Favorable treatment response of bevacizumab-combined chemotherapy for advanced or recurrent invasive mucinous adenocarcinoma of the lung: A retrospective observational study.

Invasive mucinous adenocarcinoma (IMA) of the lung is a rare variant of adenocarcinoma characterized by abundant intracytoplasmic mucin within the tumor. Although IMA has poor sensitivity to conventional chemotherapy regimens used for non-small cell lung cancer, we observed a better response to the bevacizumab (BEV) regimen. In this retrospective study, we aimed to investigate the response to BEV-combined regimens in patients with IMA. Among 16 consecutive patients diagnosed with IMA between January 2016 and December 2020 at our institution and treated with systemic chemotherapy, seven patients were treated with BEV-combined regimens. The overall response rate to BEV-combined regimens was 85.7%, with six patients showing a partial response. The median progression-free survival was 6.1 months. One patient experienced respiratory failure, which was improved after administration of BEV-combined regimen. BEV-combined systemic therapy may have a favorable effect on advanced or recurrent IMA of the lung.

Immunologic aspects of 1, 2-dimethylhydrazine-induced colon tumors in rats.

Investigation of immunologic aspects of colon tumors induced in rats by 1,2-dimethylhydrazine demonstrated that: 1) An antigen in an extract of colon tumors was not detected in the normal colon. It was related to antigens in rat fetuses and did not cross-react immunologically with carcinoembryonic antigen. 2) Mucinous adenocarcinomas of the colon were significantly associated spatially with lymphoid follicles.

Induction of gastric carcinomas in nonhuman primates by N-ethyl-N'-nitro-N-nitrosoguanidine.

N-Ethyl-N'-nitro-N-nitrosoguanidine [(ENNG) CAS: 63885-23-4] was administered to 5 Macaca monkeys (Macaca mulatta and M. irus) at a concentration of 200 or 300 micrograms/ml for 11-26 months in their drinking water. Gastric carcinomas in the pyloric region were observed in all 5 monkeys between experimental months 11 and 38. Histologically, these carcinomas were mainly poorly differentiated adenocarcinomas and signet-ring cell carcinomas, and a few moderately and well-differentiated adenocarcinomas were also found. The macroscopic and histologic appearances of these carcinomas were similar to those in humans.

Effect of BCG on dimethylhydrazine induction of colon tumors in rats.

The effect of BCG injection into the colon wall on the induction of colon tumors by 1,2-dimethylhydrazine dihydrochloride (DMH) was assessed in male rats. Persistent, generalized BCG infection followed the intracolonic injection of 6.7 times 10(6) organisms in otherwise untreated rats. In rats given DMH (30 mg/kg/wk) intragastrically for 5 weeks and then infected with BCG, colon tumors developed at the same rate and in the same incidence as in uninfected rats, but more tumors were mucinous adenocarcinomas and metastasized to the abdominal lymph nodes. In a few rats with large, established colon tumors, the injection of BCG into tumors induced no apparent change in them when examined at autopsy 1-22 weeks later.

Dietary effects on chemical carcinogenesis in animal models for colon and liver tumors.

Studies of dietary effects on chemical carcinogenesis in rats have demonstrated that colon tumor induction is enhanced by increased dietary fat intake or dietary deficiency of vitamin A in some but not all cases. The enhancing effect of a high-fat diet is augmented by lipotrope deficiency. Induction of hepatic tumors by several different carcinogens also is enhanced in rats fed a high-fat diet marginally deficient in lipotropes. The dietary effects may be exerted through alteration of metabolism of carcinogens, which has been demonstrated in lipotrope-deficient rats, through immunological mechanisms, which influence induction of colon tumors, or through effects on gastrointestinal bacteria and bile acid metabolism. Demonstration of dietary effects on carcinogenesis may require utilization of combined dietary stresses that alter metabolic loads but do not seriously impair growth.

Lysosomal enzymes in macrophages of colonic tumors induced in rats by 1,2-dimethylhydrazine dihydrochloride.

Ten weekly doses of dimethylhydrazine (30 mg/kg) were given to rats to induce colonic tumors. Histochemical and electron cytochemical studies revealed a distinct pattern of lysosomal acid phosphatase and beta-glucuronidase activity in macrophages in the stroma of these neoplasms. A dramatic increase in the number of acid phosphatase-rich macrophages was present in adenomas when compared to that in normal colonic mucosa. Fewer numbers of these cells were seen in well-differentiated adenocarcinomas, and they were barely detectable in highly invasive mucinous adenocarcinomas. It is postulated that these macrophages may play a role in preventing the invasion of adenomatous neoplasms into the submucosa. Application of histochemical techniques to study macrophage lysosomal enzymes may prove a useful diagnostic tool in differentiation of human colonic tumors for prognostic evaluation.

Histogenesis and growth pattern of 1,2-dimethylhydrazine-induced rat colon adenocarcinoma.

The histogenesis and growth pattern of colon adenocarcinoma have been studied using 74 BD IX rats given 20 mg 1,2-dimethylhydrazine hydrochloride per kg, s.c., weekly from Day 11 to their 24th week and serially sacrificed with controls. Modifications in DNA synthesis activity and early tumor changes were sought on histological and radioautographic preparations of normal-appearing colon mucosa. All visible colorectal tumors were analyzed for size, site, and pathology. Chronic dimethylhydrazine treatments resulted in a simultaneous increase in the number of both total and tritiated thymidine-labeled cells in the glands of Lieberkühn. In addition, microscopic carcinomatous foci were observed after the 15th week, and the first macroscopic adenocarcinomas appeared in 24-week-old animals. Their number thereafter exponentially increased with time. A total of 252 macroscopic tumors were obtained, of which 14 were classified as signet ring cell carcinomas and 238 as adenocarcinomas. Among the latter, local invasion could be documented in 230, including the smallest. No benign polypcancer sequence could be demonstrated in this material. The average growth pattern of those adenocarcinomas could be adequately described by a Gompertz curve, with a short initial doubling time (e.g., 7.5 days in 1.0-cu mm tumors) that progressively increases with time (e.g., 59.6 days in 5000-cu mm tumors).

Mucinous (colloid) carcinoma of urinary bladder following long-term cyclophosphamide therapy for Waldenstrom's macroglobulinemia.

Carcinoma of the urinary bladder is a known complication of cyclophosphamide therapy. Almost all such cases have been transitional cell carcinomas. We report here the second example of an adenocarcinoma of bladder and the first purely mucinous (colloid) carcinoma of urinary bladder developing after long-term cyclophosphamide therapy. The patient, a 77-year-old woman, had been treated for Waldenstrom's macroglobulinemia for at least 24 years, during which time treatment for this disease varied from 50 to 100 mg per day. The disease terminated in acute myelogenous leukemia, and she died of severe disseminated intravascular coagulopathy associated with hypermacroglobulinemia. The mucinous (colloid) carcinoma of the urinary bladder was an incidental finding at autopsy.

Attenuation of vasoactive intestinal peptide enhancement of colon carcinogenesis by ornithine decarboxylase inhibitor.

The effects of combined administration of vasoactive intestinal peptide (VIP) and the ornithine decarboxylase (ODC) inhibitor, 1,3-diaminopropane (DAP), on development of colon tumors induced by azoxymethane (AOM), on ODC activity of the colon wall, and on the labelling index of colon epithelial cells were investigated in inbred Wistar rats. Rats received weekly subcutaneous injections of AOM for 10 weeks and subcutaneous injections of VIP every other day and drinking water containing DAP (2.5 milligrams) ad libitum until the end of the experiment at week 45. Administration of VIP significantly increased the incidence of colon tumors at week 45. It also resulted in significant increases in colon ODC activity and in the labelling index during administration of AOM, but not after its cessation. Administration of both DAP and VIP significantly reduced the enhanced colon carcinogenesis by VIP. The DAP significantly attenuated the VIP enhancement of colon ODC activity and of the labelling index during AOM administration. These findings indicate that ODC inhibition attenuated enhancement of colon carcinogenesis, and suggest that enhancement of colon carcinogenesis by VIP may be mediated through its polyamine biosynthesis.

Alpha 1-antitrypsin as a biomarker in azoxymethane induced intestinal tumors in F344 rats.

Alpha 1-antitrypsin (alpha 1AT) has been detected in several human tumors and is thought to be a marker of neoplastic change and progression. As the biology of azoxymethane (AOM) induced intestinal tumors in F344 rats has many characteristics of human intestinal tumors, we have investigated alpha 1AT expression in AOM induced rat intestinal tumors. Nine of 12 colonic carcinomas and 6/8 small intestinal carcinomas had alpha 1AT positive tumor cells. Only 1/11 colonic adenomas and 0/3 small intestinal adenomas contained alpha 1AT. Thus alpha 1AT is a marker of malignancy in this model. Inhibition of carcinogenesis by piroxicam and difluoromethyl ornithine inhibited alpha 1AT expression.

Pronounced inhibition by a natural anthocyanin, purple corn color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine.

The potential of purple corn color (PCC), a natural anthocyanin, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH), receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PCC was given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PCC-treatment-related changes in clinical signs, body weight and food consumption were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by PCC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci by PhIP tended to be decreased by the PCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PCC in the diet, under the present experimental conditions.

Cell proliferation and cell loss in intramucosal signet ring cell carcinoma of canine stomachs induced by N-ethyl-N'-nitro-N-nitrosoguanidine.

Signet ring cell carcinoma was induced in canine stomachs by N-ethyl-N'-nitro-N-nitrosoguanidine, and modes of cell proliferation and turnover in the carcinoma were studied by 3H-thymidine autoradiography in conjunction with morphometric analysis. From 2 to 15 months after the cessation of 8 months carcinogen treatment, carcinomas in an early stage were obtained. Most of the cancer tissues confined to the lamina propria showed a layered structure. This comprised three layers; the superficial and the deep layer were composed of signet ring cells, and the middle layer was composed of small round cells. The dogs were labeled with 3H-thymidine by s.c. injection and by local infusion of the celiac artery. Flash-labeled autoradiographs revealed that most 3H-thymidine incorporating cancer cells were located around the middle layer, with a small amount of mucin. Using a pulse labeling experiment, those labeled carcinoma cells were shown to migrate from the middle layer towards the surface. Morphometric analysis of the autoradiographs showed that the small cells in the middle layer migrated upwards and produced mucin to become full-blown signet ring cells by 5.5 days. In 15 days, most labeled cancer cells in the superficial layer had disappeared. This mode of cellular turnover appeared to mimic a cell renewal system of the normal gastric mucosa. If the cancer cells turn over in this way, the tumor must grow slowly, remaining as an intramucosal cancer for a relatively long period.

A mode of incipient growth in chemically induced signet ring cell carcinoma of the canine stomach.

A 31-month-old female mongrel dog was orally administered with 50 mg or 100 mg of N-nitrosobutylurea (NBU) in gelatin-capsule 3 times per week for 19 months with interposing periods of complete suspension. Thirty-four foci of signet ring cell carcinoma were found in the antral region of the stomach. The majority of the foci (31 foci) were early cancer, and the remaining foci were invasive cancer. In addition to these lesions, there was "a single gland cancer" in which a row of cancer cells was confined to a single gland. The whole gland was composed of two cell layers; the inner layer facing the lumen was normal gastric cells and the outer layer was atypical or neoplastic cells underlaid by the basement membrane. Mitosis was frequently observed on the bottom of the gland. Atypical or neoplastic cells seemed to mature gradually through a process of upward migration with increase in cytoplasmic Alcian blue-PAS and HID-AB positive mucin. Some of the cells rich in mucin moved into the lamina propria. The other cells remained in the flow of the regular cell renewal system of the normal gastric cells and reached the top of the gland. This observation revealed a mode of incipient gastric cancer growth, which starts and spreads within a single gland, before it invades the surrounding lamina propria.

Genesis of 1,2-dimethylhydrazine-induced colon cancer. A light and electron microscopic study.

Rats treated with 1,2-dimethylhydrazine (DMH) exhibited colonic mucosal dysplastic foci prior to the development of tumors. Ultrastructurally, these, as well as the cancers that subsequently developed, were characterized by alterations in plasma membranes and an increase in cytoplasmic ribosomal particles, principally in stem cells and their absorptive derivatives. Rare Kulchitsky cells appeared preserved, but the mucin-producing or goblet-cell elements were compressed and atrophic. In addition, nuclear aberrations were more pronounced in the cancer than in the dysplastic foci. The principal ultrastructural difference between the so-called well-differentiated and mucinous forms of DMH-induced cancers was the presence of frequent intracytoplasmic lumens in the mucinous form. Such structures represented the analogues of signet ring cells observed by light microscopy. This experimental model of human colonic cancer shows that the mucosal stem-cell and dysplastic lesions represent their cytogenetic and histogenetic progenitors.

Enhancing effect of preadministration of carbon tetrachloride on methylazoxymethanol acetate-induced intestinal carcinogenesis.

This study concerns the modifying effect of carbon tetrachloride (CCl4) on methylazoxymethanol acetate (MAM)-induced intestinal carcinogenesis in ACI rats of both sexes. Forty five animals were given CCl4 (0.5 ml/kg body weight) through a stomach tube, followed by an i.p. injection with MAM (25 mg/kg body weight) 24 hours after CCl4 treatment. The paired administrations were done once a week for 4 weeks and animals were observed until sacrifice 30 weeks later. Pretreatment with CCl4 caused not only early death from chemical toxicity of MAM but also an increase in small-bowel tumors.

[Immunologic results obtained with an experimental system oftransplantable colonic tumors. Possible applications of these results to human intestinal tumors]. / Résultats immunologiques obtenus avec un systéme expérimental de tumeurs coliques greffables. Applications possibles de ces résultats aux tumeurs intestinales humaines

Intestinal cancers, morphologically very close to human colo-rectal adeno-carcinoma, have been induced by dimethylhydrazine in inbred rats. Graftable lines have been obtained from 5 primary intestinal tumors, and 3 cell lines have been cultivated from the grafts. This model was used to demonstrate carcinofetal antigen(s) on the surface of the intestinal cancer cells. Circulating antibodies against tumor-associated antigen(s) have been found in tumor-bearing rats. Cancer enhancement was regularly observed when specific (tumor cells) and non-specific (B.C.G.) immunologic treatments were used to prevent or cure rat intestinal tumors. These results suggest that immunotherapy of human colo-rectal cancer might be hazardous.

[Colonic cancer induced by 1,2-dimethylhydrazine (DMH) in rats after partial colectomy].

Using colonic cancer induced by DMH as experimental model, carcinogenic rate in the rats with or without partial colectomy was compared in order to study the etiology of the local recurrence of large bowel cancer after radical resection and observe the influence of operative injury on carcinogenesis. Sixty five male Wistar rats were divided into two groups: 48 with a partial colectomy (group 1) and 17 controls (group 2). All were given subcutaneous injection of DMH 20 mg/kg weekly for twenty weeks. Then, some rats were killed on scheduled time, the others were sacrificed in the 29th week. The results showed that carcinogenic rate was 87.5% and 58.8% in groups 1 and 2 (P less than 0.05). The tumor number in anastomotic site in group 1 (57.1%) was much higher than that at corresponding site in group 2 (28.6%) (P less than 0.05). It is suggested that the trauma itself be one of the promoting factors for cancer recurrence in addition to implantation during operation, residual tumor, etc. Large bowel cancer induced by DMH in rats may be used as an experimental model in studying the same cancer in the human being. Furthermore, after having given DMH, large bowel cancer incidence of the rats in different intervals is described.

[So-called pseudolymphomatosis of the stomach]. / O tak nazyvaemom psevdolimfomatoze zheludka

An observation of a polymorphnocellular variant of pseudolymphomatosis of the stomach diagnosed retrospectively is described. Initially, the case was treated as lymphogranulomatosis of the stomach, and in connection with the latter the patient was given long-term immunodepressive therapy. At autopsy (6 years later) atrophy of the lymphoreticular tissue and mucinous carcinoma of the stomach were revealed. The authors hold that the second tumour developed against the background of the immuno-depressive therapy, whereas at the beginning the condition was pseudolymphomatosis.

[Development and progression of undifferentiated carcinomas in the stomach].

Pathohistological studies of resected human stomachs and of experimental gastric cancers induced by ENNG have revealed that undifferentiated carcinomas arise at the neck region of glandular tubules both in the fundic and the pyloric mucosa, and tumor cells disclose the earliest invasion in the lamina propria by dripping from the glandular tubule. At earlier stages, the carcinoma cells tend to be confined to the middle level of the mucosa, and they extend to the horizontal direction of the mucosa. Most carcinomas at earlier stages comprise the diploid cell line. When tumors grow beyond a size of 2 cm in diameter in the mucosal layer, they begin to invade into the submucosal layer. As tumors grow, aneuploid and polyploid cancer cells arise in the diploid cell population. This is a kind of tumor progression. Aneuploid cancer cells disclose a more invasiveness, and they are ready to invade into the deep layer of the gastric wall. Scirrhous cancers are mostly composed of aneuploid cells, and it is suggested that small mucosal cancers which exclusively consist of aneuploid cells may become scirrhous cancers in a relatively short period.

[Experimental minute gastric cancer induced by N-ethyl-N'-nitro-N-nitrosoguanidine in dogs].

150 micrograms/day of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was administered to a total of 8 dogs, (4 mongrels at age of 4 months and 4 beagles at age of 6 months) over a period of 8 months by Kurihara 's method. As a result of the administration, we found development of minute cancer as follows: In 3 animals, male beagle killed at 575th day, male mongrel at 1, 105th days and male mongrel at 1, 245th days, a total of 20 neoplasms of the stomach was found (18 early cancers and 2 advanced cancers). 13 of which being the minute cancer measuring less than 0.5 cm. There were 11 mucosal cancers and 2 submucosal cancers. When classified by the macroscopic pathological type, none was classified as the elevated type (I, IIa types), 5 lesions as the flat type (IIb type), and 8 lesions as the depression type (IIc type). Two lesions of submucosal cancer belonged to IIc type. When classified by the histological type, 2 were classified as papillary adenocarcinoma, 2 as well differentiated tubular adenocarcinoma, 1 as moderately differentiated tubular adenocarcinoma, 5 as poorly differentiated adenocarcinoma and 3 as signet-ring cell carcinoma.