Tobacco smoking and the risk of subsequent primary cancer among cancer survivors: a retrospective cohort study.

BACKGROUND: Smoking is a well-known risk factor for cancer; however, there is little evidence as to whether the smoking status of cancer survivors has any risk for subsequent primary cancer (SPC) incidence, regardless of the first cancer sites. PATIENTS AND METHODS: In total, 29,795 eligible patients with a first cancer between 1985 and 2004 were examined for SPC until the end of 2006, using a record linkage between hospital-based and population-based cancer registries. The association between smoking at the time of the first cancer diagnosis and three SPC groups (i.e. specific SPC, smoking-related SPCs, and all SPCs) was calculated by Poisson regression. RESULTS: Ever smokers had 59% and 102% higher risk for all SPCs and smoking-related SPCs, respectively, than never smokers. Cancer survivors who had recently stopped smoking had 18% and 26% less risk, respectively, for these SPCs than those who smoked at the diagnosis. We also found that, compared with those who had never smoked, cancer survivors who had ever smoked had a significantly elevated risk of oral/pharyngeal, esophageal, stomach, lung, and hematological SPCs, regardless of the first cancer sites. CONCLUSIONS: These findings indicate that smoking increases not only the first cancer but also a second or SPC. Moreover, the results from recent quitters versus current smokers suggest that smoking cessation may decrease the risk for SPC, especially for smoking-related SPCs in cancer survivors. Preventive measures are necessary to reduce not only SPC incidence but also tobacco use.

Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus.

There are several established risk factors for intrahepatic cholangiocarcinoma (ICC), namely primary sclerosing cholangitis, fibropolycystic liver disease, parasitic infection, intrahepatic biliary stones and chemical carcinogen exposure. However, the majority of patients with ICC do not have any of these risk factors. Therefore, identification of other risk factors is warranted for the prevention and early detection of ICC. We evaluated the risk factors for ICC in a large-scale cohort study in the province of Osaka, Japan. This retrospective cohort study included 154,814 apparently healthy individual blood donors, aged 40-64 years at the time of blood donation in the period 1991-1993. The average observation period was 7.6 years, resulting in 1.25 million person-years of observation. Incident ICC cases were identified by linking the blood-donor database to the records in the population-based cancer registry for the province. There were 11 incident ICC cases during follow-up, with an incidence rate of 0.88 per 100,000 person-years. Compared with subjects aged 40-49 years, the subjects aged 50-54 years and 55-59 years had a significantly higher risk for ICC (hazard ratio [HR] = 5.90; 95%CI:1.08-32.31 and 11.07; 95%CI:1.98-61.79, respectively). Compared with those with ALT level of 19 Karmen Units (KU) or less, subjects with ALT level of 40 KU or higher had a significantly higher risk for ICC (HR: 8.30; 95%CI:1.47-46.83). Compared with those who tested negative for both HBsAg and anti-HCV, those who tested HBsAg-positive had a significantly higher risk for ICC (HR: 8.56; 95%CI: 1.33-55.20). Our results suggest that HBV infection and liver inflammation are independently associated with ICC development. These findings need to be verified by further large cohort studies.

Survival of testicular cancer patients in Osaka, Japan.

BACKGROUND: Testicular cancer is one of those cancers for which the prognosis has improved remarkably since the introduction of effective chemotherapy. METHODS: Study subjects were 709 testicular cancer patients who were registered to the population-based Osaka Cancer Registry (OCR) as diagnosed between 1975 and 1992. The testicular cancer patients diagnosed/treated in the Osaka Medical Center for Cancer and Cardiovascular Diseases (OMCC) were also analyzed for comparison. RESULTS: The 5-year relative survival was 75.2% for the total of 709 patients and 77.9% for those diagnosed during 1990-92. These figures were much lower than those for patients in the USA and in Europe. In contrast, the 5-year survival of the 113 patients diagnosed in the OMCC during 1975-93 was 91.5% and similar to those in the USA and in Europe. CONCLUSIONS: The present study suggests that there are problems in the speed and extent of diffusion of effective chemotherapy for testicular cancer in Osaka.

Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery.

STUDY OBJECTIVE: To examine the relationship between the duration of the preoperative smoke-free period and the development of postoperative pulmonary complications (PPCs) in patients who underwent pulmonary surgery, and the optimal timing of quitting smoking. DESIGN: Retrospective cohort study. SETTING: Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. PATIENTS: Two hundred eighty-eight consecutive patients who underwent pulmonary surgery between January 1997 and December 1998. MEASUREMENTS AND RESULTS: We collected information on the preoperative characteristics, intraoperative conditions, and occurrence of PPCs by reviewing the medical records. Study subjects were classified into four groups based on their smoking status. A current smoker was defined as one who smoked within 2 weeks prior to the operation. Recent smokers and ex-smokers were defined as those whose duration of abstinence from smoking was 2 to 4 weeks and > 4 weeks prior to the operation, respectively. A never-smoker was defined as one who had never smoked. The incidence of PPCs among the current smokers and recent smokers was 43.6% and 53.8%, respectively, and each was higher than that in the never-smokers (23.9%; p < 0.05). The moving average of the incidence of PPCs gradually decreased in patients whose smoke-free period was 5 to 8 weeks or longer. After controlling for sex, age, results of pulmonary function tests, and duration of surgery, the odds ratios for PPCs developing in current smokers, recent smokers, and ex-smokers in comparison with never-smokers were 2.09 (95% confidence interval [CI], 0.83 to 5.25), 2.44 (95% CI, 0.67 to 8.89), and 1.03 (95% CI, 0.47 to 2.26), respectively. CONCLUSIONS: These findings indicate that preoperative smoking abstinence of at least 4 weeks is necessary for patients who undergo pulmonary surgery, to reduce the incidence of PPCs.

[Time-trends in cancer incidence and mortality in Japan].

The cancer incidence and mortality in Japan are described herein. The total number of deaths from all malignant neoplasms in 1998 was 284,000, corresponding to 30.3% of the total number of deaths among Japanese. Lung was the leading site of cancer deaths (17.9%), followed by the stomach (17.9%), large bowel (12.1%), liver (11.8%), pancreas (6.2%), gallbladder and extrahepatic biliary tract (5.2%), lymphatic tissue (3.7%), esophagus (3.4%), breast (3.1%), prostate (2.4%), leukemia (2.3%) and uterus (1.8%). The stomach was the leading site of cancer deaths until 1997, but was replaced by the lungs in 1998. The age-standardized mortality rates (1975-1998) have increased gradually for males, but decreased slightly for females. The rates have decreased remarkably for the stomach and uterus, while increasing for the lungs, large bowel, female breast, gallbladder and extrahepatic biliary tract, pancreas, and others. The total incidence for all cancers in Japan was estimated to be 454,000 in 1995. The stomach was the leading cancer site (22.2%), followed by the large bowel (17.7%), lung (11.6%), liver (7.8%), breast (6.6%), pancreas (3.7%), gallbladder and extrahepatic biliary tract (3.4%), lymphatic tissue (3.1%) and uterus (2.9%). The age-standardized incidence rates for all sites (1975-1995) have increased gradually for males, while remaining constant for females after a slight increase in the late 1970s. The incidence rates have decreased for the stomach and uterus, but increased for the large bowel, female breast, lung, liver, gallbladder and extrahepatic biliary tract, pancreas, prostate and others. The increase in the incidence rate was prominent for the large bowel, female breast and prostate.

[Epidemiology of primary liver cancer in Japan].

In Japan, more than 90% of primary liver cancers consist of hepatocellular carcinoma (HCC), 80% of which is caused by chronic hepatitis C virus (HCV) infection, and the remaining 15% of which is caused by chronic hepatitis B virus (HBV) infection. The proportion of older patients among patients with HCC has been increasing in recent years because of the aging of the HCV-prevalent birth cohort born between 1925 and 1935. The cumulative risk of developing HCC among HCV carriers was estimated as 30% for males and 6% for females. Older age, being male, having a low platelet count, higher histological stage, genotype 1b, co-infection with HBV, heavy drinking and smoking increase the risk of developing HCC among patients with chronic HCV infection. Recent reports on the efficacy of interferon therapy on the incidence of HCC in Japanese patients with chronic hepatitis C demonstrate the importance of providing a screening system for chronic HCV infection and establishing a medical referral system so that patients undergo the appropriate therapy for the Japanese HCV carriers.

Descriptive epidemiology of male breast cancer in Osaka, Japan.

Male breast cancer is rare. The total number of incidence in Osaka for the period of 1966-95 was 182. Male-to-female ratio for breast cancer incidence was 1:164 in Osaka during this period. Mean age of the male breast cancer incidence was 63.3. The numbers of incidence and the crude incidence rates for male breast cancer have increased during the last 3 decades, while the age-standardized rates have remained constant. The age-specific incidence rates for males showed a gradual increase with age, while those for females showed a steep increase beginning at twenty years of age and a peak around 45-49 or 50-54 years old. The age-standardized incidence rates of male breast cancer were lower in Japan than in European countries and North America, as were those of female breast cancer. Distributions of the histological type and the extent of disease were not significantly different between males and females. Relative 5-year survival for the male breast cancer was, however, lower than that for the female, especially in the "regional" stage and "distant" stage. Further studies on the sex-difference in survival will be mandatory based on high-quality hospital cancer registries' data, which provide detailed information on the clinical stage and treatment.

Second primary cancers following breast cancer in the Japanese female population.

To assess the risk of developing second primary cancers following breast cancer in Japanese females, we performed a retrospective cohort study of 2786 patients who were newly diagnosed with breast cancer at our hospital between 1970 - 1994, until the end of 1995 (average follow-up period, 8.6 years). The expected number of each second primary cancer was calculated by multiplying the number of appropriate person-years at risk by the corresponding age- and calendar period-specific cancer incidence rates for women obtained from the Osaka Cancer Registry. One hundred and seventeen patients developed a second primary cancer other than subsequent breast cancer, yielding an observed-to-expected ratio (O / E) of 1.3 [95% confidence interval (CI) = 1.1 - 1.6]. The risk for developing a second primary cancer was significantly elevated during the first year following the diagnosis of breast cancer, and decreased with the passage of time to unity. A significantly increased risk was noted for the development of ovarian cancer (O / E = 2.4, 95% CI = 1.0 - 4.6), thyroid cancer (O / E = 3.7, 95% CI = 1.5 - 7.6) and non-Hodgkin's lymphoma (NHL) (O / E = 3.5, 95% CI = 1.4 - 7.1) among the breast cancer patients compared with the general population. Patients who received hormonal therapy as the breast cancer treatment showed a significantly increased risk for ovarian cancer (O / E = 5.5, 95% CI = 1.8 - 12.9). Patients who received chemotherapy as the breast cancer treatment had an increased risk for NHL (O / E = 5.0, 95% CI = 1.6 - 11.6). These findings indicate that Japanese female patients with breast cancer had a 30% higher risk of developing a second primary cancer than the general population, the higher risk being manifested in the early period following the diagnosis of breast cancer. Medical surveillance of breast cancer patients for NHL, as well as for ovarian cancer and thyroid cancer, is required.

The risk for second primaries in gastric cancer patients: adjuvant therapy and habitual smoking and drinking.

STUDY PURPOSE: To examine whether adjuvant therapy for gastric cancer increases the risk for second primaries, and whether smoking and drinking increase the risk. SUBJECTS AND METHODS: 1,631 patients who were newly diagnosed with gastric cancer and underwent curative operation at Osaka Medical Center for Cancer and Cardiovascular Diseases during 1978-92. Incidence of second primaries were examined through linkage to Osaka Cancer Registry as of the end of December 1995. Observed number of second primaries (O) was compared with the expected according to the incidence in general population (E). Proportional hazards model was used to estimate hazard rate ratio (HR) for second primaries. RESULTS: 149 second primaries were observed. Seventeen cases, detected within 2 months after diagnosis of gastric cancer, were excluded. O/E ratio was 1.13 for adjuvant chemotherapy, 0.93 for immuno-chemotherapy, and 0.78 for immunotherapy, while 1.14 for operation only (not significant). Age-, sex-, and stage-adjusted HR was 1.02 (95% C.I. 0.69-1.50) for chemotherapy, 0.80 (0.41-1.57) for immuno-chemotherapy, and 0.60 (0.08-4.34) for immunotherapy, as compared with the risk for operation only. Among males, HR for current smokers vs. never smokers was 1.82 (1.02-3.26). CONCLUSIONS: Adjuvant therapy for gastric cancer did not significantly increase the risk for second primaries, while smoking elevated it.

Natural history of early gastric cancer: a non-concurrent, long term, follow up study.

BACKGROUND: Controversy has arisen on the natural history of early gastric cancer (EGC). While some emphasise the effectiveness of early detection in reducing mortality from gastric cancer, others insist that EGC is a pseudo-cancer. AIMS/PATIENTS/METHODS: To elucidate the natural history of EGC, a non-concurrent, long term, follow up study was conducted in 71 patients who were diagnosed endoscopically as having EGC, which was confirmed as cancer on biopsy, but in whom surgical resection was not conducted or delayed by more than six months. RESULTS: The natural course of EGC was observed in 56 cases. Over a period of 6-137 months, 20 remained in the early stage while 36 progressed to the advanced stage. The proportion remaining in the early stage consistently decreased with time. Median duration of those who remained in the early stage was estimated as 44 months. The cumulative five year risk for progressing to the advanced stage was 63.0%. In 38 cases there was no evidence for undergoing surgical resection for gastric cancer. The cumulative five year corrected survival was estimated as 62.8% among those unresected. Hazard rate ratio for gastric cancer mortality was 0.65 (p=0.34) for screening detected versus non-screening detected. Hazard rate ratio for gastric cancer mortality was 0.51, significantly lower for patients whose operations were delayed compared with those unresected. CONCLUSIONS: Although EGC showed a relatively long natural history in general, it progressed to the advanced stage with time and led to death from gastric cancer for the most part if left untreated.

Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C: a retrospective cohort study of 738 patients.

The effect of interferon on the long-term clinical outcome of patients with chronic hepatitis C remains unclear. This study included 594 patients with chronic hepatitis C who received interferon-alpha therapy (Interferon group) and 144 patients with chronic hepatitis C who did not receive interferon (Control group). The patients in the Interferon group were classified into the following three groups based on the response of the serum aminotransaminase level of the patient during and after completion of the therapy protocol: sustained responders (n = 175), transient responders (n = 165), and non-responders (n = 254). The age, sex, serum aminotransaminase level, platelet count, histological staging, hepatitis C virus (HCV) subtype, and HCV concentration at baseline were adjusted with the Cox proportional hazards model. The length of follow-up for assessment of the risk for developing hepatocellular carcinoma (HCC) was 57.2 +/- 13.9 months in the Interferon group and 67.7 +/- 28.7 months in the Control group. Multivariate analysis showed that interferon therapy decreased the risk for developing HCC by 48% compared with that in the Control group (P = 0.064). The older the age, being male, having a low platelet count, and higher histological stage were independent factors associated with the development of HCC. The hazard rate ratio for development of HCC in the sustained responders, transient responders, and non-responders was 0.16 (95% confidence interval [CI]: 0.04-0.62), 0.27 (95% CI: 0. 09-0.79), and 0.74 (95% CI: 0.37-1.48), respectively. During follow-up, 18 patients in the Interferon group died (10 from liver-related diseases) and 17 patients in the Control group died (10 from liver-related diseases). No sustained responder or transient responder in the Interferon group died of liver-related disease. The cumulative survival rates of the Interferon and Control groups were nearly identical during the first 5 years following diagnosis. Thereafter, the cumulative survival rate of the Control group declined, resulting in an 8-year survival rate in the Interferon and Control groups of 97% and 81%, respectively (P = 0. 061). Similar trends were seen in the survival analysis of those who had died of liver disease: the 8-year survival rates of the Interferon and Control groups were 98% and 88%, respectively (P = 0. 32). Our study demonstrated that interferon therapy significantly lowered the incidence of HCC among patients with chronic hepatitis C who showed sustained normalization and among patients who showed transient normalization of the serum aminotransferase level after completion of interferon therapy. The survival analyses and determination of cause of death suggested that interferon therapy improves the long-term survival of chronic hepatitis C patients who respond to this therapy, possibly by decreasing mortality from liver-related diseases.

Effectiveness of interferon therapy for reducing the incidence of hepatocellular carcinoma among patients with type C chronic hepatitis.

STUDY PURPOSE: To evaluate the effect of interferon treatment for reducing the incidence of hepatocellular carcinoma among patients with type C chronic hepatitis. METHODS: Retrospective cohort study was conducted on 923 patients with type C chronic hepatitis, who were identified through databases of Osaka Medical Center for Cancer and Cardiovascular Diseases. Two hundred and twenty-four of those had undergone interferon treatment, while the other 699 patients had not. Kaplan-Meier method and the proportional hazards model were used for statistical analysis. RESULTS: Five-years' cumulative incidence of hepatocellular carcinoma was 2.2% among the interferon treated patients, while 9.5% among the interferon untreated. Difference between the 2 curves of the cumulative incidence was statistically significant (p=0.0015). After adjustment for possible confounders, hazard rate ratio of hepatocellular carcinoma was 0.31 in the interferon treated group, significantly lower than that in the untreated (p=0.015). Hazard rate ratio for death from causes other than hepatocellular carcinoma and liver diseases was also lower among the interferon treated group than that among the untreated, although not significant. CONCLUSIONS: Interferon treatment is suggested to reduce the risk of hepatocellular carcinoma among patients with type C chronic hepatitis, and not to increase the risk for death from causes other than hepatocellular carcinoma and liver diseases.

Evaluation of tissue harmonic imaging for the diagnosis of focal liver lesions.

This was a prospective study to evaluate tissue harmonic imaging (THI) for the diagnosis of focal liver lesions. A total of 15 reviewers read 100 randomly arranged liver images, a fundamental grey-scale image (FGI) and a THI (transmitted: 2 MHz, received: 4 MHz) of each of 50 patients (29 with liver cirrhosis, 42 with focal lesions) taken from the same section. The mean value of overall accuracy for detecting lesions (presence or absence) was significantly higher with THI (82.3%) than with FGI (79.6%) (t = 1. 96, p< 0.05). When only the 29 cirrhosis patients were analyzed, the difference was more significant (t = 2.48, p < 0.02). The correct count rate of the number of focal lesions was higher with THI (78. 0%) than with FGI (67.0%) (t = 3.61, p< 0.005) in 23 cirrhosis patients with focal lesions. The correct diagnosis of HCC was achieved at a higher rate with THI (42.5%) than with FGI (36.8%). THI was statistically effective for detecting focal lesions, particularly in cirrhotic livers.

Seasonal variation in mortality from ischemic heart disease and cerebrovascular disease in Okinawa and Osaka: the possible role of air temperature.

Okinawa is located in a subtropical area and is well-known for low mortality due to ischemic heart disease (IH-D) and cerebrovascular disease (CVD). However, the factors that contribute to these low mortality rates remain unclear. We examined the seasonal variation in the mortality due to IHD and CVD among Okinawa and Osaka residents, aged 45 to 84 years, between 1992 and 1996. In addition, we studied if there was a relationship between the monthly mortality rate from IHD or CVD and the monthly mean daily air temperature in Naha City and Osaka City. Data on the monthly mean daily air temperature was obtained from the meteorological stations in Naha City and Osaka City. Our results showed that there were inverse correlations between the monthly mean daily temperature in a city and each of the monthly mortality from IHD in Okinawa (r=-0.794, p<0.01), the monthly mortality from CVD in Okinawa (r=-0.837, p<0.001), and the monthly mortality from CVD in Osaka (r=-0.954, p<0.001). In Osaka, the monthly mortality rate from IHD was at or near its minimum value when the mean daily temperature was approximately 25 degrees C (in September), and it increased in a linear fashion as the mean monthly temperature fell (r=-0.975, p<0.001). The difference between the monthly mortality from IHD or CVD among the Okinawa and the Osaka residents increased in the winter season in comparison with that in the other seasons, with the exception for IHD in July and in August. These findings indicate that the lower mortality from IHD and CVD in Okinawa is affected, at least in part, by Okinawa's warm winter.

[Descriptive and analytical epidemiology of second primaries in Osaka, Japan].

With the improvement in survival of cancer patients, the incidence of second primaries has been increasing. Data from the Osaka Cancer Registry showed that the incidence of metachronous second primaries was associated with gender (male), age and calendar year at diagnosis of the first cancer. The 10-year cumulative risk was estimated at around 10% for those who developed their first cancer in their sixties in 1978-83. The observed number (O) of second primaries (including synchronous) was compared with the expected number (E). The O/E ratios among those who developed their first cancer at ages 0-14 and 15-29 years old were much higher than the ratios among all age groups. Patients who had developed cancer of the colon, larynx, lung, bladder, or breast (1978-86) showed a significantly higher than expected risk of developing second primaries during the 1-4 years after diagnosis of the first cancer. Based on the hospital cancer registry data from Osaka Medical Center for Cancer and Cardiovascular Diseases, associations between adjuvant chemo-immunotherapy and the risk of second primaries were examined among 1,925 gastric cancer patients who underwent curative gastrectomy. The sex-, age-, and stage-adjusted hazard rate ratio of second primaries was 1.04 for patients who underwent chemotherapy and 0.70 for patients who underwent chemo-immunotherapy, when compared with the risk for patients who did not receive adjuvant chemo-immunotherapy. Some chemotherapeutic agents appeared to increase the risk of second primaries. Second primaries among 2,824 breast cancer patients were examined and their associations with adjuvant chemo-immuno-radiotherapy were analyzed. The O/E ratio for cancers of all sites was 1.28, significantly higher than 1.0. Cancer of the stomach, colon, lung and ovary were frequently observed as a second primary among them. Among 117 patients who developed second primaries, 4 developed cancer of the corpus uteri. This corresponded to 1.89 times the expected, however, only one of the 4 patients underwent tamoxifen treatment. The O/E ratio for non-Hodgkin's lymphoma was 3.40, significantly higher than 1.0. These results suggest associations between the risk for non-Hodgkin's lymphoma and chemotherapy.

Suicide risk among cancer patients: experience at one medical center in Japan, 1978-1994.

In order to identify the risks, methods and locations of suicide among Japanese cancer patients, we followed up 23,979 cancer patients aged 15 years and older, who were newly diagnosed at one medical center between 1978-94. Suicide risk was evaluated by comparing the observed number (O) with the expected number (E), which was calculated from the suicide mortality rate among Osaka residents. By the end of 1994, there were 48 suicide death among 109,374 person-years of follow-up. Suicide risk was significantly increased within the first five years following cancer diagnosis (male: O/E=1.62, 95% confidence interval (CI)=1.03-2.43, female: O/E=2.13, 95% CI=1.22-3.47), and decreased to unity after five years had elapsed following the cancer diagnosis. Patients in their fifties (O/E=1.93, 95% CI=1.48-4.37), diagnosed between 1978-85 (O/E=1.93, 95% CI=1.19-2.95), having remote metastasis at their initial diagnosis (O/E=4.66, 95% CI=2.12-8.84), the site being in the female genital organs (O/E=3.58, 95% CI=1.54-7.06) or in the male genital organs (O/E= 5.86, 95% CI=1.58-15.05), had a significantly higher suicide risk within five years following cancer diagnosis. The highest suicide mortality was observed between the third and fifth months after cancer diagnosis (O/E=4.35, 95% CI=1.87-8.58); most of these suicides (7/8) occurred soon after discharge from hospital. Among the 39 patients who committed suicide within five years after their diagnosis, the most common method among those who took their lives while in hospital was by jumping to their death (10/16), and that among those who committed suicide in other locations was by hanging (14/23). These findings indicate that Japanese patients with cancer run the highest risk of suicide soon after having been discharged from hospital. Clinicians should assess cancer patients' psychological distress and potential risk of suicide before approving discharge from hospital.