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.

Primary non-clear-cell adenocarcinoma of the vagina in a diethylstilbestrol exposed woman.

A 54-year-old woman with a history of in-utero diethylstilbestrol (DES) exposure, who had a prior hysterectomy for symptomatic leiomyomata and dysmenorrhea, presented for vaginal bleeding. Vaginal biopsies showed a non-clear-cell adenocarcinoma, and the patient was subsequently treated with radiation therapy. We present a case of primary vaginal non-clear-cell adenocarcinoma in a patient with in-utero DES exposure. Continued monitoring of older DES-exposed women for vaginal lesions is warranted because of reported cases of non-clear-cell adenocarcinoma and persistent risk of clear cell adenocarcinoma.

Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study.

Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50-71 years at the time of the baseline questionnaire in 1995-1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01-1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05-1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.

Perineal talc exposure and epithelial ovarian cancer risk in the Central Valley of California.

Perineal talc use has been suggested as a possible risk factor for ovarian cancer based on its structural similarity to asbestos, a known human carcinogen. A population-based epidemiologic case-control study of epithelial ovarian cancer (EOC) was conducted in 22 counties of Central California that comprise the reporting area for 2 regional cancer registries. Telephone interviews were conducted with 256 cases diagnosed in the years 2000-2001 and 1,122 controls frequency-matched on age and ethnicity. The interview obtained information on demographic factors, menstrual and reproductive experience, exogenous hormone use, surgical history and family history of cancer. Questions on perineal talc use included frequency of use, duration of use and specific years when talc was used. Multivariate-adjusted odds ratio (OR) and 95% confidence intervals (CI) were derived from unconditional logistic regression. The OR for ever use of talc was 1.37 (CI = 1.02-1.85) compared to never users. However, no dose response association was found. Tubal ligation (TL) modified the effect of talc on EOC such that women with TL had an OR of 0.88 (CI = 0.46-1.68) associated with perineal talc use, whereas women with no TL had an OR of 1.54 (CI = 1.10-2.16). Talc use and EOC risk was highest in women with serous invasive tumors (OR = 1.77; CI = 1.12-2.81). This study provides some support for the hypothesis that perineal talc use is associated with an increased risk of EOC.

Active and passive tobacco smoking and the risk of borderline and invasive ovarian cancer (United States).

OBJECTIVE: A population-based case-control study was conducted to examine the hypothesis that active and passive tobacco smoking were associated with the risk of epithelial ovarian cancer. METHODS: In-person interviews were obtained from 558 women with epithelial ovarian cancer (431 invasive, 127 borderline) and 607 population controls regarding active lifetime tobacco smoking, environmental tobacco smoke exposure in utero and during childhood, and other factors that may be related to the development of ovarian cancer. RESULTS: No significant associations of ever or former tobacco smoking with the risk of invasive or borderline ovarian cancer were found, although long-term ex-smokers of 20 years or more were at significantly reduced risk of invasive cancer. Significant, positive dose-response relations of the number of cigarettes smoked per day and pack-years with the odds ratios for borderline cancer were evident. No association of active tobacco smoking with risk was found by histologic subtype of invasive ovarian cancer. Smokers were at significantly increased risk for borderline serous cystadenoma (OR: 1.91; 95% confidence intervals, CI: 1.09-3.34), but not for borderline mucinous cystadenoma. When we limited the analyses to current smokers, age-started smoking was significantly inversely related to the risk of invasive, but not borderline ovarian cancer. We found no association of gestational or childhood environmental tobacco smoke exposure with the risk of invasive or borderline ovarian cancer among never smokers. CONCLUSIONS: These findings do not support an association of active tobacco smoking with the risk of invasive ovarian cancer. An increased risk of borderline serous cystadenoma among smokers must be viewed with caution.

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.

The endometrium in breast cancer patients on tamoxifen.

We restudied histologically and immunohistochemically 17 endometrial carcinomas, 2 malignant mixed tumors and 180 endometria with benign changes during or after tamoxifen therapy. The carcinomas were subtyped according to the 1994 WHO-classification. Endometrial biopsies were taken only if the endometrial thickness was > 8 mm sonographically, when a polyp was seen, or for postmenopausal bleeding. About half of the endometrial specimens showed simple or cystic atrophy, 55-76% had cystic-atrophic polyps or regressive hyperplasia. Depending upon the dose of tamoxifen, 7-19% (30 mg) to 27-36% (20 mg) showed moderate glandular proliferation. 20-33% had foci of mucinous, clear cell or serous-papillary metaplasia. 68-70% revealed diffuse extensive fibrosis of the endometrial stroma. None of 11 patients biopsied before starting tamoxifen therapy had advanced endometrial glandular proliferation in the second endometrial biopsy after tamoxifen treatment. None of the 19 endometrial neoplasms after tamoxifen therapy was of the endometrioid type: 11 were mucinous adenocarcinomas, 4 clear cell carcinomas, 2 serous-papillary carcinomas, one carcinosarcoma and one malignant Mullerian mixed tumor. The reasons for discrepancies between suspicious sonograms and endometrial atrophy are discussed.

Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.

Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake.

Estrogen replacement therapy and risk of epithelial ovarian cancer.

Estrogen replacement therapy (ERT), in common use among menopausal women, has been inconsistently related to risk of ovarian cancer. Part of the inconsistency may be due to differences in risk according to tumor histology. We therefore compared, within histologic groups, 367 cases of invasive epithelial ovarian cancer to 564 population controls on history of ERT practices. In multivariate logistic regression analyses adjusted for age, parity, oral-contraceptive usage, and other factors, the relative odds of nonmucinous ovarian cancer increased by 5.1% for each year of ERT use [i.e., adjusted odds ratio, 1.051; 95% confidence interval (CI), 1.01-1.09, as a multiplicative factor for each year of use]. In particular, compared to never use, women who employed ERT for a total of 5 years or longer had a relative odds of 2.03 (95% CI, 1.04-3.97) of having a serous carcinoma and 2.81 (95% CI, 1.15-6.89) of having an endometrioid carcinoma. Mucinous tumors were not associated with use. ERT usage may contribute to the development of nonmucinous types of ovarian cancer, and additional histology-specific analysis of this association in other studies is warranted.

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.

High yields of K-ras mutations in intraductal papillary mucinous tumors and invasive adenocarcinomas induced by N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine in the pancreas of female Syrian hamsters.

Ductal adenocarcinoma, the most common form of pancreatic cancer in humans, is associated with activation of the K-ras oncogene in approximately 90% of cases. In contrast, K-ras mutations are found in < 50% of the relatively rare intraductal papillary mucinous tumor (IPMT), which arises in the main pancreatic ducts. Since both adenocarcinomas and IPMTs are believed to arise from ductal cells and progress through similar sequences of morphological changes (i.e. flat hyperplasia, papillary hyperplasia, atypia and carcinoma in situ), it is clear that such progression may not always necessitate activation of the ras oncogene. Experimentally ductal adenocarcinomas of the pancreas can be induced in the hamster model by a brief treatment with N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), while IPMTs can be induced by a combined treatment with HPOP and orotic acid (OA) in an initiation/promotion schedule. Since animals are exposed to the carcinogen only once, initiated normal epithelium is expected to give rise to a wide spectrum of neoplastic and preneoplastic lesions, progression of which will depend on the extent of mutagenesis induced at initiation in the targeted cells. In order to investigate the role of K-ras in progression of IPMTs as compared with adenocarcinomas we have examined the presence of K-ras mutations in the above two types of experimentally induced pancreatic cancers, as well as in associated and preneoplastic lesions. K-ras mutations at codons 12, 13 and 61 were determined by a designed restriction fragment length polymorphism method using mismatched nested primers in 77 neoplastic and preneoplastic foci microdissected from 20 pancreases. Mutations were found in all foci of atypical hyperplasia, in carcinomas in situ and invasive cancer, whether such lesions originated in lobular tissue or in the main pancreatic duct. Mutations were also found in papillary hyperplasia and flat hyperplasia in small ducts and also in the main duct at high frequency. With one exception, all ras mutations were G-->A transitions at the second base of codon 12. Mutations were occasionally accompanied by excessive presence of the mutant ras allele or loss of the wild-type ras allele, events that were more frequent in atypical hyperplasia (5/17), carcinomas in situ (5/14), IPMTs (2/5) and invasive adenocarcinomas (2/5) than in flat hyperplasia (0/6) or papillary hyperplasia (2/18). Our results demonstrate that: (i) K-ras mutations, predominantly G-->A transitions, are present in all experimentally induced hamster tumors; (ii) the incidence of K-ras mutations in IPMTs is lower in humans than in the hamster model; (iii) advanced lesions in both adenocarcinomas and IPMTs were frequently associated with an excess of the mutant over the wild-type K-ras allele. It is likely that both adenocarcinomas and IPMTs induced chemically in the hamster model arise by mechanisms which involve early activation of K-ras. Such a mechanism seems to be applicable only in a fraction of human IPMTs.

Primary non-clear-cell adenocarcinomas of the vagina in older DES-exposed women.

The association between in utero diethylstilbestrol (DES) exposure and the development of clear-cell adenocarcinoma of the vagina and cervix has been well described. However, non-clear-cell mucin-secreting adenocarcinoma in women with DES exposure has not been previously reported. We present two cases of non-clear-cell mucinous adenocarcinoma in women having a history of in utero DES exposure. These cancers were found in older women and were more advanced than the clear-cell adenocarcinoma associated with DES. Histologic features of these tumors were notable for atypical, irregular glands lined by endocervical, intestinal, and endometrioid epithelium. The development of non-clear-cell adenocarcinoma of the vagina in these patients may be associated with DES exposure in utero. Long-term surveillance of DES-exposed women may be warranted.

Fertility therapy in the setting of a history of invasive epithelial ovarian cancer.

A link between fertility drugs and epithelial ovarian cancer has been suggested by at least one case-control study, and by multiple case reports of such tumors developing following fertility drug therapy. We report the case of a woman with stage IC grade 1 mucinous epithelial ovarian cancer who died of recurrent disease shortly after receiving gonadotropin therapy for ovulation induction. The patient was initially treated with a staging procedure, unilateral salpingo-oophorectomy, and 3 courses of cytoxan and carboplatinum. Over the next 3 years she underwent 2 cycles of ovulation induction with exogenous gonadotropins. Five months after the second cycle, the patient presented with a bowel obstruction and extensive recurrence of disease. Two months later she died despite extensive surgical debulking, and cis-platinum and Taxol chemotherapy. Although a causal relationship between fertility therapy and ovarian cancer has not been established, this case report suggests ovulation induction may be inadvisable in a woman with a prior diagnosis of invasive epithelial ovarian cancer.

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.

[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.

[Growth rate of experimental colonic cancer in rats].

Colonic cancers were induced in rats by subcutaneous injection of 1,2-Dimethylhydrazine. Tumor growth patterns were estimated by means of a double contrast barium enema technique. Tumor growth was almost exponential and the average doubling time was 20 +/- 5 (m +/- S.D.) days, at which time three different types of tumor growth patterns: Constant type, decreasing type and reaccelerating type, were noted. Serial double contrast barium enema technique appeared to be an useful method of studying in vivo primary colonic cancer growth patterns in rats.