Contribution of polycyclic aromatic compounds to the carcinogenicity of sidestream smoke of cigarettes evaluated by implantation into the lungs of rats

Particles and semivolatiles from sidestream smoke of cigarettes smoked on a smoking machine were collected by a filter combination consisting of a glass fibre filter and silanized polystyrene beads. The extract of the glass fibre filter was separated by a Sephadex LH-20 column chromatography into a fraction containing non-aromatic material plus polycyclic aromatic compounds (PAC) with 2 and 3 rings and a fraction consisting of PAC with 4 and more rings. To evaluate the carcinogenicity, both fractions as well as the semivolatiles were implanted into the lungs of Osborne-Mendel rats at a dose level of one cigarette per animal and compared with three dose levels of benzo[a]pyrene (BaP). The most pronounced carcinogenic effect of the sidestream smoke (100 ng BaP per cigarette) was caused by the fraction containing polycyclic aromatic hydrocarbons (PAH) with 4 and more rings (5 carcinomas of the lungs/35 rats). This fraction represents only 3.5% by weight of the total sidestream smoke condensate. By contrast, the semivolatile material did not provoke any tumors. Only a small contribution to the total carcinogenicity (1 carcinoma of the lungs/35 rats) was observed for the fraction containing non-aromatic material and 2- and 3-ring PAHs.     

Contribution of polycyclic aromatic hydrocarbons to the carcinogenic impact of gasoline engine exhaust condensate evaluated by implantation into the lungs of rats

An attempt was made to identify the substances chiefly responsible for the carcinogenicity of gasoline engine exhaust condensate. A carcinogen-specific bioassay was performed by a comparison of the carcinogenic effect of various fractions with that of a total sample of automobile exhaust condensate, tested in two or three different doses. The results were examined by Probit analysis. After implantation into the lungs of OM rats, the condensate emitted from a gasoline-driven automobile and the fraction of polycyclic aromatic compounds consisting of more than 3 rings induced lung carcinomas and sarcomas. The tumor incidence demonstrated a clear-cut dose-response relationship. The fraction of polycyclic aromatic hydrocarbons (PAH) consisting of more than 3 rings accounted for about 81% of the total carcinogenicity of automobile exhaust condensate. This fraction represented only 2.8% by weight of the condensate. The content of benzo[a]pyrene (CAS: 50-32-8; 0.483 mg/g condensate) accounted for 2.4% of the total carcinogenicity of automobile exhaust condensate. Regarding the minor effect of the PAH-free fraction (approximately equal to 87% by wt), no evidence of cocarcinogenic activity was observed, since the total condensate as well as the PAH fraction consisting of more than 3 rings applied proportionally caused about the same tumor incidence.     

The contribution of polycyclic aromatic hydrocarbon fractions with different boiling ranges to the carcinogenic impact of emission condensate from coal fired residential furnaces as evaluated by topical application to the skin of mice

Flue gas condensate from briquet-fired residential furnaces was separated into a polycyclic aromatic compound (PAC)-free and a PAC-containing part, followed by a subfractionation of the PAC-containing fraction into 3 parts: PAC consisting predominantly of (a) 2 and 3 rings, (b) 4 and 5 rings and (c) 6 and more rings. To evaluate the carcinogenic potency of the condensate and its fractions, local application onto skin of mice in 2 or 3 doses was used. Since it was known from an earlier investigation that both the PAC-free fraction and the fraction containing PAC with 2 and 3 rings were almost ineffective, only PAC-fractions containing more than 3 rings were tested. The probit and Weibull analysis of the results showed that the condensate and the fractions containing PAC with 4 and 5 rings as well as 6 and more rings provoke local tumors after repeated application to the dorsal skin of mice. The tumor incidence exhibited a clear cut dose-response relationship. Fractions (b) and (c) were almost equally active, each contributing by about 50% to the total carcinogenicity. The content of benzo[a]pyrene (0.72 mg/g condensate) contributed by 10-11% to the total carcinogenicity of the emission.     

Contribution of polycyclic aromatic hydrocarbons and polar polycyclic aromatic compounds to the carcinogenic impact of flue gas condensate from coal-fired residential furnaces evaluated by implantation into the rat lung

For identification of the substances chiefly responsible for the carcinogenic action of the emission condensate from coal-fired residential furnaces, the implantation method was used as a carcinogen-specific bioassay for comparison of the carcinogenic effect of various fractions with that of a total sample of flue gas condensate tested in 2 or 3 different doses. After implantation into the lungs of Osborne-Mendel rats, the condensate from coal-fired residential furnaces, a fraction containing polycyclic aromatic hydrocarbons (PAHs) and thiaarenes [sulfur-containing polycyclic aromatic compounds (S-PACs)] with 4-7 rings, as well as fraction containing more polar polycyclic aromatic compounds (PACs) and PAHs with higher molecular weight, induced lung carcinomas and sarcomas. According to probit analysis, the fraction containing PAHs plus S-PACs with 4-7 rings accounted for about 68.2% of the total carcinogenicity of flue gas condensate, whereas the fraction containing more polar PACs and higher PAHs accounted for about 54.6%. All other fractions, such as nonaromatic compounds and PACs with 2 and 3 rings, constituting about 70% of the weight of the total condensate, seemed not to be carcinogenic. Only 1.4% of the total carcinogenicity of the flue gas condensate was found to be attributable to the amount of benzo[a]pyrene (CAS: 50-32-8) present in the condensate (1.14 mg/g condensate). The contribution of more than 100% of both active fractions to the total carcinogenicity (68.2 and 54.6%) may suggest an interrelation of the fractions.     

The contribution of polycyclic aromatic hydrocarbons to the carcinogenic impact of emission condensate from coal-fired residential furnaces evaluated by topical application to the skin of mice

The objective of this investigation was to identify the substances chiefly responsible for the carcinogenicity of the emission condensate from coal-fired residential furnaces. To realize this, the carcinogenic effect of various fractions was compared with that of an unseparated sample of emission condensate, tested in different doses. The probit and Weibull analysis of the results showed: (1) The condensate emitted from a coal fired residential furnace as well as the reconstituted condensate combining all fractions, provoked local tumors after repeated application to the dorsal skin of mice. The tumor incidence exhibited a clear cut dose-response relationship. (2) The fraction of polycyclic aromatic hydrocarbons (PAH) and thiaarenes with more than three rings accounted for almost the total carcinogenicity (109-118% compared with the total condensate) of the emission condensate from the coal-fired residential furnace. (3) The fraction containing azaarenes and nitroarenes (NO2-PAH) accounted only for 4-7% of the total carcinoma incidence of the emission condensate. (4) The content of benzo[a]pyrene (0.702 mg/g condensate) contributes 10-11% to the total carcinogenicity of the emission condensate. (5) The PAH-free fraction and the fraction containing PAH with 2 and 3 rings (together about 77% by wt) were almost ineffective. No cocarcinogenic activity of this fraction was obtained, since the total condensate, as well as the PAH-fraction consisting of more than three rings applied proportionally provoked about the same carcinoma incidence.     

Dose-dependent effect of tamoxifen therapy on endometrial pathologies in postmenopausal breast cancer patients

To assess whether a higher cumulative tamoxifen dose is associated with increased incidence of various types of endometrial pathologies, we compared cumulative dose of tamoxifen treatment as well as demographic characteristics, risk factors for endometrial cancer, transvaginal ultrasonographic endometrial thickness, and various treatments for the primary breast cancer between 159 postmenopausal breast cancer tamoxifen-treated patients without endometrial pathologies (group I) and 67 similar patients with endometrial pathologies (group II). A similar comparison was made between group I patients and similar patients with proliferative endometrium (group IIa), with endometrial hyperplasia (group IIb), with endometrial polyps (group IIc), and with endometrial cancer (group IId). Overall cumulative tamoxifen dose was significantly higher in group II as compared to group I (27.4 ± 33.4 and 17.4±20.2, respectively;P < 0.0252). Transvaginal ultrasonographic endometrial thickness was significantly higher in group II than in group I patients (16.3 ± 11.3 mm and 12.1 ± 6.3 mm, respectively; P < 0.0147). The frequency of diabetes mellitus, of previous postmenopausal bleeding, and of previous exposure to hormone replacement therapy was significantly higher in group II than in group I patients (P < 0.001, P < 0.0001 and P < 0.001, respectively). There were no significant differences in all parameters tested between group I, group IIa, group IIb, group IIc, and group IId. However, there was an obvious trend for higher cumulative tamoxifen dose in patients with benign endometrial pathologies as compared to those without endometrial pathologies or to those with endometrial cancer (Group I = 17.4 ± 20.2g, group IIa = 22.5 ± 18.5g, group IIb = 28.1 ± 20.3g, group IIc = 31.4 ± 42.7g and group IId = 10.4 ± 12.6g).Endometrial pathologies, except for endometrial cancer, are associated with a high cumulative dose of tamoxifen in postmenopausal breast cancer patients.     

On the contribution of polycyclic aromatic hydrocarbons to the carcinogenic impact of automobile exhaust condensate evaluated by local application onto mouse skin

The objective of this investigation was to identify the substances chiefly responsible for the carcinogenicity of automobile exhaust condensate using topical application onto the skin of mice. This was performed by comparing the carcinogenic effect of various fractions with that of an unseparated sample of automobile exhaust condensate, tested in 3 different doses. The probit and Weibull analysis of the result shows: (a) The condensate, emitted from a gasoline-driven automobile provokes local tumors after long-term application to the dorsal skin of mice. The tumor incidence demonstrates a clear cut dose-response relationship. (b) The fraction of polycyclic aromatic hydrocarbons (PAH) containing more than 3 rings accounts for about 84-91% of the total carcinogenicity of automobile exhaust condensate. This fraction represents only about 3.5% by wt of the condensate. (c) The content of benzo[a]pyrene (BaP) (0.414 mg/g) accounts for 6-7.6% of the total carcinogenicity of automobile exhaust condensate, 15 selected PAHs for about 41%. (d) Regarding the minor effect of the PAH-free fraction (about 83% by wt), no hints for a cocarcinogenic activity were observed.     

Experimental results with percutaneous applications of automobile exhaust condensates in mice.

The induction of squamous-cell carcinoma and papillomas in mice after 80 weeks' skin painting with different doses of automobile exhaust condensates and their fractions is described. The results demonstrate that the carcinogenic activity of the condensate resides in its polycyclic aromatic hydrocarbon fractions. Benzo[a]pyrene accounts for approximately 9% of the activity of the condensate. The sebaceous gland suppression test, used as a screening method, is predictive of carcinogenicity and is positive for those condensate subfractions which contain carcinogenic PAH.     

Radiation therapy of seminoma: 17-year experience at the Joint Center for Radiation Therapy

One hundred and sixteen patients with stage I and II primary testicular seminoma were treated at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1984. Complete follow-up is available for 114 patients (98%) with a median follow-up time of 6 years. Actuarial relapse-free survival (RFS) and survival for the entire group at 10 years were 94 and 86%, respectively, with 27 patients still at risk beyond 10 years. Actuarial RFS and survival at 10 years by stage were 97 and 92% for stage I, 93 and 81% for stage IIa, 100 and 100% for stage IIb, but only 75 and 51% for stage IIc. The difference in actuarial survival between stage IIc patients and stage I, IIa and IIb patients was significant (p less than 0.01). These results indicate that radiation therapy is excellent treatment for stage I and II seminomas as long as the largest mass of disease is not greater than 5 cm (stage IIc). Patients with stage IIc seminoma are now treated with cisplatin-containing combination chemotherapy followed by radiation therapy to areas of bulk disease. Although the majority of patients with stage II disease in this series received mediastinal irradiation, this is no longer recommended at the JCRT.     

Endoscopic resection with local injection of HSE (ERHSE) in early gastric carcinomas

We have developed a new therapeutic method of endoscopic resection with local injection of HSE (ERHSE) for the early gastric carcinomas. ERHSE was performed for a total of seventy eight lesions of seventy five cases. Seventy eight early gastric carcinomas consisted of IIc (35), IIa (32), I (6), IIa + IIc (4) and IIc + IIa (1). Ten cases out of 75 underwent gastrectomy, because the invasion of carcinoma was detected in the submucosa or to the resected margin. No evidence of local recurrence has been obtained in the sixty five cases treated by this method.     

Analyses of the APC and TGF-β Type II Receptor Genes, and Microsatellite Instability in Mucosal Colorectal Carcinomas

APC and transforming growth factor-β type II receptor (TGF-β RII) gene mutations, and microsatcllitc instability have been found in sporadic colorectal carcinomas. To clarify further the early alterations in colorectal carcinogenesis, we investigated these genetic changes in 23 protruding- and 24 superficial-type mucosal colorectal carcinomas. TGF-β RII gene mutations and microsatellite instability were rarely found in these lesions. Nevertheless, APC was mutated in 16 of the 47 (34.0%) mucosal colorectal carcinomas and was significantly more frequently mutated in protruding- (I) and superficial elevated-type (Ila) (14/32,43.8%) than in other superficial-type (IIa+IIc, IIb, IIc, and IIc+IIa) (2/ 15,13.3%) mucosal colorectal carcinomas (P<0.04). These results indicate that the APC gene may be involved from the beginning in the tumorigenesis of many early colorectal carcinomas, particularly of the protruding and superficial elevated types. However, there might be a distinct pathway for other superficial-type colorectal carcinomas, possibly not involving APC as an initial step of tumorigenesis.     

Gastric cancer presenting a variety of macroscopic and histopathological findings

A 68-year-old man was admitted to hospital because of nausea and vomiting. Examination of the upper digestive tract led to a total gastrectomy. A histopathological examination revealed a Borrmann type 3 advanced cancer in the prepyloric antrum that showed a moderately differentiated adenocarcinoma. Found on the anterior wall of the middle corpus was an advanced cancer, mimicking a type IIc early cancer, that was poorly differentiated with dispersed signet ring cells. Between these two advanced cancers, another superficially extended cancer, consisting of a type IIa and IIb early cancer, was found. The type IIa cancer, located on the posterior wall of the angle, was a papillary adenocarcinoma and the type IIb cancer on the lesser curvature of the antrum was moderately differentiated. Therefore this patient displayed not only a type IIa and a type IIb cancer, but also a Borrmann type 3 cancer and an advanced cancer, mimicking type IIc, that were linked into one large lesion. Although the present case was not determined as being a multiple gastric cancer, it suggests the likelihood of a multicentric generation, growth, and extension of synchronous multiple cancers, in view of the variety of macroscopic and histopathological findings presented.     

Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group.

PURPOSE: To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy. PATIENTS AND METHODS: Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc). RESULTS: Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy. CONCLUSION: Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.     

Tumours in mice after subcutaneous injection of automobile exhaust condensates.

Automobile exhaust condensate (AEC), either mixed with benzo[a]pyrene (BaP) or suspended or dissolved in tricaprylin, was injected subcutaneously into NMRI mice in a series of experiments. The addition of AEC decreased the incidence of tumours which developed with 30, 90 and 270 microgram BaP. Reduction of tumour incidence was proportional to the amount of AEC added. With an injection of 10 microgram BaP, the latent period was greatly increased when AEC was added, but the occurrence of tumours was the same. Components of AEC appear to inactivate BaP, at least temporarily. In further experiments AEC and nine fractions thereof were injected subcutaneously into mice. The fraction comprising only polycyclic aromatic hydrocarbons (PAH) induced the highest incidence of tumours. In contrast, when it was administered in combination with other fractions the PAH fraction was less active. Application of the products of further fractionation of PAH showed that polycyclic compounds with seven or more rings can also induce tumours in this model.     

Initial radiographic findings of early gastric cancer detected in health check programs and human "dry dock" collective health checks and treated by endoscopic mucosal resection

Abstract. Background: The purpose of this study was to evaluate the capacity of detection (detectability), by radiographic examination, of minute gastric cancer that was indicated for endoscopic mucosal resection (EMR). Methods: Fifty-five lesions in 55 patients with minute gastric cancer were endoscopically resected between 1992 and 2000 at the Foundation for Detection of Early Gastric Carcinoma. Of these 55 patients, 33 patients underwent indirect (with image intensifier and 100-mm roll film) and/or direct radiographic examination of the upper gastrointestinal tract as the initial screening examination, and subsequent upper gastrointestinal endoscopy. The remaining 22 patients underwent upper gastrointestinal endoscopy as the initial screening examination. As the first step, radiographic (indirect and direct) images were reviewed, and the abnormalities which had eventually led to the detection of the minute early gastric cancer (EGC) were reconfirmed. Then, they were analyzed in terms of the reproducibility of abnormal findings which enabled the detection of such a minute EGC, and in terms of whether they could be treated by EMR. The size, morphology, and location of the radiographically detected lesions were analyzed. Results: Seventeen lesions of EGC were detected in the group in which indirect radiography was initially performed. Of these 17 lesions, some abnormality corresponding to the site of the lesion was pointed out in 7 lesions (2 lesions of type IIa and 5 lesions of type IIc). On the other hand, the remaining 10 lesions (type IIa, 3; type IIc, 5; type IIa + IIc, 1; and type IIb, 1) were detected by endoscopy, which was carried out to confirm the other abnormalities in the indirect radiographic images. Sixteen lesions of EGC were detected in the group in which direct radiography was initially performed. Of these 16 lesions, some abnormality corresponding to the site of the lesion was pointed out in 8 lesions (4 lesions of type IIa and 4 lesions of type IIc). The remaining 8 lesions (3 lesions of type IIa and 5 lesions of type IIc) were not detected by direct radiography. Conclusion: Indirect and direct radiographic examination enabled the detection of approximately 50% of EGCs which could be treated by endoscopic resection. The significance of radiographic examination should not be underestimated, even in the detection of EGCs which can be endoscopically resected. Received: June 18, 2001 / Accepted: December 7, 2001     

A case of superficial squamous cell carcinoma of the esophagus showing multicentric development

A 43-year-old male was admitted to the hospital with a complaint of mild dysphagia. A barium esophagogram showed an annular narrowing in the lower esophagus. Further, an endoscopic examination revealed erosive mucosa of the esophagus about 35 cm anal to the incisor. Lugol staining also revealed a geographical unstained lesion. The histologic diagnosis of a biopsy specimen indicated a squamous cell carcinoma and a total resection of the esophagus was performed. The operated material macroscopically showed a tumor of a superficially mixed type (IIa + IIc + IIb). The resected specimen histologically consisted of 18 squamous carcinomas that were separated with the normal squamous epithelium from each other. The major part of these lesions were limited to the epithelium, and only a few specimens microscopically showed an invasion of cancer nests in the propria mucosae. Great permeation of cancer cells into lymph vessels and the metastasis of one regional lymph node also were noted. Taken together, these findings indicated that the squamous cell carcinomas of this case seemed to have multicentrically developed from the normal esophageal mucosa.     

A case of IIa + IIc type early carcinoma of the rectum, with no invasion of the submucosa

A case of a IIa + IIc type early carcinoma of the rectum is reported. A 62-year-old man, who had been checked by immunological latex agglutination faecal occult blood testing, underwent a colorectal examination at Hakodate Chu-o Hospital. A barium enema revealed a slightly elevated lesion with a central depression in the lower rectum. Colonoscopic examination showed a IIa + IIc type of early rectal carcinoma. Study of the resected specimen also confirmed a IIa + IIc type early rectal carcinoma, 17 x 15 mm in diameter. Histologically, a lesion was located within the mucosa and consisted of both a carcinoma and an adenoma. Immunological latex agglutination faecal occult blood testing was thought to be useful for mass screening detection of a colorectal carcinoma.     

Treatment of early gastric cancer by endoscopic double snare polypectomy (EDSP)

The indication for EDSP was studied in 75 patients with early gastric cancer diagnosed endoscopically which had been obtained over a period of 11 years (1979 to 1985) at the Cancer Institute Hospital, Tokyo and the following results were obtained. EDSP consists of two procedures using double channel fiberscope; a sessile or depressed lesion pulled upward by one snare cautery (standard EDSP) is transformed into a subpedunculated one, which allows another snare cautery of pseudostalk, and it is excised by using coagulation current. EDSP was performed in 53 cases of IIa type and 22 cases of IIc type. Excision by one snare cautery was possible in 90.9% (40/44) of IIa lesion measuring less than 2 cm and in 100% (14/14) of IIc lesion measuring less than 1 cm, the total being 85.3% (64/75). There was no residual cancer in 41 cases of IIa lesion (93.2%) and 17 cases (85.0%) of IIc lesion with two recurrent cancers confirmed by follow-up endoscopy. Residual cancer was found in 6 cases (9.1%) which were operated on. The results mentioned above show the usefulness of EDSP and selection of case without lymph node metastasis permitting complete excision by one snare cautery is of much importance. EDSP is indicated for IIa lesion of differentiated type measuring less than 2 cm, IIc lesion of differentiated type without ulceration measuring less than 1 cm and IIc lesion of undifferentiated type without ulceration measuring less than 0.5 cm that is not located in the fundic gland area.     

Testicular seminoma: analysis of treatment and failure for stage II disease

Seventy-three patients with seminoma testis stage II have been retrospectively analyzed with regard to prognostic factors and value of prophylactic mediastinal irradiation and chemotherapy. Although survival differences were seen between stage IIa, IIb and IIc, these were not statistically significant. Neither was there a significant difference between IIc patients with tumors greater than 10 cm and less than 10 cm in diameter. The incidence of HCG-producing seminomas in the present series was 16%. No significant difference in survival nor relapse rate was found between HCG-producing and HCG-non-producing seminomas. Prophylactic mediastinal irradiation did not influence the survival nor the relapse rate and may therefore be omitted. In the present series there was no significant improvement neither in relapse rate nor survival in patients receiving pre-irradiation chemotherapy. However, the total number of patients is small and optimal pre-irradiation chemotherapy still have to be defined.