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.

Gastric cellular turnover and the development of atrophy after 31 years of follow-up: a case-control study.

OBJECTIVE: Why only some patients colonized with Helicobacter pylori (H. pylori) develop atrophy, a preneoplastic change, is not known. Because gastric mucosal mass is dependent upon a balance between epithelial proliferation and turnover, we hypothesized that atrophy may develop due to increased apoptosis relative to proliferation. METHODS: Gastric epithelial apoptosis was measured by terminal deoxyuridine nucleotide nick end labeling (TUNEL) assay and proliferation by Ki-67 immunohistochemistry in gastric corpus biopsies in a unique cohort of patients followed for 31 yr (1952-1983). Sixteen patients who developed atrophy over this time were selected (cases), with two matched controls, who did not develop atrophy, for each. Apoptosis and proliferation were measured in the corpus biopsies taken in 1952. RESULTS: Cases (N = 16) and controls (N = 32) were well matched for age, sex, initial histology, and severity of H. pylori infection. In the initial (1952) biopsies, 4.3 +/- 1.7 cells (mean +/- SEM) per gland were Ki-67-positive in the cases, compared with 2.1 +/- 0.4 in controls (p = 0.48). 9.2 +/- 2.3 cells per gland were terminal deoxyuridine nucleotide nick end labeling-positive in cases, compared with 6.3 +/- 0.8 in controls (p = 0.29). Proliferation to apoptosis ratios were similar in both groups (cases, 0.38 +/- 0.16; controls 0.39 +/- 0.08, p = 0.37). CONCLUSIONS: Patients who later developed atrophy, initially had mildly (but not statistically significant) increased gastric epithelial cell proliferation and apoptosis, compared with those patients who did not develop atrophy, suggesting increased cellular turnover in the atrophy group. However, in these patients with gastritis, the ratio of apoptosis to proliferation was not a determinant of risk for development of atrophy decades later.

Long-term course and consequences of Helicobacter pylori gastritis. Results of a 32-year follow-up study.

BACKGROUND: The long-term course of Helicobacter pylori gastritis is not well known because there are few follow-up studies available, and the follow-up time has been short. METHODS: The progression of H. pylori infection and chronic gastritis was retrospectively examined in 102 patients followed up for 32 years. In all patients a blind suction biopsy from the corpus mucosa was taken in 1952, and an endoscopic re-examination with biopsy specimens from the antrum and corpus was performed in 1983. RESULTS: In the first examination 85 patients (83%) were H. pylori-positive as assessed from Giemsa-stained corpus mucosa specimens as compared with 70 H. pylori-positive patients (69%) at the end of the follow-up (1983). Two of the 17 patients who were initially H. pylori-negative became positive in 1983, implying an infection rate of 0.4% per patient-year. On the other hand, 17 of the 85 patients who were initially H. pylori-positive became negative in 1983, representing a disappearance rate of 0.6%. However, the stomach became completely normal in only eight cases, which represents a healing rate of 0.3% per patient-year. All patients with duodenal ulcer disease were H. pylori-positive at the first examination and remained so during the follow-up. In these patients chronic gastritis affected predominantly the antral mucosa, and corpus atrophy did not develop. Parietal cell antibodies appeared during the follow-up in six cases, and five of them were H. pylori-positive at the first examination. In most of these cases gastritis progressed into severe grades of corpus atrophy accompanied by the disappearance of H. pylori infection and normalization of the antral mucosa. CONCLUSIONS: New H. pylori infection and complete healing of infected mucosa may occur in adult life, but this is rare. Duodenal ulcer disease is associated with persistent H. pylori infection and absence of corpus atrophy. The appearance of parietal cell antibodies leads to progression of corpus atrophy and disappearance of H. pylori.

The relationships between chronic gastritis and gastric acid secretion.

Helicobacter pylori is the main cause of chronic gastritis in humans. Autoimmune mechanisms and Helicobacter heilmannii infection are other causes, both of which are of minor significance in a worldwide perspective. Atrophic gastritis is a quite common late consequence of H. pylori gastritis and will develop on a multifactorial basis, but not in all infected persons. The evolution of atrophic gastritis is a slow and gradually worsening process leading to subtypes, in which the antrum and corpus are affected to dissimilar extent and degree. The distal part of the stomach is the site where the atrophic sequelae (atrophic gastritis and intestinal metaplasia) of H. pylori infection occur most often. A minority of cases develop corpus-limited, or corpus-predominant atrophic gastritis. Along with the worsening of atrophic gastritis, inflammation and density of colonization of the mucosa by H. pylori tend to decrease in grade. In general, the degree of gastric mucosal inflammation, acute and chronic, is positively related to the degree of colonization of the mucosa by H. pylori. Acid secretion and local acidity are factors which modulate the ecology and density of colonization of H. pylori in the stomach, and may thus also modulate the evolution of chronic gastritis into topographically dissimilar subtypes. Acid secretion varies among individuals, this variation being perhaps caused by hereditary differences in parietal cell mass, or by differences in the sensitivity of parietal cells to hormonal or neural stimuli. It is hypothesized that in genuine hypersecretors, H. pylori colonization and subsequent gastritis with atrophic and metaplastic sequelae may be limited to the antrum, while in hyposecretors gastritis predominates in the corpus. In the latter, atrophic gastritis in the corpus then leads to further impairment of acid output. In these cases, H. pylori infection and gastritis may, finally, heal in the antrum, resulting in hypochlorhydria and atrophic gastritis that is limited to, or predominant in the corpus.

H. pylori corpus gastritis--relation to acid output.

H. pylori acquisition is the main cause of chronic gastritis in humans. After acquisition, non-atrophic gastritis appears which develops with time into atrophic gastritis in approximately one third of infected subjects. Gastritis may affect the gastric antrum, both antrum and corpus or, occasionally, corpus alone. Acid secretion and local acidity are factors which are considered to influence the ecology and flourishing of H. pylori infection in the stomach, and can, therefore, also modulate the evolution of gastritis into topographically dissimilar subtypes. In the present study, we analysed whether there occurs an association between the intensity of chronic gastritis (inflammation) of the corpus mucosa and the pentagastrin stimulated peak acid output (PAO) in 94 subjects who had an H. pylori positive, non-atrophic gastritis. It appeared that the mean PAO was significantly higher in subjects who had mild or no chronic corpus gastritis than in those who had severe corpus gastritis. The prevalence of subjects with mild or no gastritis was highest among those with a high PAO ( > or = 30 mmol/hr) and lowest among those with a low PAO ( < 30 mml/hr). Furthermore, the mean score of chronic corpus gastritis was significantly (P < 0.01) lower in those with PAO < or = 19 mmol/hr than among those with PAO > or = 40 mmol/hr. We conclude that the intensity of chronic inflammation (gastritis) in the corpus mucosa is inversely related to PAO. This supports the hypothesis that acid output may affect the course of H. pylori gastritis and can modulate the topographic distribution of gastritis in the stomach.

Rate of Helicobacter pylori acquisition among Finnish adults: a fifteen year follow-up.

BACKGROUND AND METHODS: To investigate the acquisition rate of Helicobacter pylori infection among Finnish adults, we obtained, in 1991, serum samples from 181 subjects who were shown to have histologically normal, noninfected gastric mucosa in 1974-76. RESULTS: During the 15-year follow-up period 12 (6.6%) of the 181 subjects developed H. pylori antibodies (IgG), the overall annual acquisition rate being 0.44%. The acquisition rate correlated somewhat with age. Antibodies developed in 1(4.5%) of the 22 subjects less than 40 years old (in 1991) and in 4 (31%) of 13 subjects who were 70 years old or older. If it is assumed that H. pylori acquisition is a continuous and stable event through the whole life span, and the rate is similar in all birth cohorts, the observed annual acquisition rate of 0.44% or an increase of this rate with age does not explain the current prevalence of chronic gastritis in Finland. Extrapolations of the known and estimated prevalence rates of chronic gastritis in 1974/76 and 1991 indicated rather that the H. pylori acquisition is a birth-cohort-dependent phenomenon and that most of the acquisitions occurred in childhood in every cohort (generation). After being high in childhood (less than 20 years old), the acquisition rate exponentially slowed down with age in all cohorts. CONCLUSIONS: Among adults the acquisition rate of H. pylori infection is low, and the main period of acquisition is childhood. The relationship between the acquisition rate and age is inverse and exponential.

Fall in the prevalence of chronic gastritis over 15 years: analysis of outpatient series in Finland from 1977, 1985, and 1992.

To investigate whether the occurrence of chronic gastritis (and Helicobacter pylori acquisition) has changed in Finland in the past 15 years, the prevalence rates of chronic gastritis in biopsy specimens in consecutive series of outpatients (aged 20 or more) who had undergone diagnostic upper gastrointestinal endoscopy in 1977 (702 patients), 1985 (1309 patients), or 1992 (1447 patients) were compared. The prevalences of gastritis in these series were also compared with that in a random sample (438 subjects) of people who underwent endoscopy in 1974-76. It seemed that the prevalence of gastritis was significantly lower in the outpatients in 1992 than in the random endoscopy sample in 1974-76. The reduction was most noticeable in young age groups (20-49 years) in which the decline was 38% (drop from 66% to 41%). In addition, it seemed that the prevalence of gastritis was very dissimilar in different birth cohorts. The prevalence was high (70-80%) in 1977, 1985, and 1992 in the cohorts born at the beginning of the century and lower (40-50%) in those born during later decades. The prevalence rates had remained unchanged in the same cohorts over the 15 years (from 1977 to 1992) suggesting that the people had mainly been infected with H pylori and contracted gastritis before the age of 20. In conclusion, gastritis is a cohort phenomenon and its prevalence has fallen in Finland in the last 15 years. This decrease is caused by a decline of the rate of H pylori acquisition in birth cohorts, particularly in childhood and adolescence (below age of 20).

Is Helicobacter pylori involved in the pathogenesis of the gastritis characteristic of pernicious anaemia? Comparison between pernicious anaemia relatives and duodenal ulcer relatives.

The aim of the study was to evaluate whether Helicobacter pylori could be involved in the early stages of the severe corpus atrophy that is characteristic of overt pernicious anaemia and is usually H. pylori-negative. The behaviour of H. pylori infection and chronic gastritis was studied in 159 first-degree relatives of pernicious anaemia (PA) probands and was compared with that in 137 first-degree relatives of duodenal ulcer (DU) probands. DU is as a rule associated with H. pylori infection. PA relatives showed a markedly higher prevalence of severe corpus atrophy and of parietal cell antibodies than DU relatives. However, the prevalences of H. pylori did not show significant differences between the two groups of relatives. The age-specific prevalences of H. pylori infection increased similarly in both series of relatives up to geriatric age, together with an increase in the mean scores of corpus gastritis. However, in older age the prevalence of H. pylori in PA relatives showed a marked decrease, in spite of the increase in the mean gastritis score. The present result suggests the possibility that H. pylori is involved in the early PA stages that lead to severe corpus atrophy. The later progress of gastritis seems to be dependent on factors other than H. pylori, most likely 'autoimmune' mechanisms.

Positive serum antibody and negative tissue staining for Helicobacter pylori in subjects with atrophic body gastritis.

Helicobacter pylori is rarely found in gastric biopsy specimens from individuals with atrophic gastritis of the body mucosa. To determine if subjects with atrophic body gastritis have evidence of previous infection with H. pylori, immunoglobulin G antibody to H. pylori was measured by enzyme-linked immunosorbent assay in sera of 399 Finnish subjects. In 124 subjects, multiple biopsy specimens from body and antrum had been evaluated for the presence of H. pylori by Giemsa staining. Antibody correlated well with H. pylori staining except in the subgroup with atrophic body gastritis, in whom the prevalence of seropositivity (86%) was significantly greater than the prevalence of positive staining (33%) (P less than 0.001). Twenty-five subjects had positive antibody and negative staining. This group had a significantly higher prevalence of atrophic body gastritis (80%), lower maximal acid output, lower serum pepsinogen I levels, and higher serum gastrin concentrations than did seropositive subjects with H. pylori. These data suggest that most patients with atrophic body gastritis, despite having a low incidence of current overt infection, have been infected with H. pylori at some point in their lives.

The Sydney System: epidemiology and natural history of chronic gastritis.

Chronic gastritis is a common disease which forms an important background to the pathogenesis of several gastric diseases. In most instances, gastritis seems to be a bacterial (microbial) disease. It begins as long-lasting, chronic inflammatory reaction directed against Helicobacter pylori (HP), or occasionally against other spiral bacteria, which colonize in the space between the surface epithelium and the mucous layer. Gastritis may, irrespectively of the HP-related or HP-independent origin, progress to an atrophy (chronic gastritis with atrophy) in the underlying mucosa. Prevalence of gastritis increases with increase in age, but great variations exist in the age-specific prevalence and in mean age of onset of the gastritis in different populations. A high rate and an early onset of the HP-related gastritis associates with low socio-economic status. Chronic gastritis, and the gastritis with atrophy in particular, may interfere with the function of the affected gastric mucosa, and may subsequently increase or decrease the risk of some gastric diseases, such as cancer and peptic ulcer. Both antral and corpus gastritis with coexistent severe atrophic changes have been shown to be associated with an increased risk of gastric cancer. In addition, gastritis seems to also play an important role in the pathogenesis of peptic ulcer. Virtually all patients with DU and GU have coexisting and preceding gastritis. The cumulative risk of ulcer has been estimated to be high in subjects with gastritis, but, in contrast, to be low in subjects who have normal gastric mucosa.

Characteristics of gastric mucosa which precede occurrence of gastric malignancy: results of long-term follow-up of three family samples.

The aim of the study was to evaluate what family characteristics and what morphological, functional and immunological changes of the gastric mucosa precede the development of gastric malignancy in a follow-up of 11-14 years. The material consisted of 301 first-degree relatives of gastric carcinoma patients, 183 relatives of pernicious anaemia patients, and of 358 control relatives of probands computer matched from the general population by age and sex for the carcinoma probands. All subjects were endoscopically examined in 1973-1976 and followed up to the end of 1987. According to cancer registry data, 11 cases of malignant gastric tumours (9 carcinomas, one carcinoid tumour and one anaplastic tumour with suspicion of Hodgkin's disease) had been diagnosed during the follow-up: 6 belonged to gastric carcinoma, 2 to pernicious anaemia and 3 to control families. The occurrence of malignancy was significantly related to the presence of advanced gastritis with atrophy and of intestinal metaplasia before the start of the follow-up. In relatives with achlorhydria and low serum pepsinogen I levels the incidence of malignancy did not significantly differ from that in controls of similar age and sex distribution. The risk of getting malignancy was about four-fold in female members of gastric carcinoma and pernicious anaemia families but was not increased in control families. The risk was increased only in female members and concerned only gastric malignancy being the expected one or even lower than the expected in regard to malignancies of other location.

Enrichment of combined antral and corpus atrophic gastritis ("combined AG") in sibs of gastric carcinoma patients.

The occurrence of different combinations of antral and corpus atrophic gastritis (AG) was studied in 127 sibs and 159 children of 73 gastric carcinoma patients. Seventy-three control probands, age- and sex-matched for the carcinoma probands, and their 379 first-degree relatives were used as controls. Sibs of gastric carcinoma patients revealed a significant enrichment of AG affecting simultaneously both antrum and corpus (combined AG), while no such enrichment could be demonstrated in children, who behaved on the whole similarly to the controls. In addition, sibs of gastric carcinoma patients showed a significant aggregation of combined AG also when compared with children of similar age. This suggests that genetic factors in addition to environmental ones participate in the accumulation of combined AG in sibs. The lack of phenotype AB in children excludes the possibility of dominant Mendelian inheritance, but leaves the possibility of a recessive autosomal or multigenetic inheritance. The enrichment of combined AG in sibs of gastric carcinoma patients could be one of the factors involved in the increased liability of close relatives of gastric carcinoma patients to contract gastric malignancy.

Chronic gastritis profiles in sibs of probands calculated to carry a highly increased risk of gastric carcinoma.

Of 1161 subjects consisting of 4 family samples (gastric carcinoma patient relatives, pernicious anaemia, duodenal ulcer and control families) 18 subjects representing 17 families had distinct atrophic changes in the gastric mucosa that were considered on the basis of risk calculations to carry an at least 7-fold risk to develop gastric carcinoma. Twelve of these 18 subjects could be used as probands and their 41 sibs were subjected to a closer statistical analysis. Sibs of probands having a very high relative risk of gastric carcinoma (18-fold or more) differed markedly from the general population. All sibs had some form of atrophic gastritis and there was a significantly higher than expected prevalence of subjects with severe corpus mucosal atrophy. It is concluded that sibs of subjects with severe atrophic changes may carry an increased risk of gastric malignancy.

Helicobacter pylori and duodenal ulcer. A study of duodenal ulcer patients and their first-degree relatives.

Out of 59 duodenal ulcer (DU) probands and their 199 first-degree relatives Giemsa-staining for the determination of Helicobacter pylori (HP) was performed in 51 probands and 155 relatives. Controls were matched by age and sex from a family sample representing the same geographical area. In all, 155 controls were found for the probands and relatives. The occurrence and score of HP density showed an excellent correlation with morphology of the mucosa, signs of acute inflammation and presence of gastric metaplasia in the duodenal bulb. The prevalence of HP was 94% in DU probands and significantly higher than in their relatives and controls. In sibs of DU probands the prevalence of HP (64%) was also significantly higher than in controls (51%) obviously due to the presence of a subgroup of sibs with signs of active or past duodenal ulcer disease, which show higher than expected prevalence of HP, and of acid hypersecretion and high levels of serum pepsinogen I (PG I). Peak acid output (PAO), serum pepsinogen I and II and fasting serum gastrin levels were in relatives without atrophy higher in HP positive than negative cases but significant differences were present only with regard to the pepsinogens. The occurrence of HP positivity as well as of high PAO and pepsinogen levels might be considered risk factors of DU disease in close relatives of DU probands. On the other hand, the significance of HP positivity as cause of abdominal complaints is doubtful, in view of the complete lack of correlation between HP and morphology and complaints in the present study.

Functional characteristics of duodenal ulcer patients and their first-degree relatives.

The behaviour of acid secretion, serum pepsinogen I and II (PG I and PG II) and morphology of the gastric mucosa were analyzed in 59 duodenal ulcer probands (DU probands), their 199 first-degree relatives and 228 control subjects. DU probands had as a rule antral gastritis with normal or slightly altered corpus mucosa, and higher mean peak acid output (PAO), PG I and II levels than their relatives and controls. Sibs of DU probands differed from their controls mainly with regard to morphology which showed features characteristic of DU probands, i.e. antral gastritis with normal or slightly altered corpus mucosa. Moreover, high PAO levels were found highly significantly more often in sibs of DU probands (13%) than in controls (6%). Likewise, the prevalence of endoscopic signs of active or past duodenal ulcer were present in sibs highly significantly more often than in controls and they accumulated in the subgroup of sibs with high PAO or PG I levels. It seems probable that the occurrence of high PAO and PG I levels in sibs of DU probands can be considered as signs of increased liability to duodenal ulcer. PAO and PG I were as expected significantly higher in male than in female probands, relatives and controls. Exclusion of cases of corpus gastritis decreased the levels but the sex difference persisted. PAO, PG I and II revealed a significant increase of the levels in middle age followed in older age in case of PAO and PG I by a significant decrease. The decrease was abolished when the cases of corpus gastritis were excluded suggesting an effect of gastritis. However, the earlier increase of the levels remained virtually unaffected although there was a uniform decrease of the mean values. This suggests the participation of factors unrelated to gastritis. The nature of the factors remains unknown, but literature data and data derived from our recent study suggest involvement of anatomical factors such as an increase in the size of acid and PG I secreting area.

Increase of serum pepsinogen I with age in females with normal gastric mucosa but not in males, possibly due to increase in acid-pepsin secreting area.

The mean pepsinogen I (PG I) level in a Finnish family sample was different in males and females and the difference was statistically significant. After exclusion of subjects with gastritis there remained 67 females and 68 males with morphologically completely normal antral and corpus mucosa. In females there was a significant increase of PG I with advancing age, the regression coefficient being 0.37 and statistically significant (p less than 0.01). In males no such increase was found, and individual cases revealed an almost random distribution with age. A similar increase with age has been noted in gastric acid output in females but not in males. Assuming that there is a linear relationship between PG I levels and the total chief cell mass, the PG I level would be determined by three main variables: thickness of the glandular layer, density of chief cells, and area occupied by chief cells. Of these variables the thickness and chief cell density showed neither in females nor in males any statistically significant increase with age, leaving the area as the variable which would account for the increase of PG I.

What fraction of hospital ulcer patients is eligible for prospective drug trials?

Data of all 397 gastric ulcer patients diagnosed and treated at Jorvi Hospital, Finland, during 1980-1984 were collected and the outcome followed up for 5-7 years. The commonly used exclusion criteria of prospective drug trials were applied to this series. Only 29% of patients would have been eligible for a trial. The excluded patients were older, their ulcer was larger and more proximally located. Nearly all major complications of gastric ulcer disease leading to surgery (bleeding, perforation, obstruction) and deaths due to gastric ulcer disease appeared in the excluded group. Exclusion criteria may profoundly affect the selection of patients and the results. When many patients are excluded the applicability of results to the whole material is questionable.

Helicobacter pylori and gastritis in children with abdominal complaints.

Gastroscopy with biopsies was performed in 178 children with upper abdominal pain. Of them 109 (61%) had gastritis and 104 (58%) Helicobacter pylori (HP) in antrum and/or corpus. Gastritis consisted in most cases (87% of antral and 86% of corpus gastritis) of mild superficial round cell infiltration. Mucosal atrophy was not found. Accumulation of granulocytes was present in 43 patients and lymphonoduli were found in 33 patients, usually in connection with gastritis. Gastritis affected only the antrum in 18%, only the corpus in 5% and both antrum and corpus in 62% of the cases of gastritis. There was a good correlation between morphology and bacteriology in the antrum and a satisfactory one in the corpus. However, in some cases gastritis was present without bacteria and in some cases a normal mucosa was associated with bacteria. Gastritis and HP prevalences showed a general increasing trend with age, but significances were with one exception lacking. It is tentatively concluded that gastritis begins in childhood as a slight and chronic superficial infiltration affecting usually antrum and corpus simultaneously. In the majority of cases gastritis is associated with HP infection, which seems to start the process. It is possible that the HP-related gastritis is a common cause of abdominal complaints in children; however, convincing evidence is lacking.