with those obtained by fresh leaf analyses.

Subjective disease experience in Sjögren's syndrome. A computerized discrimination analysis.

A study was made of the ability of a computerized discrimination analysis to distinguish between primary or secondary Sjögren's syndrome on the one hand and, on the other, various rheumatic diseases which may be, but in this study were not, complicated by Sjögren's syndrome. The analysis was based on a questionnaire including 76 two- or three-scale items. Among these 76 questions, five with a maximum potential for distinguishing between various subgroups were selected and obviously represent the questions for the physician to ask when taking the patient's history. As shown by classification matrix tables, computerized analysis of questionnaires might represent a useful way to assess the prevalence of clinical cases of Sjögren's syndrome and to aid health care administrators in assessing the extent of the Sjögren's syndrome problem. In contrast, manual analysis of patients' graded answers did not provide any simple or practicable method for the diagnostic work-up of cases. Therefore it seems that subjective symptoms should not be included in the diagnostic criteria for Sjögren's syndrome, which in clinical work should be based on objective evidence alone.

Oral biopsy and fine needle aspiration biopsy from subcutaneous fat in diagnosis of secondary amyloidosis.

The reliability of oral biopsy (OB) and fine needle aspiration biopsy from subcutaneous fat (FNAB) in the diagnosis of secondary amyloidosis was compared using the specimens taken from 124 patients, 107 adults and 17 children, suffering from long lasting rheumatoid diseases. 41 of the patients (33.0%) were shown to be positive for amyloidosis with one or both methods. OB was positive in 28, FNAB in 33, and both methods in 20 patients. In addition, rectal biopsy (RB) was positive in 14 out of 43 cases, where it had been taken. In 3 patients, this method was positive for amyloidosis, although OB and FNAB were negative. Thus, the total number of patients positive for amyloidosis in this study was 44 (35.5%). The mean duration time of the disease was significantly longer in the adult and child patient groups with amyloidosis than in those without amyloidosis. The diagnostic sensitivity of OB was 64%, and that of FNAB 75%. The results speak for the use of FNAB as the first choice method in the diagnosis of secondary amyloidosis.

Fine-needle aspiration biopsy from subcutaneous fat. An easy way to diagnose secondary amyloidosis.

Secondary amyloidosis is usually diagnosed by demonstrating amyloid deposits on histological sections by Congo red staining. An alternative method is a fine needle aspiration biopsy (FNAB) from subcutaneous fat which, in this study, was carried out on 301 patients. In order to test the efficiency of FNAB we analysed 146 patients from whom in addition to FNAB one or two histological samples including 125 oral and 65 rectal biopsies were available. FNAB proved very reliable for demonstrating secondary amyloidosis as estimated by the index of sensitivity (0.82). The corresponding figures for rectal and oral biopsy were 0.97 and 0.64 respectively. Although the rectal biopsy proved to be the best method, we strongly recommend FNAB from the subcutaneous fat as the preferred method for screening and diagnosing secondary amyloidosis.

Maxillofacial fractures sustained in bicycle accidents.

The present report is an analysis of 93 patients (52 male; 41 female) treated in 1981-1983 for maxillofacial fractures sustained in bicycle accidents. These accidents accounted for 7.1% of all facial bone fractures treated during the same period. Most accidents were single vehicle accidents (88%) and took place during the summer months. Of the patients, 65% had mandibular fractures, 35% had midface fractures and 5% had fractures in both the middle and lower thirds of the face. Condylar fractures were by far the most common of the mandibular fractures (67%)--a result which differs from studies concerning the profile of mandibular fractures in general. The majority of the middle third fractures were zygomatic (65%). Multiple injuries were diagnosed in 38% of the cyclists and other head injuries were the most common associated injury. Mean hospitalization of the in-patients (38%) was 4.1 days and the average sick leave was 14 days. The results of the study indicate that the use of protective helmets should be strongly recommended to cyclists, although most commercially available helmets do not protect the whole facial area and especially not the chin.