Trends in Breast Cancer Mortality, Incidence, and Survival, and Mammographic screening in Tuscany, Italy

Objective: The study describes breast cancer mortality trends in Tuscany (period 1970–97), comparing Florence with the rest of Tuscany (Florence excluded), and, for Florence, incidence (period 1985–94) and survival (1985–86 versus 1991–92) trends, taking into account the diffusion of screening. Methods: Mortality and incidence rates, age-adjusted on the European population, and 95% confidence intervals (95% CI). Five-year relative survival rates and estimates of risk of dying provided by the Cox model. Results: Mammographic screening, started at the beginning of the 1970s in some municipalities, largely involved the Florence area after 1990 (mammograms/years: from 8000–9000 to 28,000–29,000, respectively, before and after 1990). In the same period no population-based screenings were ongoing in the rest of Tuscany. A significant mortality drop was observed in Tuscany (–3.7%/year), starting at the beginning of the 1990s and observed for ages 74 (especially ages 40–49: –11.2%/year). The drop was similar in Florence and in the rest of Tuscany. In ages 50–69, incidence, increasing between 1985–87 and 1988–90 (+6.5%), rose sharply in 1991–94 (+17.0%); it was stable in other ages. Local disease increased more markedly in ages 50–69 (globally: +88.3%), but also in other ages (+20–30%). Regional and metastatic cancers decreased. A significantly better 5-year survival was observed among cases diagnosed in 1991–92, persisting after adjustment by extent of disease. Conclusion: Even if the causes of breast cancer mortality trends are not easy to clarify in an observational study, our data suggest that the drop in mortality observed in Tuscany at the beginning of the 1990s could be largely explained by both earlier detection, outside of an organized screening program, and by better treatments. The increase in incidence and the shift in stage distribution that occurred before the enlargement of the screening area and in age groups not involved in the program, supports the role of a `spontaneous' widespread earlier detection. The better survival of the period 1991–92, only partly explained by the shift in stage at diagnosis, indirectly supports the role of improvement in therapy.     

Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma

Based on remarkable activity in refractory lymphomas, a combination of etoposide, cisplatin (both administered by 4-day continuous infusions), cytarabine (Ara-C), and dexamethasone (EDAP) was evaluated in 20 patients with advanced myeloma refractory to standard melphalan and prednisone (MP) and/or vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dexamethasone (VAD) and even to high doses of melphalan (HDM) (seven patients). Forty percent of patients responded regardless of previously recognized risk factors (eg, duration of drug resistance, tumor mass, and serum lactic dehydrogenase [LDH] level). While the median survival was only 4.5 months, patients with good performance (Zubrod less than 2) and low or intermediate tumor stage survived more than 14 months compared with only 2 months for the remaining group. EDAP could be readily administered in the outpatient clinic, but neutropenic fever prompted hospital admission in 80% of patients, half of whom developed penumonia and sepsis, a fatal outcome in four patients. Severe myelosuppression was of short duration, so that subsequent cycles could be administered every 3 to 4 weeks. No serious extramedullary toxicity, including renal toxicity, was encountered. Marrow toxicity and hence infectious complications may be reduced by elimination of Ara-C without compromising treatment efficacy. We conclude that the lack of cross-resistance with VAD and even HDM makes EDAP or a similar combination an attractive regiment to be formally explored in an alternating sequence with VAD in high-risk myeloma.     

Consumption of alcohol,coffee, and tobacco,and gastric cancer in Spain

A case-control study on gastric cancer was carried out between 1987 and 1989 in four regions of Spain. Three hundred and fifty-four cases of histologically confirmed adenocarcinoma were included (235 men and 119 women). For each case, a control was selected, matched by sex, age, and area of residence, from the same hospital as the case. No association was observed with smoking, nor with the consumption of coffee or tea. The usual consumption of alcohol was associated with gastric cancer in men (odds ratio = 1.54, 95 percent confidence interval = 1.03–2.31), but there was no dose-response relationship. No association was observed in women. All estimations were carried out taking into account the effect of the dietary factors associated with gastric cancer. In accordance with previous evidence, the association observed between gastric cancer and alcohol appears not to be causal.Drs Agudo and González are with the Unit of Epidemiology, Hospital de Mataró, Mataró, Spain. Dr Marcos is with the Department of Preventive Medicine, Hospital Clínico, Zaragoza, Spain. Dr Sanz is with the Department of Pathology, Hospital del INSALUD, Soria, Spain. Dr Saigi is with the Department of Oncology, Hospital General de Granollers, Granollers, Spain. Dr Verge is with the Department of Surgery, Hospital de Terrassa, Terrassa, Spain. Dr Boleda is with the Department of Oncology, Hospital S. Camil, Sant Pere de Riba, Sapin. Dr Ortego is with the Department of Pathology, Hospital Clínico, Zaragoza, Spain. Address correspondence to Dr Agudo, Unit of Epidemiology, Hospital de Mataró, c. Hospital 31, 08301 Mataró, Spain. This study received financial support from the Health Research Fund (FIS) of the Spanish Ministry of Health (Financial Aid for Research exp. 87/1703, exp. 89/0018 and exp. 89/0743) and from the International Agency for Research on Cancer (Collaborative Research Agreement AEP/88/02).     

Strain and sex differences in N-nitrosohexamethyleneimine carcinogenesis in NZB, NZC, NZO, and NZY mice

The carcinogenic activity of N-nitrosohexamethyleneimine [(NHEX) CAS: 932-83-2; hexahydro-1-nitroso-1H-azepine] was studied in male and female mice of the four inbred strains NZB/BlGd, NZC/BlGd, NZO/BlGd, and NZY/BlGd. A total of 158 mice received NHEX treatment; 1,338 untreated controls were used, all kept under identical laboratory conditions for their natural life-spans. Beginning at age 50 days a 1.56-mM NHEX solution (200 mg/liter) was given instead of drinking water for 8 weeks, which resulted in nearly the same total dosage of 0.7 +/- 0.04 g or 5.7 +/- 0.2 mmol NHEX/kg body weight in both sexes of all four strains. In both sexes of all four strains the main types of tumors after NHEX treatment were squamous papillomas and carcinomas of the esophagus, squamous stomach, and oropharynx and hepatocellular carcinomas. Tumors of the hepatic bile ducts, glandular stomach, and lung and malignant lymphomas were also induced by NHEX, but these tumors had a predilection for certain strains only. The incidences of other tumors characteristic of the untreated mice in each particular strain, such as tumors of the ovary in NZC, tumors of the breast in NZY, and tumors of the duodenum in NZO, were not increased significantly by NHEX treatment. The incidence of main tumor types in NHEX-treated mice varied greatly between strains, e.g., esophageal papillomas and carcinomas in 81% of male NZC versus 32% in male NZB mice. Some marked sex differences also emerged in NHEX-treated animals, e.g., the occurrence of liver angiosarcomas only in males of three strains and the 53% incidence of hepatocellular tumors in male NZY mice compared to the absence of liver tumors in female NZY mice.     

Resources and Productivity in Radiation Oncology in Denmark, Finland, Iceland, Norway and Sweden During 1987

Data concerning megavoltage equipment and use of mega-voltage external beams in cancer management during 1987 in Denmark, Finland, Iceland, Norway, and Sweden were collected from all 37 centres serving a population of 23 million in these countries. Population per Linear Accelerator Equivalent (LAE) unit ranged from 0.30 million/LAE unit (Denmark) to 0.19 million/LAE unit (Sweden). the number of field treatments were 227 548 (Denmark), 259 917 (Finland), 10 426 (Iceland), 147 960 (Norway) and 490 126 (Sweden). the number of field treatments per million population per year ranged from 35 229 (Norway) to 58 438 (Sweden). the number of field treatments per LAE unit/year ranged from 13 192 (Denmark) to 9 546 (Norway). the fraction of cancer patients receiving megavoltage radiotherapy in 1987 out of all newly diagnosed cancer patients during 1987 was 24% in Denmark, 37% in Iceland, 25% in Norway, and 34% in Finland and Sweden. We conclude that Denmark and Norway probably did not provide adequate levels of radiotherapy for their cancer patients during 1987.     

Diabetes,diabetes treatment,and mammographic density in Danish Diet,Cancer, and Health cohort

Purpose

We examined whether diabetes and diabetes treatment are associated with MD in a cohort study of Danish women above age of 50 years.

Methods

Study cohort consisted of 5,644 women (4,500 postmenopausal) who participated in the Danish Diet, Cancer, and Health cohort (1993–1997) and subsequently attended mammographic screening in Copenhagen (1993–2001). We used MD assessed at the first screening after the cohort entry, defined as mixed/dense or fatty. Diabetes diagnoses and diabetes treatments (diet, insulin, or oral antidiabetic agents) were self-reported at the time of recruitment (1993–1997). The association between MD and diabetes was analyzed by logistic regression adjusted for potential confounders. Effect modification by menopausal status and body mass index (BMI) was performed by introducing an interaction term into the model and tested by Wald test.

Results

Of 5,644 women with mean age of 56 years, 137 (2.4%) had diabetes and 3,180 (56.3%) had mixed/dense breasts. Having diabetes was significantly inversely associated with having mixed/dense breasts, in both, the crude model (odds ratio; 95% confidence interval: 0.33; 0.23–0.48), and after adjustment for adiposity and other risk factors (0.61; 0.40–0.92). Similar inverse associations were observed for 44 women who controlled diabetes by diet only and did not receive any medication (0.56; 0.27–1.14), and 62 who took oral antidiabetic agents only for diabetes (0.59; 0.32–1.09), while women taking insulin had increased odds of mixed/dense breasts (2.08; 0.68–6.35). There was no effect modification of these associations by menopausal status or BMI.

Conclusions

Having diabetes controlled by diet or oral antidiabetic agents is associated with a decrease in MD, whereas taking insulin is associated with an increase in MD.

     

Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion

The Rho subgroup of the Rho GTPases consisting of RhoA, RhoB and RhoC induces a specific type of actin cytoskeleton and carry out a variety of functions in the cell. mDia and ROCK are downstream effectors of Rho mediating Rho action on the actin cytoskeleton; mDia produces actin filaments by nucleation and polymerization and ROCK activate myosin to cross-link them for induction of actomyosin bundles and contractility. mDia is potentially linked to Rac activation and membrane ruffle formation through c-Src-induced phosphorylation of focal adhesion proteins, and ROCK antagonizes this mDia action. Thus, cell morphogenesis, adhesion, and motility can be determined by the balance between mDia and ROCK activities. Though they are not oncogenes by themselves, overexpression of RhoA and RhoC are often found in clinical cancers, and RhoC has been repeatedly identified as a gene associated with metastasis. The Rho-ROCK pathway is implicated in Ras-mediated transformation, the amoeboid movement of tumor cells in the three-dimensional matrix, and transmigration of tumor cells through the mesothelial monolayer. On the other hand, the Rho-mDia1 pathway is implicated in Src-mediated remodeling of focal adhesions and migration of tumor cells. There is also an indication that the Rho pathway other than ROCK is involved in Src-mediated induction of podosome and regulation of matrix metalloproteases. Thus, Rho mediates various phenotypes of malignant transformation by Ras and Src through its effectors, ROCK and mDia.     

Objective assessment, selection, and certification in surgery

Historically, surgical competence has been evaluated subjectively. Fundamental changes in surgical technology and training have focused attention on the use of objective measurement of performance to improve patient safety and reduce errors. Surgical performance can be measured using a variety of tools, both in the clinical and simulated environments. Objective assessments can play a role in training by improving the evaluation and feedback. At the end of training or when a new skill is acquired, objective assessments may be used to ensure that a proficiency level has been reached and potentially as a condition for independent practice. When assessments are used for high-stakes evaluations like certification, they must be demonstrably reliable and valid. The definition of assessment, and the necessary components of a valid instrument, will be summarized. An overview of practical applications of objective assessment as it applies to training, selection, and certification of surgeons will be presented.     

Mate drinking, alcohol, tobacco, diet, and esophageal cancer in Uruguay

A case-control study was conducted in Uruguay to investigate the role of mate drinking, alcohol, tobacco, and certain dietary factors in the etiology of esophageal cancer. The study included 261 patients with squamous cell carcinoma of the esophagus and 522 hospital controls matched by sex and age. A strong association with a clear dose-response relationship was observed with the amount of mate drunk daily and duration of the habit. The relative risk for those drinking over 2.5 liters of mate per day was 12.2 (95% confidence interval, 3.8-39.6) after adjusting for the effects of age, area of residence, alcohol, and tobacco. Strong associations were also observed with tobacco smoking and alcohol drinking which appear to act in a multiplicative way. The relative risk for those who smoke and drink heavily compared to that of light smokers and drinkers was 22.6. The risk associated with black tobacco was about three times higher than that associated with blond tobacco. A clear protective effect was found for the consumption of fruits and vegetables but a dose-response relationship was present only for fruits. Finally, an increased risk was also found for those eating barbecued meat daily.     

Contrasts in cancer prevalence in Connecticut,Iowa, and Utah

BACKGROUND: Cancer prevalence--the proportion of a population with cancer, including those recently diagnosed, those in treatment, and survivors--is an important indicator of future health care requirements. Only limited information on cancer prevalence is available for the United States. In particular, comparative interstate studies are not available. In this study, we estimate and analyze the prevalence of seven major cancers in Connecticut, lowa, and Utah using the tried and tested PREVAL method applied to National Cancer Institute registry data. METHODS: We analyzed data on 242,851 carcinomas of the stomach, colorectum, pancreas, breast, uterus (corpus), ovary, and non-Hodgkin lymphoma (NHL), diagnosed in white Americans from 1973 through 1992. Observed prevalence was estimated by applying the PREVAL method to incidence and life status data from the cancer registries. Complete prevalence was estimated by applying correction factors obtained by modeling incidence and survival rates. RESULTS: The ratio of the highest to the lowest prevalence (as proportions) ranged from 1.69 for uterine carcinoma to 2.73 for stomach carcinoma, showing that marked differences in cancer prevalence exist within the United States. Utah had the lowest prevalence for each carcinoma. Connecticut and lowa had similar prevalence levels for carcinomas of the colorectum, pancreas, and ovary and for NHL. Breast carcinoma was the most prevalent, with 826 cases per 100,000 of population in Utah, 1518 per 100,000 in lowa, and 1619 per 100,000 in Connecticut. Cancer survival did not differ greatly among the three registry populations. The major determinants of prevalence differences were incidence and the population age distribution. CONCLUSIONS: PREVAL provides reliable estimates of the numbers of living people in a population who have had a cancer diagnosis. Prevalence depends on incidence and survival and on the age structure of population. All these factors have changed markedly in recent years and will continue to do so in the future. Cancer prevalence should be monitored over time to evaluate changes by area, sex, age, and cancer site. The prevalence figures presented are directly comparable with those from European cancer registries.     

Vinblastine, infusion, bleomycin, and cis-dichlorodiammine-platinum chemotherapy in metastatic melanoma

A chemotherapy regimen containing vinblastine-bleomycin-platinum has been studied in 42 patients with advanced malignant melanoma. Forty-seven percent of evaluable and 43% of all patients experienced objective response. Complete responses were seen in visceral sites. Median duration of response has not been reached but will exceed 26 weeks. Toxicity is predominantly marrow suppressive, gastrointestinal, pulmonary, and mucocutaneous. Pulmonary toxicity was never severe when bleomycin dose was limited to less than 300 mg/m2 body surface area. Half of the patients relapsed with CNS metastases as a first presenting sign of recurrence. Because hospitalization is required in this program its dollar cost is high.     

Pheochromocytoma: advances in genetics, diagnosis, localization, and treatment

Pheochromocytomas are rare, catecholamine-secreting tumors arising most frequently in the chromaffin cells of the adrenal glands. Recent studies have suggested that genetic mutations are more frequent than previously appreciated in patients with these lesions. Advances continue to be made not only in the genetic evaluation of these patients but also in the biochemical confirmation and tumor localization. Surgery remains the definitive treatment, and advances in laparoscopic techniques as well as cortical-sparing procedures have reduced the morbidity associated with tumor resection.